Study setting

Research population: Drivers of a public transport company, who work in multiple irregular shifts, often switching irregularly between late and early shifts with short recovery times.

The public transport company supplies public bus and tram services throughout multiple Belgian regions, employing at least 5500 drivers at the time of writing. Of this workforce, at least one-third is obese and about the same proportion has high blood pressure. Based on reports of the drivers themselves, 4% suffer from mental-health issues, alone leading to 49 sick leave days per year per employee.

Study setting: Data will be collected in two urban, geographically different regions that are similar with regard to work and stress load (intensity of traffic, mean number of passengers, variable and backward-rotating schedules with intermittent, restricted resting times).

Eligibility criteria

Inclusion criteria:

Exclusion criteria:

Regular medication for high blood pressure and uncontrolled high blood pressure (defined as exceeding 140/90 mmHg) at screening, regular medication for diabetes, sleeping pills, or sedative medication for depression (defined as trazodone, mirtazapine, and amitriptyline). Because our secondary outcomes imply the evolution of blood pressure and blood sugar parameters, drivers with such pre-existing controlled or non-controlled comorbidity will not be eligible for participation.

High risk of moderate-to-severe obstructive sleep apnea syndrome (OSAS) as assessed with the STOP-Bang questionnaire, a simple, easy to remember, and self-reportable screening tool. We will use a cutoff score of 6 or higher to indicate the presence of OSAS [22].

Drivers combining their job as a professional driver with another job elsewhere.

Excessive sleepiness as defined as a score in excess of 12 on the Epworth Sleepiness Scale (ESS). Although the habitual cutoff is > 9, we opted for this higher threshold because we will be examining the effect of the intervention on daytime sleepiness. All applicants with an ESS > 12 will be excluded and referred to a general practitioner for further evaluation.

A BMI higher than 35 kg/m2. We chose this cutoff value based on the data provided by the external occupational health service, which showed that in 2018, 42.6% of their drivers had a mean BMI of 25–30 and 27.5% had a BMI between 30 and 40.

The presence of major depression as defined by a score exceeding the threshold of 1.75 on the Hopkins Symptom Checklist (HSCL-25), where higher scores were demonstrated to be highly indicative of depressive disorder according to the DSM-5 [23] and characterized as “a case requiring treatment.”

Quality assurance: The principal investigator (PI) and co-investigators are all certified medical specialists who will adhere to ICH-GCP guidelines to guarantee the quality of the research.

Statistics will be provided by qualified statisticians.

The PI is a neurologist and sleep expert who has a particular interest in and expert knowledge on circadian biology and shift-work management.

The co-investigators have extensive experience in the research of fatigue and/or sleep-wake disorders.

Who will take informed consent?

Eligible applicants will be screened by occupational health physicians (OHPs) of the participating service regions who will explain all aspects of the study and check the in- and exclusion criteria during a pre-inclusion evaluation. When they consider the candidate eligible for inclusion and upon his/her agreement, the driver will be provided with written information and the consent form, which (s)he is asked to sign and return within a week of the assessment.

Additional consent provisions for collection and use of participant data and biological specimens

Not applicable.

InterventionsExplanation for the choice of comparators

The study will include an intervention and a control group.

The intervention provided to the intervention group (see also the “Intervention description ” section) is based on an evidence-based good standard of care and includes:

Healthy scheduling (fast forward-rotating shift schedules adapted to chronotype, adequate resting times, napping, bright-light therapy)

Education program for drivers (psychoeducation promoting sleep hygiene, cognitive-behavioral strategies, stress-management techniques, information on chronotherapy such as bright-light therapy and napping)

The control group or “waiting-list group” will include drivers who will:

