Quantitative assessment of meaningful within-patient change was performed using data from an open-label, 2-week trial of zolpidem conducted in Germany and the US (NCT03056053) [8] and a phase III, randomized, double-blind trial of daridorexant conducted in 10 countries (Australia, Canada, Denmark, Germany, Italy, Poland, Serbia, Spain, Switzerland, and the US), in which subjects were randomized 1:1:1 to receive one of two daridorexant doses (25 or 50 mg) or placebo daily for 3 months (NCT03545191) [9]. These trials are summarized in Table 1. In both trials, ethical approval was obtained for each study site, and all subjects provided written informed consent.

Participants in both the open-label and phase III trials were adults aged ≥ 18 years with insomnia disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and an Insomnia Severity Index (ISI) score ≥ 15 at screening. Potential participants were excluded if they had a psychiatric disease that might interfere with study participation or confound the results, periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, rapid eye movement sleep behavior disorder, narcolepsy, or history of a sleep-related breathing disorder.

The SDQ includes 10 questions and three VASs on the previous night’s sleep that are completed in the morning. It also includes two questions on daytime napping and two VASs that are completed in the evening (ESM Table 1). Subjects in the open-label and phase III trials completed the SDQ daily throughout screening and treatment. Question 9 of the CSD assessing sTST (“In total, how long did you sleep?”) is slightly modified in the SDQ as “In total, how long did you sleep last night?”. The accompanying instructions (“This should just be your best estimate, based on when you went to bed and woke up, how long it took you to fall asleep, and how long you were awake. You do not need to calculate this by adding and subtracting; just give your best estimate”) remain unchanged from the CSD (ESM Table 1). sTST was assessed every morning. The prespecified scoring rule for calculating weekly average sTST (in minutes/day) required subjects to have ≥2 days of sTST data during a given week.

sTST was also calculated using morning questionnaire responses that comprised components of sTST. Calculated sTST was defined as time of final awakening in the morning (question 8) minus time of beginning to try falling asleep (question 4) minus length of time taken to fall asleep (question 5) minus total duration of night-time awakenings (question 7). Calculated sTST was set to missing if the value derived for a given night was negative (nonsensical) or >16 h (implausible).

Subjects also completed other patient-reported outcome (PRO) assessments (Table 1). The ISI is a 7-item measure for evaluating the severity and functional and emotional impacts of insomnia disorder over the previous month [10]. Each item is scored on a scale from 0 to 4, and the scores for individual items are summed to give a total score of 0–28 points. An ISI total score of 15–21 points indicates moderate insomnia, and a score of 22–28 points indicates severe insomnia. Subjects completed the ISI at baseline and day 15 in the open-label trial and at baseline, month 1, and month 3 in the phase III trial.

The Patient Global Assessment of Disease Severity (PGA-S) is a single-item measure assessing the severity of daytime symptoms and impacts of insomnia disorder over the previous 7 days on a 6-point scale from ‘none’ to ‘very severe’. The Patient Global Impression of Severity (PGI-S) is another single-item measure that assesses the severity of night-time insomnia symptoms over the previous 7 nights on a 4-point scale from ‘none’ to ‘severe’. Two Patient Global Impression of Change scales (PGI-C) were used to assess changes in the severity of night-time insomnia symptoms over the previous 7 nights (phase III trial only) and of daytime sleepiness and impacts due to insomnia over the previous 7 days (open-label and phase III trials). For the PGI-C scale, changes in severity are scored on a 7-point scale from ‘very much better’ to ‘very much worse’, as compared with the week before starting treatment. In the open-label trial, the PGA-S was completed at baseline, day 8, and day 15, and the PGI-C was completed at day 8 and day 15; the PGI-S was not used. In the phase III trial, the PGA-S, PGI-S, and PGI-C were completed at baseline, month 1, and month 3.

