FormalPara Key Points

The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a new patient-reported outcome instrument that assesses the impact of insomnia on three aspects of daytime functioning (Alert/Cognition, Mood, and Sleepiness).

Blinded data from a phase III clinical trial were used to investigate how much IDSIQ scores would need to improve for patients to consider the change to be meaningful.

Decreases of 17 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, and 4 points for the Mood and Sleepiness domains would be meaningful improvement for patients with moderate to severe insomnia.

1 Introduction

Chronic insomnia greatly affects daytime functioning. It can cause fatigue, sleepiness, and cognitive impairments and is associated with comorbid mood disorders [1,2,3,4]. Such impacts are an important aspect of assessing the effects of insomnia treatments in clinical trials and are best captured by patients themselves using patient-reported outcome (PRO) instruments. However, until recently, research into the effects of insomnia treatments on daytime functioning was limited by a lack of validated PRO instruments developed according to industry guidelines [5, 6] and with items relevant to people with chronic insomnia. To address this problem, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) was recently developed as a new PRO instrument for evaluating daytime functioning in people with insomnia [7]. The IDSIQ comprises 14 items across three domains: Alert/Cognition (six items), Mood (four items), and Sleepiness (four items). Evidence from a rigorous psychometric evaluation supports the IDSIQ’s reliability and validity [7].

An important aspect of developing a PRO instrument to assess the effect of treatment on the patient experience of insomnia, and aiding the interpretation of that instrument, is determining meaningful within-patient change, which is the minimum score change from baseline that an individual patient would consider to be important [5, 6]. Meaningful within-patient change for the IDSIQ total score and the individual IDSIQ domains was previously estimated based on data on daytime symptoms from a single-arm, open-label trial of zolpidem in 114 adults with insomnia [7].

The objective of the analysis reported here was to estimate the minimum within-patient change for IDSIQ scores that an adult patient would consider meaningful, using data from a larger sample of subjects from a phase III clinical trial of daridorexant (ACT-541468) in adults with insomnia, which included patient assessments of night-time as well as daytime symptoms.

2 Methods

2.1 Study Design

The present analysis used data from a phase III, randomized, double-blind, placebo-controlled, parallel-group trial of the safety and efficacy of two dose levels of daridorexant (NCT03545191), a dual orexin receptor antagonist that was recently approved for treating insomnia [8, 9]. Full details of the trial are reported elsewhere [10]. Briefly, the trial was conducted between 2018 and 2020 in North America, Europe, and Australia. Subjects were randomly assigned 1:1:1 to receive daridorexant 25 mg, daridorexant 50 mg, or placebo daily for 3 months double-blind. The double-blind treatment period was preceded and followed by run-in and run-out periods of daily single-blind placebo treatment. The run-out period was followed by a 23-day safety follow-up period or continuation to a 9-month extension trial (NCT03679884). Ethical approval was obtained for all study sites.

2.2 Subjects

Adults aged ≥ 18 years with insomnia disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [11] and an Insomnia Severity Index (ISI) [12] score ≥ 15 at screening were enrolled. Each subject provided written informed consent. Subjects were excluded if they had an acute or unstable psychiatric condition (based on the Mini International Neuropsychiatric Interview [13]), a Mini Mental State Examination [14] score < 25 (subjects aged ≥ 50 years only), or periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, rapid eye movement sleep behavior disorder, or narcolepsy. Subjects with a history of sleep-related breathing disorders (including chronic obstructive pulmonary disease and sleep apnea) or self-reported suicidal ideation with intent/suicide attempts were also excluded.