Intervention description

The duration of the intervention will be 6 months. This is a relatively liberal timeframe given that several intervention studies have shown that positive outcomes can be achieved between two weeks to 3 months, while educational programs as short as 1 to 3.5 h have been found to already exert a positive effect on sleep duration, alertness, and fatigue [24, 25]. However, given the complexity of factors involved in and affected by shift work, it is unlikely that in a real-life setting meaningful and consistent health benefits can be obtained by implementing a single or a limited number of interventions. As has been suggested by various experts in the field, this takes a holistic approach. We have explicitly chosen to test a multimodal intervention that addresses core issues, in line with Wong et al.’s [16] 2019 Working Time Society consensus statements on the need for a multi-level approach to managing occupational sleep-related fatigue. In their excellent review of workplace interventions to promote sleep and health also published in 2019, Redeker et al. stated that interventions using a single approach will not be effective and point to the pressing need to develop and implement policies to improve worker sleep health and the important public health problem associated with lack of recuperative sleep [17]. Several studies have addressed sleep training programs and their effectiveness on sleep parameters [24,25,26]. For a shift-work population, circadian challenges, limited time available for sleep, stress load, the effect of physical activity, and appropriate exposure to light on sleep-wake patterns, all need to be addressed. Psychoeducational programs should moreover include components based on cognitive-behavioral therapies for insomnia. The educational part of our intervention is in line with these expert recommendations. Ergonomic or healthy shift scheduling itself implies multiple measures: adapting the direction and cycle times of rotations to chronotypes, allowing for adequate resting times between shifts, and providing the possibility to take short naps in case of daytime/worktime sleepiness. The explicit choice for a multimodal intervention to be tested as a whole is thus in line with the assertion of other experts that workplace interventions using a single approach will not be effective.

Nevertheless, an embedded process evaluation of what did and did not work would be helpful in interpreting the final results. Therefore, we will also add a qualitative evaluation by means of a small questionnaire provided to the intervention group at the final assessment, in which they can provide their subjective evaluation of what measure provided the most benefit and why, and what part of the intervention did not work according to them and why.

Multimodal intervention: description of the three components

1.

Implementing healthy scheduling. This will imply:

(a)

The introduction of forward-rotating shift schedules [13, 27, 28] with

(b)

Schedules being adapted to chronotype [29,30,31],

(c)

Allowing for adequate resting times between shifts, in particular after a late/night shift [13, 32]

(d)

Allowing for adequate resting times (i.e., a minimum of 48 h) between series of shifts

(e)

Allowing for napping, in particular during the first two days of an early shift [33, 34]

The optimization of shift schedules has been found a promising method to reduce the overall negative health impact associated with shift work [27]. Healthy, or ergonomic, shift scheduling comprises multiple measures: the modification of shift rotations (forward and fast) adapted to the individual worker’s chronotype and providing suitable between-shift resting times as well as napping facilities in case of daytime sleepiness.

For the sake of clarity and to avoid interference from ongoing schedules, the intervention group will, as a whole, be separated from all fellow drivers.

A backward rotation schedule was prospectively related to an increased need for recovery as compared to a forward rotation schedule [13, 27]. Fast forward-rotating schedules have generally shown to be most beneficial [28].

Allowing for chronotype finds its relevance in the need to reduce circadian misalignment and social jetlag [29, 35]. It is evident that late(r) chronotypes will adapt more easily to afternoon and late shifts, while the inverse applies for early chronotypes [31]. For example, Juda et al. [29] concluded that when working morning shifts, later chronotypes experienced the highest sleep constraints resulting in more pronounced signs of social jetlag, shorter sleep durations, and reduced sleep quality.

Furthermore, van de Ven et al. [30] showed that workers whose chronotype did not align with the shift being worked had shorter sleep durations, lower quality of sleep, and longer recovery times. To add to the evidence, we will be comparing chronotype “pairs,” with drivers having nocturnal (evening and late-night) chronotypes working the opposite schedule from those of peers with diurnal (early and extremely early) chronotypes. A healthy schedule would then be a fast forward-rotating pattern with early chronotypes working more early shifts (3–4) than late chronotypes, with the inverse being applied for late(r) chronotypes.

Several studies have highlighted the relevance of the length of the recovery period in-between two successive shift series and the absence of quick returns [32]. We will hence adopt resting times of at least 48 h between the last shift of a series and the first of a new series of shifts.

Sleep deprivation and the resulting daytime sleepiness affect shift workers most at the start of early shifts. The rationale to offer drivers in our study early-morning bright-light chronotherapy (using Luminette®) prior to each early shift is twofold. We first expect the therapy to make drivers more alert and energetic and less sleepy during their working day. In a study by Bragard et al., the self-reported incidence of daytime slumbering had significantly decreased and the participants’ general health perception and physical functioning significantly improved after one month of Luminette® [36]. Secondly, we anticipate the therapy will counteract sleep deprivation by fostering the drivers’ biological sleep-wake cycle, potentially aiding them to go to sleep earlier in the evening following an early shift [37]. Light is known to be the most powerful synchronizer of endogenous circadian rhythms, where exposure to bright light in the early morning and avoidance of (bright) light in the evening should produce a phase advance. Drivers in the intervention group on early shifts will have the opportunity to use Luminette® and will be educated on the use of the device as well as on the impact of light on the sleep-wake cycle and on, among other topical issues, the importance of avoiding light in the evenings when working early shifts.

