Relationship between sleep efficacy endpoints and measures of functional status and health‐related quality of life in participants with narcolepsy or obstructive sleep apnea treated for excessive daytime sleepiness

Abstract This study examined the correlation between improvements in excessive daytime sleepiness in participants with obstructive sleep apnea or narcolepsy and changes in functional status, work productivity and health‐related quality of life. Data from two 12‐week randomized controlled trials of solriamfetol were analyzed. Participants completed the Epworth Sleepiness Scale, 10‐item Functional Outcomes of Sleep Questionnaire, Work Productivity and Activity Impairment questionnaire and 36‐Item Short Form Health Survey and performed the Maintenance of Wakefulness Test at baseline and weeks 4, 8 and 12. Patient Global Impression of Change was assessed at weeks 4, 8 and 12. Pearson correlations were calculated for change in scores from baseline to week 12. For both studies, changes in the 10‐item Functional Outcomes of Sleep Questionnaire were highly correlated (absolute value >0.5) with changes in Epworth Sleepiness Scale scores; changes in multiple domain scores of the 36‐Item Short Form Health Survey and Work Productivity and Activity Impairment questionnaire were moderately correlated (0.3–0.5) with changes in Epworth Sleepiness Scale scores in both studies and highly correlated for participants with narcolepsy. Changes in Maintenance of Wakefulness Test scores correlated moderately with changes in Epworth Sleepiness Scale scores in both studies. At week 12, Patient Global Impression of Change ratings correlated highly with Epworth Sleepiness Scale and 10‐item Functional Outcomes of Sleep Questionnaire scores for both disorders. Other correlations were low. Self‐reported assessments of sleepiness and global improvement appear to be more strongly correlated with measures of functioning and health‐related quality of life than objectively assessed sleepiness.


| INTRODUC TI ON
Individuals with obstructive sleep apnea (OSA) and narcolepsy often experience excessive daytime sleepiness (EDS) (Fernandez-Mendoza et al., 2015;Krahn et al., 2015), and as a result may experience fatigue, a decline in work performance, difficulty staying awake while driving, and impairment in focus and personal relationships (Al-Lawati, 2018;D'Ambrosio et al., 1999;Mulgrew et al., 2007;National Sleep Foundation, 2020;Ulfberg et al., 1996;Ward et al., 2013). EDS can also worsen functionality and social engagement in older adults (Gooneratne et al., 2003;Lee et al., 2013). The standard of care for OSA is primary airway therapy with continuous positive airway pressure (CPAP), although treatment may include oral appliances, hypoglossal nerve stimulation, behavioral treatment options (e.g., weight loss) and surgery (Epstein et al., 2009;Strollo et al., 2014). For many patients, primary airway therapy is not sufficient to resolve EDS; it has been estimated that 9%-22% of those treated with CPAP have persistent EDS (Gasa et al., 2013;Pepin et al., 2009;Weaver et al., 2007). Pharmacotherapy can be used as an adjunct to treatment with CPAP to address EDS (Avellar et al., 2016). There are a variety of pharmacological treatments for EDS in narcolepsy (Billiard et al., 2006;Keam & Walker, 2007;Ruoff et al., 2016), including stimulants, dopamine reuptake inhibitors and dopamine-norepinephrine reuptake inhibitors.
Measuring the efficacy of pharmacological and non-pharmacological treatments for EDS in patients with OSA and narcolepsy typically involves evaluating changes in measures of sleepiness or the ability to stay awake. However, there are limited data on how improvements in measures of sleepiness impact functioning, productivity and health-related quality of life (HRQoL), and how closely, if at all, these distinct concepts are correlated with one another.
These analyses sought to examine whether improvements in daytime sleepiness (as measured by the Epworth Sleepiness Scale [ESS] and the Maintenance of Wakefulness Test [MWT]) are associated with changes in functional status, work productivity and HRQoL as assessed by several patient-reported outcome measures. Analyses also explored the relationship between Patient Global Impression of Change (PGI-C) ratings and measures of EDS, functioning, work productivity and HRQoL.