The open-label trial included Clinician Global Impression of Severity (CGI-S) and Clinician Global Impression of Change (CGI-C) as additional single-item measures of insomnia disorder (Table 1). The CGI-S assesses the severity of a patient’s daytime symptoms and impacts of insomnia disorder over the previous 7 days on a 6-point scale from ‘none’ to ‘very severe’. The CGI-C assesses changes in the severity of a patient’s daytime symptoms and impacts due to insomnia over the previous 7 days on a 7-point scale from ‘very much better’ to ‘very much worse’, as compared with the week before starting treatment. The CGI-S was completed at baseline and day 15 and the CGI-C was completed at day 15.

Analyses were performed using SAS® version 9.4 or later (SAS Institute, Cary, NC, USA) on the full analysis set (FAS). In the open-label trial, the FAS comprised all subjects who received at least one dose of zolpidem; in the phase III trial, the FAS comprised all randomized subjects. Descriptive statistics were calculated for subject demographics and PRO scores. For sTST, baseline was a weekly average value, and day 8, day 15, month 1, and month 3 were weekly average values for the week preceding the given time point. For the other PROs and the clinician assessments, baseline, day 8, day 15, month 1, and month 3 were a single score/rating at the given time point.

Meaningful within-patient change estimates were derived using recommended anchor-based and distribution-based approaches [11, 12]. In the anchor-based analysis, Spearman correlation coefficients were first calculated for changes in weekly average sTST and the corresponding changes in scores for potential anchors. Anchors with moderate or stronger correlations of less than or equal to − 0.30 [11, 13] were considered acceptable for inclusion in the anchor-based analysis of meaningful within-patient change. For weekly average sTST, mean and median (95% confidence interval [CI]) changes from baseline to day 8 and day 15 in the open-label trial and from baseline to month 1 and month 3 in the phase III trial were calculated for subjects who met prespecified thresholds defining clinically relevant score changes for the anchors. These score changes were a 1- or 2-point decrease (improvement) from baseline for the PGA-S, PGI-S, and CGI-S; ‘a little better’ or ‘moderately better’ for the PGI-C (daytime and night-time symptoms) and CGI-C; and a 6-point decrease from baseline for ISI total score [14, 15].

Similar correlation analyses for sWASO and sLSO yielded only weak to moderate correlations with potential anchors. It was therefore decided not to pursue meaningful within-patient change estimates for sWASO and sLSO.

In distribution-based analyses, the standard error of measurement (SEM) was calculated for weekly average sTST at day 8 and day 15 (open-label trial) and month 1 and month 3 (phase III trial). The 0.25, 0.33, and 0.50 standard deviations (SDs) were calculated for weekly average sTST at baseline and at each post-baseline assessment.

The anchor- and distribution-based analyses were repeated in a subsample of 200 subjects who participated in a second randomized, double-blind, placebo-controlled trial of daridorexant (NCT03575104) [9]. The subsample comprised the first 120 subjects aged 18–64 years and the first 80 subjects aged ≥65 years who were randomized in the trial and who had baseline data for the PGA-S (daytime symptoms), PGI-S (night-time symptoms), and PGI-C (daytime and night-time symptoms).

The estimates obtained from the anchor- and distribution-based approaches were compared or ‘triangulated’ to obtain a final estimate of meaningful within-patient change [11, 16, 17]. This involved evaluating the different estimates in a descriptive, non-inferential way to identify a set of similar values where they converged. This set of values was then used to identify a narrow range of values representing a meaningful within-patient change.

In addition, cumulative distribution function (CDF) curves for sTST were plotted using data from subgroups of subjects categorized based on score changes on the PGA-S, PGI-S, and CGI-S, and ratings for the PGI-C (daytime and night-time symptoms) and CGI-C. In these CDF curves, the x-axis represents a continuous plot of subjects’ change from baseline in weekly average sTST, from the greatest worsening to the greatest improvement, and the y-axis shows the cumulative percentage of subjects who attained that level of change.

A concordance analysis was conducted using data from the phase III trial to evaluate agreement between sTST (directly reported in SDQ question 9) and calculated sTST (based on separate SDQ items; described in Sect. 2.3). The distributions of sTST and calculated sTST at baseline, month 1, and month 3 were summarized using descriptive statistics. Individual differences at baseline, month 1, and month 3 (calculated sTST minus sTST) were also evaluated using descriptive statistics, as well as histograms and Bland–Altman analysis plots.