Taking a short nap (15–30 min) has been shown to be an efficient method to prevent daytime sleepiness and boost alertness after a bad, sleep-deprived night [33, 34, 38]. Hence, drivers will be given the opportunity to take one 15-min morning nap during day 1 and/or day 2 of their early shift.

The public transport company has an intelligent planning tool. It offers a modular solution for planning and analysis, scheduling, operations, and customer information, where each organization can select modules according to their own needs.

2.

Education program for drivers

Our newly developed program targeting shift-working drivers involves:

Psychoeducation on the sleep-wake cycle, biorhythms, and chronotypes and chronotherapy

Cognitive and behavioral strategies and information based on the principles of the cognitive-behavioral treatment of insomnia (CBT-i)

Information on the impact of light on wakefulness and sleep (including the use of bright-light therapy)

Information on napping and creating awareness of and how to recognize daytime sleepiness

Introducing tools for stress reduction

Information on the advantages of physical exercise on the quality of the sleep-wake cycle

Information on healthy eating in the context of shiftwork

If we want to promote the health of people working shifts and reduce fatigue or sleepiness, it is crucial to educate them about the importance and essence of healthy sleep-wake habits and to provide them with practical tools to help them handle the effects of changing shifts on their biorhythms in a more effective, conducive way. Studies evaluating education and sleep training programs for various shift-working populations and their effectiveness in improving sleep parameters and wakefulness [24,25,26] conclude that the various circadian challenges, ways to make the most of the limited time available for sleep, reduction of the work-related stress load, and the benefits of physical activity and sufficient exposure to light all need to be addressed.

CBT-i has been validated and is widely recommended as the most efficient and effective first-line treatment of insomnia and insomnia symptoms. The treatment comprises education on sleep-wake hygiene, stimulus control, and relaxation techniques, which components will all be included in our education program.

Furthermore, participants will be informed about and instructed in the practical use of bright-light therapy, nutrition, exercise, and napping. As to nutrition, since the results of dietary surveys show that the timing of meals is negatively affected by shift work [39] and a meta-analysis found that the prevalence of high-energy snacking is increased among shift workers [40], our program will address both proper meal timing and healthy nutrition.

The proposed education program has been developed by the PI and is founded on evidence-based principles described in the literature. Besides being a neurologist and sleep expert, she has also taken post-academic courses in education and coaching, has a university degree in CBT-i, and has ample experience in the delivery of training programs and CBT-i. However, to avoid bias, the PI will not be directly involved in the education of the drivers. Instead, she will be providing an extensive train-the-trainer program for certified trainers employed by the transport company who will be delivering the program.

The education program will consist of a one-day, 8-h session. The drivers randomized to the intervention group will complete the program within the first month after the conclusion of the randomization process (6 group sessions with a maximum of 15 participants per group). The drivers randomized to the control group will be informed that they have been placed on a waiting list and will be offered information on the program at a later date.

3.

Information campaign for planners and team coaches

The campaign will cover:

Epidemiological data and information on shift-work syndrome

Explanation of the rationale and characteristics of healthy scheduling

Information on chronotypes and available chronotype questionnaires to determine the drivers’ individual chronotypes and optimal chronotype-specific scheduling

Provision of written informed consent stating that the data collected will remain strictly confidential and will only be used to create personalized schedules.

Criteria for discontinuing or modifying allocated interventions

Allocated interventions will not be modified.

When asked for their informed consent, all participants will be informed orally and in writing about their right to discontinue their participation to the study at any time.

Safety considerations:

Applicants who are excluded according to the STOP-Bang Score criterion (scores ≥ 6), will be informed at intake about the risk of existing OSAS by the OHP and referred to a general practitioner to evaluate the necessity of referral to a sleep-wake clinic.

Applicants with an ESS score > 12 will be excluded from participation and referred to their general practitioner.

