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STUDY OBJECTIVES: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union for excessive daytime sleepiness in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnea (OSA; 37.5–150 mg/day). In 12-week studies, solriamfetol was associated with improvements in quality of life in participants with narcolepsy or OSA. These analyses evaluated the long-term effects of solriamfetol on quality of life. METHODS: Participants with narcolepsy or OSA who completed previous solriamfetol studies were eligible. A 2-week titration was followed by a maintenance phase ≤ 50 weeks (stable doses: 75, 150, or 300 mg/day). Quality of life assessments included Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-Item Short Form Health Survey version 2. Mean (standard deviation) changes from baseline to end of study were evaluated. Data were summarized descriptively. Adverse events were assessed. RESULTS: Safety population comprised 643 participants (417 OSA, 226 narcolepsy). Solriamfetol improved Functional Outcomes of Sleep Questionnaire short version Total scores (mean change [standard deviation], 3.7 [3.0]) and 36-Item Short Form Health Survey version 2 Physical and Mental Component Summary scores (3.1 [6.9] and 4.3 [8.4], respectively); improvements were sustained throughout treatment. On Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, solriamfetol reduced (improved) % presenteeism, % overall work impairment, and % activity impairment by a minimum of 25%. Common adverse events (≥ 5%): headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection. CONCLUSIONS: Long-term solriamfetol treatment was associated with clinically meaningful, sustained improvements in functional status, work productivity, and quality of life for up to 52 weeks. Adverse events were similar between narcolepsy and OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; Identifier: NCT02348632; URL: https://clinicaltrials.gov/ct2/show/NCT02348632 CITATION: Weaver TE, Pepin J-L, Schwab R, et al. Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med. 2021;17(10):1995–2007.

Introduction The Epworth Sleepiness Scale (ESS) measures excessive daytime sleepiness. This analysis examined test-retest reliability of ESS scores in participants with narcolepsy or obstructive sleep apnea (OSA) in solriamfetol studies. Methods Intraclass correlation coefficient (ICC) estimates and 95% confidence intervals (CIs) for ESS scores from two 12-week, placebo-controlled trials (1 narcolepsy; 1 OSA), and one long-term open-label extension (OLE) trial (narcolepsy or OSA) were calculated separately for each trial, based on assessments (at time-point pairs) when scores were expected to be stable (at weeks 4 and 8, 8 and 12, and 4 and 12 in the 12-week trials, and weeks 14 and 26/27, 26/27 and 39/40, and 14 and 39/40 in the OLE). ICCs were analyzed for the overall population in each trial and by treatment and adherence to primary OSA therapy. An ICC >0.7 has been recommended as a quality criterion for acceptable test-retest reliability. Results In the 12-week narcolepsy trial, ICCs (95% CI) were 0.83 (0.79, 0.87) for weeks 4 and 8 (n=199), 0.87 (0.83, 0.90) for weeks 8 and 12 (n=196), and 0.81 (0.76, 0.85) for weeks 4 and 12 (n=196). In the 12-week OSA trial, ICCs (95% CI) were 0.74 (0.69, 0.78) for weeks 4 and 8 (n=416), 0.80 (0.76, 0.83) for weeks 8 and 12 (n=405), and 0.74 (0.69, 0.78) for weeks 4 and 12 (n=405). In the OLE trial, ICCs (95% CI) were 0.82 (0.79, 0.85) for weeks 14 and 27/26 (n=495), 0.85 (0.82, 0.87) for weeks 27/26 and 40/39 (n=463), and 0.78 (0.74, 0.81) for weeks 14 and 40/39 (n=463). Treatment (solriamfetol combined/placebo) or adherence to primary OSA therapy did not impact reliability. Conclusion In 3 large clinical trials of participants with narcolepsy or OSA, the ESS demonstrated an acceptable level of test-retest reliability. Support Jazz Pharmaceuticals

Study Objectives To evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA). Methods Participants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study. Results In the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs. Conclusions This study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified. Trial Registration NCT02348632

Introduction Solriamfetol is a dopamine and norepinephrine reuptake inhibitor indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with obstructive sleep apnea (OSA; 37.5-150 mg/d) or narcolepsy (75-150 mg/d). Previous studies reported small mean increases in blood pressure (BP); however, the time course of these effects has not been evaluated. In addition, effects on BP dipping, which has been shown to be a risk factor for adverse cardiovascular outcomes have not been evaluated. These analyses evaluated the effects of solriamfetol treatment on BP using 24-hour ambulatory blood pressure monitoring (ABPM) and on the percentage of OSA patients with a non-dipping BP profile. Methods Twenty-four-hour ABPM was conducted at baseline and week 8 in a 12-week randomized controlled trial in participants with OSA (n=474). Results At week 8, increases in BP were apparent in the 75 and 300 mg dose groups from ~6 AM until 8 PM. At baseline, 58% (placebo) and 55% (combined solriamfetol) of participants were non-dippers (defined as Conclusion The effects of solriamfetol on BP at the highest approved dose of 150 mg/d are transient across the day. Solriamfetol was not observed to have an increase in non-dipping classification in participants with OSA at any dose studied. Support Jazz Pharmaceuticals

Introduction Solriamfetol is a dopamine and norepinephrine reuptake inhibitor indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy (75-150 mg/d) or obstructive sleep apnea (37.5-150 mg/d). Previous studies reported small mean increases in blood pressure (BP); however, the time course of these effects has not been evaluated. In addition, effects on BP dipping, which has been shown to be a risk factor for adverse cardiovascular outcomes, have not been evaluated. These analyses evaluated the effects of solriamfetol treatment on BP using 24-hour ambulatory blood pressure monitoring (ABPM) and on the percentage of narcolepsy patients with a non-dipping BP profile. Methods Twenty-four-hour ABPM was conducted at baseline and week 8 in a 12-week randomized controlled trial in participants with narcolepsy (n=236). Results At week 8, increases in BP were apparent in the 150 and 300 mg dose groups from 8 AM until 4 PM and 6 PM, respectively. At baseline, 52% (placebo) and 48% (combined solriamfetol) of participants were non-dippers (defined as Conclusion The effects of solriamfetol on BP at the highest approved dose of 150 mg/d are transient across the day. Solriamfetol was not observed to have an increase in non-dipping classification in participants with narcolepsy at any dose studied. Support Jazz Pharmaceuticals