2.3 Patient-Reported Outcome Assessments

Subjects completed the IDSIQ [7] daily in the evening throughout the study using an electronic diary. The IDSIQ comprises 14 items across three domains: Alert/Cognition (six items), Mood (four items), and Sleepiness (four items). Scores range from 0 to 60 for the Alert/Cognition domain, 0 to 40 for the Mood and Sleepiness domains, and 0 to 140 for the total score (see electronic supplementary material [ESM] Fig. 1 for the IDSIQ conceptual framework, and the online supplement of Hudgens et al. for a copy of the IDSIQ questionnaire) [7]. For each IDSIQ item, respondents were asked to indicate the average symptom severity or impact they experienced during the day on an 11-point numeric rating scale (NRS) ranging from 0 (not at all/none at all) to 10 (very/a lot), with a higher score indicating a greater severity or impact. The recall period was ‘today’ (during daytime hours on the day the IDSIQ was completed). Weekly average IDSIQ scores for baseline, month 1, and month 3 were based on the mean of daily entries in the 7 days prior to the visit. The IDSIQ was either completed in full or was marked as missing; programming of the eDiary in which subjects recorded IDSIQ scores did not permit partial completion. The prespecified scoring rule for calculating a weekly average IDSIQ score required subjects to have ≥ 2 days of data in each week; otherwise, the mean score was set to missing. Patients with < 2 days of diary data were omitted from the analysis. These criteria are based on a missing data simulation for the IDSIQ, conducted prior to this analysis, which showed that when the proportion of subjects with only two values for calculation of a weekly mean was varied from 0 to 100%, there was no effect on type I error probability and high power was maintained. Across all simulation scenarios, there was no bias in estimated mean treatment effect or variability, with minimal loss in precision as the number of subjects with two values increased. Weekly average scores for subjects with 2 or more days of data implicitly used mean imputation, where missing data points were given the same value as the mean of the non-missing data points of that same week [10].

The ISI [12] is a 7-item instrument for evaluating the symptoms and functional and emotional impacts of insomnia over the previous month. Each item is scored on a scale from 0 to 4, with a higher score indicating a greater symptom severity or impact. An ISI total score of 15–21 points indicates moderate insomnia, and a score of 22–28 points indicates severe insomnia. A 6-point decrease (improvement) in the ISI total reflects substantial reductions in feeling worn out/fatigued and being unable to think clearly [15, 16]. Subjects completed the ISI at screening, baseline, month 1, and month 3.

Subjects completed additional single-item measures weekly during treatment: the Patient Global Assessment of Disease Severity (PGA-S), Patient Global Impression of Severity (PGI-S), and Patient Global Impression of Change (PGI-C). The PGA-S was used to assess the severity of daytime symptoms and impacts of insomnia over the previous 7 days on a 6-point scale from ‘none’ to ‘very severe’. Similarly, the PGI-S assessed the severity of night-time insomnia symptoms over the previous 7 nights on a 4-point scale from ‘none’ to ‘severe’. Finally, two PGI-C scales were used to capture the severity of night-time insomnia symptoms over the previous 7 nights and daytime symptoms and impacts of insomnia over the previous 7 days, as compared with the week before starting treatment, on a 7-point scale from ‘very much better’ to ‘very much worse’.

2.4 Psychometric Analysis

PRO data for the weeks corresponding to baseline, month 1, and month 3 were used in the statistical analyses, which were performed using SAS® version 9.4 or later (SAS Institute Inc., Cary, NC, USA). The analyses used the full analysis set (FAS), which included all randomized subjects. Descriptive statistics were calculated for subject demographics and PRO scores.

Meaningful within-patient change for IDSIQ scores was estimated in accordance with US FDA recommendations [5] using anchor-based [17] and distribution-based approaches. As noted by the FDA, distribution-based methods do not directly consider the patient voice and are insufficient for identifying meaningful change [6]. Determination of thresholds for change was guided by the anchor-based approaches. Distribution-based estimates were considered supplemental and provided additional information about variability in the IDSIQ scores. In the anchor-based approach, Spearman correlation coefficients were first calculated for changes in scores for the IDSIQ and for potential anchors: PGA-S, PGI-S, PGI-C (daytime and night-time symptoms), and ISI total score. PRO measures with correlation coefficients ≥ 0.30 [17] were included in a subsequent anchor-based analysis. Mean and median IDSIQ score changes from baseline to month 1 and month 3 with 95% confidence intervals (CIs) were calculated for subjects who met prespecified thresholds defining clinically relevant score changes for the anchors. These clinically relevant score changes were a 1- or 2-point decrease (improvement) from baseline for the PGA-S and PGI-S, ‘a little better’ or ‘moderately better’ compared with the week before starting treatment for the PGI-C; and a 6-point decrease (improvement) from baseline for ISI total score [15, 16].