At any time, participants will have the opportunity to obtain more information on their questionnaire results.

In case his/her intermediate score on the Checklist Individual Strength (CIS-20), a validated self-administered questionnaire evaluating fatigue that participants will be completing at several timepoints during the study, shows a marked increase, the participant will be interviewed again and re-examined.

In case at intake depression (score of > 1.75 on the HSCL-25) is suspected, the driver will not be allowed to enter the study and referred to his/her general practitioner.

Strategies to improve adherence to interventions

Randomization will anticipate motivational bias, with candidate participants completing a short qualitative questionnaire to assess relevant motivational determinants.

Whether applicants eventually do or do not take part in the study will have no consequence whatsoever for any treatment they may need from the UZA or for their employment status.

Applicants and participants will be given a week to complete the various questionnaires.

The informed consent form will include a paragraph urging participants to follow all instructions as strictly as possible throughout the study period. To promote adherence to the daily sleep-wake diary, they will receive an email with a link to the sleep-wake diary every morning at 4 am to enable participants working an early shift to complete the diary before starting work. The public transport company will provide us with the drivers’ professional email addresses for this and other purposes.

By opting for a waiting list in the control condition we also aim to anticipate compensatory rivalry (where the control group could improve more than the intervention group). The control group will hence be informed that if the intervention proves effective, they will also be invited to complete the program in a second timeframe.

The intervention group will be separated from all other drivers for purposes of clarity and to avoid existing schedules from interfering with the experimental schedules.

If participants (still) have questions after completing the questionnaires, they will be given the opportunity to contact their occupational health physician by email and will be referred for appropriate professional help if indicated.

Minimizing contamination

Contamination will be very difficult, if not impossible, to avoid completely. Nevertheless, we reckon that contamination will remain restricted and at best provide better awareness of health habits in the control group. Since we, like other experts in the field, hold that workplace interventions aimed at optimizing shift schedules will not be effective using a single approach, our intervention will include healthy schedules and psychoeducation to address multiple factors such as individual variability, circadian challenges, time available for sleep, sleep hygiene, and stress load. The drivers in the control group will have no personal experience with or gain in-depth knowledge about any of these themes. For this reason, we do not expect that improvements in some health habits in the controls will lead to significant confounding changes. Moreover, the ergonomic schedules will be new to the company and specific for the drivers in the intervention group, which will be treated as a distinct group throughout the study period.

However, to control for contamination, we will add a question to each of the assessments to probe for any modifications in health habits during the study period. The investigators responsible for these assessments will be informed about the possibility of contamination as to raise their awareness on this issue.

Relevant concomitant care permitted or prohibited during the trial

The company has a stringent preventive and repressive policy on substance use (illicit drugs, alcohol, sedative medication) before and during working hours as part of the company’s legal obligation to prevent harm and protect the safety of its employees, passengers, and other road users.

None of the drivers randomized to the control group is allowed to join the educational program provided to the intervention group for the duration of the trial.

Provisions for post-trial care

Not applicable.

Outcomes Patient characteristics and baseline comparisons

Demographic and other baseline characteristics will be summarized per study group. For categorical variables, frequencies and percentages will be reported. Continuous variables will be summarized as means with standard deviations or medians with interquartile ranges as appropriate.

The following screening and baseline data will be collected:

Primary and key secondary endpoints: symptomatic burden (sleepiness, fatigue)

Change in sleepiness from baseline to 6 months: sleepiness as assessed with the Epworth Sleepiness Scale (ESS).

Change in fatigue from baseline to 6 months as assessed with the CIS (Checklist Individual Strength).

Outcome measurements regarding primary and key secondary endpoints (symptomatic burden)

Daytime sleepiness: evolution of ESS scores as assessed at baseline and monthly up to and including the final 6-month evaluation and the statistical relevance of improvement (first to last score).

Fatigue: evolution of CIS scores from baseline to 3 and 6 months and the statistical relevance of improvement (first to last score).

Analysis of the primary and key secondary endpoints (see also SPIRIT guidance 20a) Supplementary secondary endpoints: significant improvement on

General health-related quality of life (HR-QoL as assessed with the SF-36).

Absenteeism: sick leave in terms of the number of days off work due to illness will be derived from official records of and provided by the company.