| Study population and data sources
Two separate studies were conducted with patients with EDS; one included patients whose EDS was associated with OSA, whereas the other involved those with narcolepsy. Each study ensured that enrolled participants' EDS was due to that study's qualifying condition (i.e., for those in the narcolepsy trial, their EDS could not be due to OSA). Each study was a phase 3, multicenter, randomized, 12-week, double-blind study (Schweitzer et al., 2019;Thorpy et al., 2019) of solriamfetol, a dopamine and norepinephrine reuptake inhibitor approved in the United States and European Union to improve wakefulness in adults with EDS associated with OSA or narcolepsy (Sunosi, 2019(Sunosi, , 2020. Both were trials of adults (aged 18-75 years) diagnosed with narcolepsy (type 1 or type 2) or OSA with a baseline ESS score ≥10 and body mass index from 18 to <45 kg/m 2 . Eligible participants also were required to have baseline mean sleep latency <25 (narcolepsy) or <30 (OSA) min on the MWT and usual nightly total sleep time ≥6 h. Key exclusion criteria included usual bedtime later than 1:00 a.m., occupation requiring nighttime or variable shift work, or any other clinically relevant medical, behavioral or psychiatric disorder associated with EDS. For the OSA study, participants had been diagnosed according to International Classification of Sleep Disorders-3 criteria and reported current or prior use of a primary airway therapy, including a CPAP machine, oral appliance or surgical intervention (Schweitzer et al., 2019). Key exclusion criteria included usual bedtime later than 1:00 a.m., occupation requiring nighttime or variable shift work, or any other clinically relevant untreated medical, behavioral or psychiatric disorder (Schweitzer et al., 2019;Thorpy et al., 2019). Both studies were approved by institutional review boards or ethics committees at each site and performed in accordance with the Declaration of Helsinki; all participants provided written informed consent.
In both studies, participants completed several patient-reported outcome measures at baseline and again at weeks 4, 8 and 12, including the ESS and multiple measures of functioning and HRQoL.
The ESS is a self-administered questionnaire to measure the level of daytime sleepiness (Johns, 1991). The MWT assesses the ability to stay awake for a defined period of time while seated in a comfortable chair in a darkened room (Mitler et al., 1982). Participants also completed the PGI-C at each post-baseline assessment, which is a single-item rating that assesses the change in the participant's condition from the start of treatment using a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Because the PGI-C measures change, it was not completed at baseline but was completed at every post-baseline visit. The 10-item version of the Functional Outcomes of Sleep Questionnaire (FOSQ-10) is an abbreviated version of the FOSQ (Weaver et al., 1997) and assesses the impact of EDS on the ability to carry out activities of daily living (Chasens et al., 2009).
Like the FOSQ, the FOSQ-10 is scored to provide a Total score and five subscale scores: General Productivity, Activity Level, Vigilance, Social Outcomes and Intimacy. The Work Productivity and Activity Impairment (WPAI) questionnaire (Reilly et al., 1993) is a six-item questionnaire that produces four types of scores: the percentage of work time missed due to a problem (Absenteeism); the percentage of impairment experienced while working due to a problem (Presenteeism); the percentage of overall work impairment that is due to a problem (Work Impairment), which represents an aggregate of Absenteeism and Presenteeism; and the percentage of activity impairment that is due to a problem (Activity Impairment), which measures impairment in activities outside of work, during the past 7 days. The WPAI can be adapted to a specific health condition by replacing the word 'problem' throughout with the name of the condition; 'OSA' and 'narcolepsy' were used as the specific condition in each respective study.
Work-related questions (i.e., measures of absenteeism, presenteeism and work impairment) are evaluated in participants who are currently employed, whereas activity impairment is evaluated in all participants.
The 5-Level EuroQoL 5-Dimension (EQ-5D-5L) (EuroQol Research Foundation, 2019) is a five-item generic measure assessing health status regarding mobility, self-care, performance in usual activities, pain/discomfort and anxiety/depression. Responses to these items produce a single index value for health status (Utility Index value); there is also a single-item visual analog scale in which respondents are asked to rate their current health status on a scale from 'the best health you can imagine' to 'the worst health you can imagine'. The Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF-36v2) (Hays & Stewart, 1992;Ware & Sherbourne, 1992) is a 36item generic measure assessing vitality, physical functioning, bodily pain, general health, role physical, role emotional, social functioning and mental health. Two summary scores are also calculated (Physical Component Summary and Mental Component Summary scores).

| Statistical analysis
Data from the two studies (NCT02348593 and NCT02348606) were analyzed separately, both without regard to treatment assignment. The analyses were based upon the modified intent-to-treat population that includes data from participants who were randomly assigned, received at least one dose of study medication, and had a baseline and at least one post-baseline assessment.
Pearson correlation coefficients were calculated, pooling across all treatment groups, between the ESS, MWT and the FOSQ-10, EQ-5D, SF-36 and WPAI scores separately at baseline, the end of treatment, and as changes from baseline to the end of treatment.
Correlations were also calculated between these measures and PGI-C at the end of treatment. Some measures are scored so that a higher score represents better functioning or lesser severity (FOSQ-10, EQ-5D, SF-36v2, MWT, PGI-C), whereas other measures are scored so that a higher score represents worse functioning or greater severity (ESS, WPAI). As a result, some correlations are negative and others are positive. When interpreting their magnitude, correlations with absolute values of 0.10 to <0.30, 0.30 to 0.50, and >0.50 are reported as low, moderate and high correlations, respectively (Cohen, 1988). Correlation coefficients were not adjusted for multiple comparisons; therefore, p-values presented are nominal.