In the distribution-based analysis, the standard error of measurement (SEM) and standard deviations (SDs) of 0.25, 0.33, and 0.50 of the weekly average scores were calculated at baseline (SD only), month 1, and month 3. SEM [18,19,20] and 0.50 SD [21] have been proposed as useful measures of clinically meaningful change.

To obtain final meaningful within-patient change estimates, values obtained from the anchor-based approach were compared or ‘triangulated’ [17, 22, 23]. In this process, a descriptive non-inferential evaluation of meaningful within-patient change estimates was conducted to identify a similar set of values where the various estimates converged. This set of values was then used to identify a single meaningful within-patient change value.

3 Results

3.1 Baseline Characteristics

The analysis included 930 subjects with moderate to severe insomnia at screening based on ISI scores. Subjects had a median age of 59 years (range 18–88 years), and most were female (67.1%) and White (90.2%). At baseline, most subjects had moderate to very severe daytime symptoms based on the PGA-S (76.2%) and moderate to severe night-time symptoms based on the PGI-S (69.3%) (ESM Table 1). The amount of missing data for the IDSIQ was low: over 90% of subjects had 5–7 days of data that contributed to weekly average IDSIQ scores at each time point (baseline, month 1, and month 3).

3.2 Anchor-Based Analysis

PGA-S, PGI-S, PGI-C (daytime and night-time symptoms compared with before treatment), and ISI total score were evaluated as potential anchors for estimating meaningful within-patient change. Spearman correlation coefficients for the correlations between score changes for these PRO measures and IDSIQ score changes ranged from 0.36 to 0.44 at month 1 and from 0.45 to 0.57 at month 3 (Table 1). The correlation coefficients were all above the prespecified threshold of 0.30. All the tested PRO measures were therefore used in the anchor-based estimation of meaningful within-patient change.

Table 1 Correlations of weekly average IDSIQ score changes and scores/score changes for potential anchors at month 1 and month 3
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Mean IDSIQ score changes from baseline to month 1 for subjects with a 1-point or 1-step improvement on the anchors were −10.5 to −13.8 points for the IDSIQ total score, −4.7 to −5.7 points for the Alert/Cognition domain, −2.8 to −3.9 points for the Mood domain, and −3.0 to −4.1 points for the Sleepiness domain (Table 2). Mean changes at month 1 in subjects with a 6-point decrease in ISI total score were −7.3 points for the IDSIQ total score, −2.9 points for the Alert/Cognition domain, −2.3 points for the Mood domain, and −2.1 points for the Sleepiness domain. For subjects with a 2-point or 2-step improvement on the anchors at month 1, the corresponding mean score changes were −19.3 to −27.6 points for the IDSIQ total score, −7.8 to −11.3 points for the Alert/Cognition domain, −5.9 to −8.7 points for the Mood domain, and −5.5 to −7.6 points for the Sleepiness domain. Estimates based on median changes in the IDSIQ total score and domain scores from baseline to month 1 were similar to those based on the means.

Table 2 Anchor-based analysis of IDSIQ weekly average score changes from baseline to month 1
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Mean changes from baseline to month 3 were slightly higher than changes at month 1. At month 3, mean IDSIQ score changes from baseline for subjects with a 1-point or 1-step improvement on the anchors were −15.0 to −18.8 points for the IDSIQ total score, −6.7 to −8.1 points for the Alert/Cognition domain, −3.7 to −5.1 points for the Mood domain, and −4.7 to −5.7 points for the Sleepiness domain (Table 3). Mean changes at month 3 in subjects with a 6-point decrease in ISI total score were −16.0 points for the IDSIQ total score, −6.9 points for the Alert/Cognition domain, −4.5 points for the Mood domain, and −4.6 points for the Sleepiness domain. The corresponding mean score changes for subjects with a 2-point or 2-step improvement on the anchors at month 3 were −26.4 to −37.5 points for the IDSIQ total score, −11.3 to −16.1 points for the Alert/Cognition domain, −7.1 to −10.5 points for the Mood domain, and −7.8 to −11.0 points for the Sleepiness domain. Median changes from baseline to month 3 were similar to estimates derived using mean values.