Sleep outcomes: Total sleep time (TST) and sleep efficiency (SE) as derived from self-recorded sleep-wake patterns and scores on the Pittsburgh Sleep Quality Index (PSQI).

Clinical health outcomes: blood pressure, BMI, fasting blood glucose, glycosylated hemoglobin (HbA1c), high-sensitive C-reactive protein (hsCRP).

Mood and anxiety as gauged with the Hopkins Symptom Checklist (HSCL-25).

Outcome measurements regarding secondary endpoints

HR-Qol (SF-36): evolution of total SF-36 scores from baseline to 3 and 6 months and the statistical relevance of first-to-last score improvement

Absenteeism: formal data collected and provided by public transport companies

Sleep outcomes: scores on the PSQI at baseline, 3 and 6 months and the statistical relevance of the baseline to 6-month change. Evolution of mean total sleep time (TST) and sleep efficiency as derived from self-recorded/self-reported sleep-wake patterns

Clinical health outcomes: blood pressure, BMI, fasting blood glucose, hemoglobin A1c, hsCRP: evolution of each measure from baseline, to 3 and up to 6 months and the statistical relevance of the improvement (first-to-last change). Analysis of the most relevant improvement

Mood parameters as assessed with the HSCL-25 at baseline and at 6 months

Analysis of the secondary endpoints (see also SPIRIT guidance 20a)

To evaluate the sensitivity of the results of the primary and key secondary outcome analysis, linear regression will be used to model the change in fatigue and the change in sleepiness, both from baseline to 6 months, with group as a predictor and taking into account potential confounders (i.e., gender, age, years of shift work, diabetes, BMI and smoking status).

We will also conduct a per-protocol analysis in which only the data of the drivers who have fully adhered to the protocol will be compared.

To handle missing data, we will use a mixed model with multiple imputation by chained equations. The imputation procedure will include intervention, gender, age, years of shift work, diabetes, BMI and smoking status, and the available CIS and ESS measurements, respectively. This will generate 20 completed datasets that will be analyzed separately. The results will be pooled.

As fatigue and sleepiness will be assessed at three time points (baseline, 3 and 6 months), we will also test a linear mixed model with participant as a random effect to model the parameters’ evolution over time. This model allows for the correction of confounders and a between-group difference estimation at the different time points.

To compare the continuous 6-month outcomes (SF-36, PSQI, HSCL-25, absenteeism, clinical health outcomes) for the two groups, we will use an independent samples t-test or Mann-Whitney U test (whichever is appropriate). Additionally, to correct for confounders, we may fit a linear regression model.

A linear mixed model will be used to test the continuous outcomes (sleep times, CIS) over time.

The qualitative sleep-wake data will be collected and analyzed by a co-investigator at the Antwerp University Hospital.

Qualitative assessment of implementation and proximal effect of the intervention (change process) by short interview provided to both groups at the end of the study

Questions posed at the end of the study:

1.

To what extent are you satisfied with your well-being? (To be rated on a 7-point Likert scale ranging from extremely satisfied to extremely dissatisfied)

2.

If your experience was positive, can you explain why this is? Which part of the intervention seemed most useful to you and why?

3.

If your experience was negative, can you explain why this is? Which part of the intervention seemed most useless to you and why?

4.

Intervention group: Would you like to continue working your new schedule? Control group: Would you like to change to a new personalized schedule?

Exploratory analysis (see also SPIRIT guidance 20b)

Since we are interested to see whether the intervention effects will differ depending on chronotype, we will be looking for interactions between the intervention and the various chronotypes.

We will also be exploring associations between chronotype and the other variables tested (i.e., BMI, mental-health status (HSCL-25), fatigue, and sleepiness indices).

Participant timeline

See also “Schematic overview of study progress” (Supplementary material).

Besides keeping a daily online sleep-wake diary (with a link to the diary being provided daily by email), participants will be asked to participate in the following evaluations:

1.

Screening session to test in- and exclusion criteria and obtain informed consent

2.

Baseline—intake visit including all assessments/examinations and randomization

3.

Full assessment 3 months after start of the program

4.

Full assessment 6 months after the start of the program

Fatigue will be monitored on a more regular basis. Participants will be asked to fill out the CIS at baseline and once a month for the duration of the intervention (Table 1).