| Participant characteristics
The analyses included a total of 690 participants across the two studies ( Table 1). The OSA study involved 459 participants, 63% of whom were male, 76% white and 97% from North America, with a mean age of 54 years. Participants with OSA had a mean (standard deviation [SD]) ESS score of 15.2 (3.32) and a mean (SD) FOSQ-10 score of 13.9 (3.01). The narcolepsy study involved 231 participants, 65% of whom were female, 80% white and 81% from North America, with a mean age of 36 years. Participants with narcolepsy had a mean (SD) ESS score of 17.2 (3.18) and a mean (SD) FOSQ-10 score of 11.7 (3.03). At the baseline evaluation, 64% of participants with OSA and 61% of participants with narcolepsy were currently employed and provided responses to ≥ 1 of the WPAI work-related items (OSA: absenteeism, n = 293; presenteeism, n = 293; work impairment, n = 288; narcolepsy: absenteeism, n = 140; presenteeism, n = 136; work impairment, n = 131).

| Correlations between measures of sleepiness, functioning and HRQoL at baseline
At baseline, correlations were low between the MWT or ESS and other functional and HRQoL measures with the exception of the Mean (SD) FOSQ−10 score 13.9 (3.01) 11.7 (3.03) Note: ESS, Epworth Sleepiness Scale (possible scores range from 0 to 24, with higher scores reflecting more excessive daytime sleepiness); FOSQ-10, Functional Outcomes of Sleep Questionnaire-10 (possible scores range from 5 to 20, with higher scores representing better functioning); SD, standard deviation. a NCT02348606.

| Correlations between changes in measures of sleepiness and changes in measures of functioning/ HRQoL from baseline to week 12
For participants with OSA, change in ESS score was highly corre- WPAI-Presenteeism (-0.349; p<0.001) and WPAI-Work Impairment (-0.336; p < 0.001), for which they were moderate (see Table S1).
The ESS and MWT were moderately correlated at week 12 for both indications (p < 0.001). PGI-C ratings correlated highly with the ESS and FOSQ-10 for both indications (absolute value, 0.504-0.584; p < 0.001) and with SF-36 for participants with OSA (-0.581; p < 0.001). (-0.352; p < 0.001) and Physical Component Summary (-0.300; p < 0.001) scores in participants with OSA (Table S1). Utility Index scores and WPAI-Absenteeism. Improvements in ESS scores were also moderately to highly correlated with improvements in WPAI scores, except for absenteeism (possibly due to its low base rate). Notably, almost 40% of study participants were not currently employed at baseline (39% of the narcolepsy study population, 36%

| D ISCUSS I ON
of the OSA study population) and, therefore, were not included in the assessment of work-related impairment. As a result, the assessment of absenteeism evaluated in the current analysis reflects work time missed among participants who were currently employed and does not take into account impairment among individuals who were unable to work due to their illness.

Correlations in baseline scores between either the ESS or MWT
and all other measures were low, although previous studies have reported a moderate correlation between the ESS and FOSQ (Billings et al., 2014;Gooneratne et al., 2003). Despite these low correla- The burden of EDS within these patient populations is considerable. EDS occurs in 100% of patients with narcolepsy and affects significant numbers of patients with OSA, including those currently receiving CPAP treatment (Koutsourelakis et al., 2009). Persistent EDS in patients with OSA treated with CPAP is associated with poorer emotional health and energy (Pepin et al., 2009), as well as depression (Koutsourelakis et al., 2009). Patients with narcolepsy who experience EDS report difficulties at work (completing detail-oriented tasks, decreased productivity and making mistakes) and detriments to physical, emotional, cognitive and social health (Waldman et al., 2018a(Waldman et al., , 2018b were stronger than those between the objective measure of sleepiness (MWT) and these measures. Week 12 correlations with these measures were also stronger for the ESS and PGI-C than for the MWT. Taken together, these results suggest that self-reported assessments of sleepiness may be more strongly associated with functional and HRQoL outcomes than objectively assessed sleepiness.

ACK N OWLED G EM ENTS
The authors would like to thank Craig Solid of Solid Research Group, LLC, for medical writing support, which was supported by Jazz Pharmaceuticals. Editorial assistance with formatting, proofreading and copy editing was provided by Peloton Advantage, LLC, and was funded by Jazz Pharmaceuticals. and has received research support from Jazz Pharmaceuticals.

AUTH O R CO NTR I B UTI O N S
All authors collaborated in the preparation of the manuscript and critically reviewed and provided revisions to the paper. All authors had access to the data and assume responsibility for the completeness and accuracy of the data and data analyses. All authors gave final approval of the manuscript for submission.

DATA AVA I L A B I L I T Y S TAT E M E N T
All relevant data are provided within the manuscript and supporting files.