Table 3 Anchor-based analysis of IDSIQ weekly average score changes from baseline to month 3
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Change estimates derived using anchor-based methods were further illustrated and supported by cumulative distribution function curves (ESM Fig. 2).

3.3 Distribution-Based Analysis

Per FDA recommendations [5], distribution-based analyses were conducted to obtain supportive evidence for the anchor-based meaningful within-patient change estimates. At month 3, SEM for the IDSIQ total score was 18.49 points and 0.5 SD was 13.60 points (ESM Table 2). For the Alert/Cognition domain, the SEM was 7.90 points and 0.5 SD was 5.71 points, while the SEM was 5.63 points and 0.5 SD was 4.47 points for the Mood domain. Finally, for the Sleepiness domain, the SEM was 5.55 points and 0.5 SD was 3.93 points. SEM and 0.5 SD estimates for month 1 were slightly lower than those obtained at month 3. However, at month 1 and month 3, the SEM and 0.5 SD values were all within the ranges derived from the corresponding anchor-based analyses.

3.4 Triangulation of Meaningful Within-Patient Change Estimates

Thresholds for meaningful within-patient change from baseline were determined using anchor-based estimates at month 1 and month 3. For subjects with a 1-point or 1-step improvement on the patient global anchors or a 6-point decrease in ISI total score, mean change estimates at month 1 and month 3 were supportive of a meaningful within-patient change threshold of approximately 15 points for the IDSIQ total score (Fig. 1), 7 points for the Alert/Cognition domain (Fig. 2), 4 points for the Mood domain (Fig. 3), and 4 points for the Sleepiness domain (Fig. 4). The corresponding estimates for subjects with a 2-point or 2-step improvement on the patient global anchors at month 1 and month 3 supported a threshold of approximately 19 points for the IDSIQ total score, 8 points for the Alert/Cognition domain, 6 points for the Mood domain, and 5 points for the Sleepiness domain. When the various estimates for mean and median changes at both timepoints were considered together, the results were supportive of meaningful within-patient change estimates starting at 17 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, and 4 points for the Mood and Sleepiness domains. Supplemental information from distribution-based estimates supported the primary findings using anchor-based methods (ESM Table 2).

Fig. 1
figure 1

Triangulation of IDSIQ total score change from anchor-based analyses. Data are the mean (95% confidence interval) for weekly average score changes from baseline to month 1 (red) and from baseline to month 3 (black). IDSIQ Insomnia Daytime Symptoms and Impacts Questionnaire, ISI Insomnia Severity Index, PGA-S Patient Global Assessment of Disease Severity, PGI-C Patient Global Impression of Change, PGI-S Patient Global Impression of Severity, SD standard deviation, SEM standard error of measurement

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Fig. 2
figure 2

Triangulation of IDSIQ Alert/Cognition domain score change from anchor-based analyses. Data are the mean (95% confidence interval) for weekly average score changes from baseline to month 1 (red) and from baseline to month 3 (black). IDSIQ Insomnia Daytime Symptoms and Impacts Questionnaire, ISI Insomnia Severity Index, PGA-S Patient Global Assessment of Disease Severity, PGI-C Patient Global Impression of Change, PGI-S Patient Global Impression of Severity, SD standard deviation, SEM standard error of measurement

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Fig. 3
figure 3

Triangulation of IDSIQ Mood domain score change from anchor-based analyses. Data are the mean (95% confidence interval) for weekly average score changes from baseline to month 1 (red) and from baseline to month 3 (black). IDSIQ Insomnia Daytime Symptoms and Impacts Questionnaire, ISI Insomnia Severity Index, PGA-S Patient Global Assessment of Disease Severity, PGI-C Patient Global Impression of Change, PGI-S Patient Global Impression of Severity, SD standard deviation, SEM standard error of measurement

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Fig. 4
figure 4

Triangulation of IDSIQ Sleepiness domain score change from anchor-based analyses. Data are the mean (95% confidence interval) for weekly average score changes from baseline to month 1 (red) and from baseline to month 3 (black). IDSIQ Insomnia Daytime Symptoms and Impacts Questionnaire, ISI Insomnia Severity Index, PGA-S Patient Global Assessment of Disease Severity, PGI-C Patient Global Impression of Change, PGI-S Patient Global Impression of Severity, SD standard deviation, SEM standard error of measurement