Table 1 Schematic study overviewSample size

For the primary and key secondary research question, we will be looking at two outcome measures, namely change in sleepiness (ESS) and in fatigue (CIS), both from baseline to the 6-month endpoint. We expect the outcomes for the intervention group to be superior to those obtained in the control group.

With regard to ESS, Patel et al. [41] mentioned 2 or 3 units as being indicative of a clinically minimally important difference in obstructive sleep apnea. Viitasalo et al. [13] found the largest SD for the ESS to be 5.3 units. Assuming a standard deviation of 5.3 and a significance level of 0.05, an achieved sample size of 72 per group is required to detect an effect of 2.5 with 80% power using a two-sample t-test. Taking into account at least 20% drop-out, 88 drivers will be recruited into each group. Hence, a total of 176 drivers will be recruited for the study.

As to the CIS, we will consider a drop of 10 units to reflect a clinically minimally important difference (CMID). This number is in part based on Vercoulen et al. [42, 43] who considered scores of 27 or higher to indicate abnormal fatigue and scores ≥ 35 severe fatigue, where a drop of 8 or more units signifies a change in severity classification. Additionally, we refer to Worm-Smeitink et al. [44] who, comparing CIS scores for breast cancer survivors and healthy controls in 2017, observed a 10-unit difference between the study population and the controls, with the former reporting higher levels of fatigue. We are thus confident that a difference of 10 units denotes a clinically relevant change.

For the standard deviation, we rely on Beurskens et al. [45] who reported an SD of 18.9 units for a blue-collar population. Assuming a standard deviation of 19 and a significance level of 0.05 an achieved sample size of 58 per group would be required to detect an effect of 10 with 80% power using a two-sample t-test. Taking into account at least 20% drop-out, 70 drivers should be recruited into each group.

Based on these findings, we will adopt a minimum of 70 for each group in our study. Taking into account a drop-out of 20%, we will be recruiting 88 drivers per group (i.e., 176 drivers overall) to achieve this. Hence, with a total recruitment of 176 drivers, the study is sufficiently powered for both primary and key secondary outcomes. A power of 80% was a compromise as we needed the recruitment to be feasible and still be able to achieve sufficient power.

Recruitment

In each of the two service regions of the company taking part in the study, recruitment will be via posters and information screens in the respective terminals and online via their intranet, inviting drivers working in the relevant regions to apply for participation in the study either by mail, email or telephone. All the drivers in the relevant service regions will also receive an individual invitation by email via their professional email account provided by the company for internal communications.

Assignment of interventions: allocationSequence generation

Stratified randomization will be used to allocate the drivers 1:1 to the intervention or control group. Stratification will be by service region (n = 2), age (younger or older than 40 years), gender and BMI (BMI ≤ 25; BMI 26–30; BMI 31–35). We will employ Qminim, a web-based randomization system that uses minimization to ensure a similar distribution of the stratifying factors between the study conditions.

Concealment mechanism

After the intake visit with the occupational health physician (OHP) of the relevant service region, all data of the drivers that have agreed to participate and have given their informed consent will be coded, and therefore, encrypted data will be sent to the PI for further evaluation.

The stratified randomization will be done by Qminim a web-based randomization system which uses minimization to ensure a similar distribution of the stratifying factors between the study conditions.

The administrator of the coded database will be one of the OHPs. The coded data will be stored and accessible for at least 20 years, with the encryption key remaining with the occupational health service. All investigators will only have access to the coded data.

Implementation

See also above: 16b

The OHPs will be responsible for the enrolment of the drivers and the coding of service regions (n = 2), age (≤ than 40 years vs. > 40 years), gender, and BMI (≤ 25; 26–30; 31–35). Since the participants randomized to the intervention group will be assigned to a rotation schedule adapted to their chronotype (three types), codes for the chronotypes will be created. The Qminim system will assure anonymized and random assignment of the participants to the two conditions.

Assignment of interventions: blindingWho will be blinded

The statistical analyst and the PI will be blinded to the participants’ identity and only have access to coded data.

Procedure for unblinding if needed

Not applicable.

Data collection and managementPlans for assessment and collection of outcomes

All (eligible) participants will be examined by an occupational health physician prior to the study (screening visit), at intake (baseline) and at two scheduled time points (3 and 6 months).

See also “Schematic overview of study progress” (Supplementary material, Timeline), which also des