Background and Objectives <p>Jazz DUET (<b>D</b>evelop hypersomnia <b>U</b>nderstanding by <b>E</b>valuating low-sodium oxybate <b>T</b>reatment) was a phase 4, prospective, multicenter, single-arm, open-label, multiple-cohort study of individuals with idiopathic hypersomnia or narcolepsy evaluating safety and effectiveness of low-sodium oxybate (LXB; Xywav^®) treatment on sleep and daytime symptoms. Results from the idiopathic hypersomnia cohort are reported here.</p> Methods <p>The DUET study included a screening period (with a 2-week washout for current oxybate users), an&#xa0;8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period, an 8-day end-of-treatment period (EOT) period, and a&#xa0;2-week safety follow-up. The primary endpoint was the change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the idiopathic hypersomnia cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score; Patient Global Impression of Change (PGI-C) and Severity (PGI-S) for overall idiopathic hypersomnia disease, sleep inertia, and fatigue; and changes in sleep quality and feeling rested upon awakening (from self-reported daily sleep diary). Exploratory outcomes included sleep patterns measured by actigraphy, the British Columbia Cognitive Complaints Inventory, Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem. Incidence and severity of treatment-emergent adverse events (TEAEs) were assessed.</p> Results <p>Forty-six participants with idiopathic hypersomnia enrolled and took LXB for ≥ 1 night after the BL period; <i>n</i> = 40 completed. Most enrolled participants were female (80.4%), White (84.8%), and non-Hispanic/Latino (76.1%), with mean (SD) age of 38.1 (11.8) years; 19 (41.3%) were taking concomitant alerting agents. Least squares mean (LSM; standard error [SE]) changes in ESS score and IHSS total score from BL to EOT were − 8.4 (0.7), <i>p</i> &lt; 0.0001, and − 15.5 (1.5), <i>p</i> &lt; 0.0001, respectively. On the PGI-C at EOT, most participants (94.6%; 95% CI 81.8, 99.3) reported improvement in overall idiopathic hypersomnia disease. Additionally, participants showed improvements (BL vs EOT) in sleep quality (36.7% vs 6.7% reporting “poor” or “very poor”) and level of feeling rested upon awakening (73.3% vs 26.7% reporting “slightly” or “not at all rested”), and number of awakenings on actigraphy (LSM [SE] change − 3.4 [0.6], <i>p</i> &lt; 0.0001). Participants also exhibited improved daytime functioning in parallel with reduced nocturnal sleep time. From BL to EOT, LS&#xa0;mean (SE) changes for work time missed, impairment while working, overall work impairment, and activity impairment were − 4.6% (1.8%), <i>p</i> = 0.0179;&#xa0;− 30.7% (3.9%), <i>p</i>&#xa0;&lt; 0.0001;&#xa0;− 32.4% (4.3%), <i>p</i> &lt; 0.0001;&#xa0;and − 37.3% (4.3%),&#xa0;<i>p</i> &lt; 0.0001, respectively. Treatment-emergent adverse events (occurring in ≥ 10% of participants) included nausea (19.6%), dizziness (17.4%), headache (17.4%), and vomiting (10.9%).</p> Conclusions <p>Individuals with idiopathic hypersomnia treated with open-label LXB showed improvements in subjective and objective measures of sleep and symptoms. Treatment-emergent adverse events were consistent with the known safety profile of LXB. This study supports the effectiveness of LXB in treating this condition with a 24-h burden of symptoms.</p> Clinical Trial Registration <p>ClinicalTrials.gov NCT05875974.</p> <p>[Graphical abstract available]</p> Graphical Abstract <p></p>