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4 Discussion

This study used phase III trial data to refine the meaningful within-patient change estimates for the IDSIQ total score and the IDSIQ domain scores. We performed a thorough analysis incorporating multiple anchors reflecting night-time symptoms of insomnia (PGI-S and PGI-C) and daytime symptoms and impacts (PGA-S and PGI-C), as well as ISI total score. The mean IDSIQ score changes from baseline to month 1 and month 3 for subjects with clinically relevant score changes on the anchors suggested meaningful within-patient change estimates starting at 17 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, and 4 points for the Mood and Sleepiness domains. These meaningful within-patient change estimates were supported by results from the distribution-based analysis.

At the time when development work on the IDSIQ was initiated, there was a lack of validated fully relevant PRO instruments for assessing the impact of insomnia on daytime functioning. Dedicated PRO instruments such as the Sleep Functional Impact Scale [24] and Sleep Impact on Activity Diary [25] are now available. However, few sleep and insomnia instruments have included the validation step of evaluating clinically meaningful within-subject change to aid in interpretation of score changes over time [15, 26, 27]. In the present evaluation of meaningful within-patient change for the IDSIQ, we adopted a robust approach using data from a large phase III randomized controlled trial. In line with FDA guidelines [5, 6], the analysis included anchor- and distribution-based analyses. The slightly higher estimates for meaningful within-patient change from baseline to month 3 compared with month 1 suggest that a longer follow-up period may provide a better indication of the temporal changes that occur in the daytime symptoms and impacts of insomnia. Moreover, the negative impacts that insomnia can have on daytime functioning may take longer to show improvements than total sleep time, and increases in the quantity and quality of sleep over a prolonged period may be needed to improve daytime functioning. It is also possible that the higher estimates for meaningful within-patient change at month 3 compared with month 1 could be a result of a changing perception of status. Subjects may initially perceive a change as being meaningful at an earlier time point, but then as a result of adjusting to an improved status, an even greater change is required to be perceived as meaningful at a later time point.

The present meaningful within-patient change estimates for change from baseline to month 1 and month 3 were relatively consistent with previous estimates of 20 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, and 4 points for the Mood and Sleepiness domains, which were derived from a smaller, single-arm, open-label trial of zolpidem [7]. Differences in sample size, duration of follow-up, and study design may have contributed to the minor variations in meaningful within-patient change estimates for IDSIQ total score derived from the phase III and open-label trials. Importantly, the phase III trial used for the present analysis had a much larger sample size than the open-label trial (930 vs. 114 subjects) and a longer treatment period (3 months vs. 14 days) that made it possible to evaluate longer-term outcomes. Moreover, unlike the open-label trial, which only included global anchors for daytime symptoms, the present analysis was supplemented by using additional anchors (PGI-S and PGI-C) that captured the night-time symptoms of insomnia that can also contribute to impaired daytime functioning.

In terms of limitations for this analysis, trial participants had moderate to severe insomnia, which may not be representative of most patients treated in clinical practice. The trial population was also predominantly White and therefore may not fully reflect the racial and ethnic diversity of people with insomnia. The study inclusion criteria also did not require a specific baseline level of daytime symptoms/impacts of insomnia, and as such may not represent the daytime experiences in the general insomnia population. Finally, the trial duration of 3 months may not accurately reflect patients’ experiences and changes in daytime symptoms and impacts of insomnia due to treatment. However, longer-term data have recently been published for an extension study following on from the initial studies included in this analysis, which reported IDSIQ results up to 1 year of treatment [28].

5 Conclusions

This analysis demonstrates the meaningful within-patient change for the IDSIQ total score and domain scores, and that these scores are sensitive to changes in the patient experience of insomnia. The stable estimates of meaningful within-patient change suggest that the IDSIQ is appropriate for evaluating changes in the daytime symptoms and impacts of insomnia in clinical trials and that it can be used to support efficacy findings based on objective and subjective assessments of sleep quantity.