Akerman, Sarah

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) assessing the effectiveness of low-sodium oxybate (LXB; Xywav®) treatment on daytime and nighttime symptoms in participants with narcolepsy (type 1 [NT1] or 2 [NT2]) or idiopathic hypersomnia. Data presented are from the narcolepsy cohort. Methods DUET included a screening period (with 2-week washout for current oxybate users), 8-day baseline (BL) period, 2- to 8-week LXB titration period, 2-week stable-dose period, 8-day end-of treatment (EOT) period, and 2-week safety follow-up. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Key secondary endpoints for the narcolepsy cohort included change in polysomnography parameters: total shifts from deeper to lighter sleep stages, stage N3 sleep duration (minutes), and number of awakenings. Additional endpoints included Patient Global Impression of Change (PGIc)–overall narcolepsy disease. Primary and key secondary endpoints were controlled for multiplicity with sequential testing; other P-values are considered nominal. Results Fifty-five narcolepsy participants enrolled and were dosed with LXB (NT1, n=26; NT2, n=29); 13 transferred to another cohort and 34 were completers (NT1, n=16; NT2, n=18). Enrolled participants were mostly female (72.7%) and White (80.0%); mean (SD) age was 33.4 (12.9) years (NT1=34.6 [12.6]; NT2=32.4 [13.2]). For completers, least-squares mean (LSM) (SE) changes in ESS score were −7.7 (0.9), P<.0001, overall; NT1=−6.5 (1.4), P<.0001; NT2=−8.8 (1.3), P<.0001. Compared with BL, sleep architecture at EOT showed fewer deeper to lighter sleep stage shifts (LSM [SE]: −13.1 [2.9], P<.0001, overall; NT1=−13.9 [4.3], P=0.0029; NT2=−12.3 [4.1], P=0.0050); increased stage N3 sleep (minutes) (45.0 [8.8], P<.0001, overall; NT1=49.8 [13.0], P=0.0006; NT2=40.8 [12.3], P=0.0023); and fewer awakenings (−3.2 [0.9], P=0.0015, overall; NT1=−4.1 [1.4], P=0.0056; NT2=−2.3 [1.3], P=0.0771). Most participants (93.3%, n=30; NT1, 86.7%, n=15; NT2, 100%, n=15) reported improvement (very much, much, minimally) in overall narcolepsy disease on PGIc. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion Participants with NT1 and NT2 taking open-label LXB showed improvements in daytime sleepiness (decreased ESS scores) and reduced symptom burden (improved PGIc), which paralleled improvements in sleep architecture and disruption. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Introduction: Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on daytime and nighttime symptoms, including excessive daytime sleepiness (EDS) and polysomnography in participants with idiopathic hypersomnia (IH) or narcolepsy. Data presented are from the IH cohort. Methods DUET included screening (with 2-week washout for oxybate users), 8-day baseline (BL), 2- to 8-week LXB titration, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the IH cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score, Patient Global Impression of Change (PGIc)−overall IH disease, PGIc−sleep inertia, and Patient Global Impression of Severity (PGIs)−sleep inertia. Exploratory endpoints included IHSS component scores (daytime functioning, sleep inertia). Primary and key secondary (IHSS total score) endpoints were controlled for multiplicity with sequential testing; all other P-values are considered nominal. Results Forty-six people with IH enrolled and were dosed with LXB; 40 were completers. Enrolled participants were mostly female (80.4%) and White (84.8%), with a mean (SD) age of 38.1 (11.8) years. For completers, BL mean (SD) ESS score and IHSS total score were 16.5 (2.7) and 32.9 (7.1), respectively; least-squares mean (LSM) (SE) changes from BL to EOT were −8.4 (0.7), P<.0001 and −15.5 (1.5), P<.0001. BL mean (SD) IHSS component scores for daytime functioning and sleep inertia were 17.7 (4.2) and 10.7 (3.1), respectively; LSM (SE) changes from BL to EOT were −8.8 (1.0), P<.0001 and −4.8 (0.4), P<.0001. At EOT, most participants reported improvement (very much, much, minimally) on PGIc−overall IH disease (94.6%) and PGIc−sleep inertia (81.1%). At BL, 25.0% of participants reported sleep inertia severity as very mild/mild/not present on PGIs–sleep inertia vs 59.0% at EOT. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion People with IH taking open-label LXB showed improvements in EDS and sleep inertia (decreased ESS and IHSS component scores) and reported reduced multi-symptom burden (decreased IHSS total scores and improved PGIc/PGIs ratings). Support (if any) Jazz Pharmaceuticals

Abstract Introduction High sodium intake can increase blood pressure (BP) and future cardiovascular risk. Individuals with narcolepsy have an elevated cardiovascular comorbidity burden before considering medication-specific risks. Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration (FDA) to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy and idiopathic hypersomnia in adults. LXB has the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but contains 92% less sodium. The objective of XYLO is to measure ambulatory and in-clinic systolic BP (SBP) changes after switching to LXB from a high-sodium oxybate in participants with narcolepsy (NCT05869773). Methods This 6-week, open-label, multicenter, switch study is enrolling participants 18–70 years of age with narcolepsy (type 1 or 2) taking 6–9 g/night of high-sodium oxybate for ≥6 weeks. Hybrid enrollment supports both on-site and decentralized (monitored at the participant’s home by mobile health professionals) participation, and may broaden the pool of eligible participants. After ≥2 weeks on stable high-sodium oxybate dose/regimens (screening period), participants switch to the same dose/regimen of LXB for 6 weeks (intervention period). The primary endpoint is the change in 24-hour SBP from baseline (the most recent screening measurement prior to switching) to the end-of-treatment visit (approximately 6 weeks after switching) measured via 24-hour ambulatory BP monitoring (ABPM). Secondary endpoints evaluate change from baseline to end-of-treatment visit in-clinic SBP, as well as daytime average SBP and nighttime average SBP measured via 24-hour ABPM. Results Recruitment began in June 2023. This study uses a group sequential design with an adaptive sample size target of 57–77 participants completing the 6-week intervention period. This design provides 90% power to detect a mean difference of 3.5 mmHg (a clinically relevant change) in 24-hour SBP (assuming a standard deviation of the differences in 24-hour SBP of 8 mmHg). Conclusion XYLO will enable the assessment of 24-hour BP changes following transition from a high-sodium oxybate to LXB. Planned hybrid enrollment with a decentralized option may increase study access leading to a more diverse clinical trial population. Support (if any) Jazz Pharmaceuticals