Dosing Optimization of Low-Sodium Oxybate in Narcolepsy and Idiopathic Hypersomnia in Adults: Consensus Recommendations.

INTRODUCTION: Low-sodium oxybate (LXB) is approved for treatment of narcolepsy in patients aged 7 years and older and treatment of idiopathic hypersomnia in adults. LXB contains the same active moiety with 92% less sodium than sodium oxybate (SXB). As the indication for oxybate treatment in patients with idiopathic hypersomnia is new and allows for individualized dosing optimization, guidance for beginning LXB treatment is needed. In particular, clinicians may benefit from guidance regarding treatment initiation, dosing/regimen options, potential challenges, and treatment expectations. Additionally, pharmacokinetic profiles differ slightly between both treatments, and further guidance on transitioning from SXB to LXB in patients with narcolepsy may aid clinicians. METHODS: An expert panel of five sleep specialists was convened to obtain consensus on recommendations for these topics using a modified Delphi process. RESULTS: Across two virtual meetings, the panel agreed on 31 recommendations with a high degree of consensus that fell into four overarching topics: (1) introducing LXB to patients; (2) initiating LXB for adult narcolepsy and idiopathic hypersomnia; (3) addressing challenges in using LXB; and (4) transitioning from SXB to LXB. The panel recommended that clinicians provide a clear overview of how LXB works for treating symptoms in narcolepsy or idiopathic hypersomnia, as appropriate for their patients, explain safety aspects, and set expectations prior to initiating LXB treatment. Strategies for initial dosing and regimen are provided. Strategies for adjusting the dose, regimen, timing, and consideration of individual factors were developed for specific instances in which patients may have trouble staying asleep or waking up, as well as guidance for addressing potential adverse events, such as nausea, dizziness, anxiety, and depression. Discussion points based on existing literature and clinical experience were included as relevant for each statement. CONCLUSION: Clinicians may use this resource to guide LXB dosing optimization with patients.

Cataplexy response with extended-release once-nightly sodium oxybate: Post hoc responder analyses from the phase 3 REST-ON clinical trial.

Background: Once-nightly sodium oxybate (ON-SXB), an extended-release oxybate formulation, yielded significant (P < 0.001 at 6 g, 7.5 g, and 9 g) reductions in cataplexy episodes in participants in the phase 3 REST-ON clinical trial (NCT02720744). This post hoc analysis from REST-ON further characterized changes in cataplexy episodes in participants with narcolepsy type 1 (NT1). Methods: Participants with narcolepsy aged ≥16 years received ON-SXB (1 wk, 4.5 g; 2 wk, 6 g; 5 wk, 7.5 g; 5 wk, 9 g) or placebo. Percentages of participants with NT1 who had ≥25%, ≥50%, ≥75%, and 100% reductions from baseline in mean number of weekly cataplexy episodes were determined. Two-sided P values comparing ON-SXB vs placebo were calculated with Fisher exact test. Results: Participants with NT1 (ON-SXB, n = 73; placebo, n = 72; modified intent-to-treat population) had a baseline mean number of weekly cataplexy episodes of 18.9 (ON-SXB) and 19.8 (placebo). Of participants receiving the highest doses of ON-SXB (7.5 and 9 g), approximately half had a 50% reduction, one-third had a 75% reduction, and one-tenth had a 100% reduction in their cataplexy episodes vs placebo. Significantly greater proportions of participants receiving ON-SXB vs placebo had respective reductions in weekly cataplexy episodes of ≥25% at weeks 1 (4.5 g; P < 0.05), 3 (6 g; P < 0.001), 8 (7.5 g; P < 0.001), and 13 (9 g; P = 0.001). Conclusions: A significantly greater proportion of participants receiving ON-SXB vs placebo experienced reductions in weekly cataplexy episodes at all tested doses. Approximately 10% of participants taking the 2 highest ON-SXB doses had complete elimination of their cataplexy.

Brain fog in central disorders of hypersomnolence: a review.

Brain fog is an undefined term describing a cluster of symptoms related to fatigue and impaired memory, attention, and concentration. Brain fog or brain fog-like symptoms have been reported in central disorders of hypersomnolence and in a range of seemingly unrelated disorders, including coronavirus disease 2019, major depressive disorder, multiple sclerosis, lupus, and celiac disease. This narrative review summarizes current evidence and proposes a consensus definition for brain fog. Brain fog is prevalent in narcolepsy and idiopathic hypersomnia, with more than three-quarters of patients with either disorder reporting this symptom in a registry study; it has also been reported as particularly difficult to treat in idiopathic hypersomnia. Studies directly evaluating brain fog are rare; tools for evaluating this symptom cluster typically are patient reports, with few objective measures validated in any disorder. Evaluating brain fog is further complicated by confounding symptoms, such as excessive daytime sleepiness, which is a hallmark of hypersomnolence disorders. No treatments specifically address brain fog. The paucity of literature, assessment tools, and medications for brain fog highlights the need for research leading to better disambiguation and treatment. Until a clear consensus definition is established, we propose brain fog in hypersomnia disorders be defined as a cognitive dysfunction that may or may not be linked with excessive sleepiness, related to an underlying neuronal dysfunction, which reduces concentration and impairs information processing, leading to a complaint of lack of clarity of mental thinking and awareness. CITATION: Rosenberg R, Thorpy MJ, Doghramji K, Morse AM. Brain fog in central disorders of hypersomnolence: a review. J Clin Sleep Med. 2024;20(4):643-651.

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal CNS Drugs. Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ™) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep. WHAT WERE THE RESULTS?: Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting. WHAT DO THE RESULTS MEAN?: A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia.

STUDY OBJECTIVES: To evaluate 6-month efficacy and safety of low-sodium oxybate in people with idiopathic hypersomnia during an open-label extension period (OLE) of a phase 3 clinical trial. METHODS: Efficacy measures included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change (PGIc), Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Treatment-emergent adverse events were collected throughout the OLE. RESULTS: The OLE population included 106 participants. Most were female (71%) and White (83%), and the mean (SD) age was 41.0 (13.8) years. ESS scores decreased (improved) during the OLE (mean [SD], study baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7]), and IHSS total scores trended toward a decrease (study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]. Median (minimum, maximum) paired differences from OLE week 2 to OLE end were ESS, -1.0 (-20, 7; nominal P = .012); IHSS, -1.0 (-31, 19; nominal P = .086). The proportion of participants reporting PGIc ratings of "very much improved" increased from 36.7% at OLE week 2 to 53.8% at the OLE end. The FOSQ-10 and WPAI:SHP scores remained stable during OLE. The incidence of newly reported treatment-emergent adverse events decreased over the duration of the OLE. CONCLUSIONS: Efficacy and safety of low-sodium oxybate were maintained or improved during the 6-month OLE, supporting long-term treatment with low-sodium oxybate in adults with idiopathic hypersomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) With an Open-label Safety Extension; URL: https://clinicaltrials.gov/study/NCT03533114; Identifier: NCT03533114 and Registry: EU Clinical Trials; Name: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension; URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001311-79/results; Identifier: 2018-001311-79. CITATION: Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023;19(10):1811-1822.

Clinician Preferences for Oxybate Treatment for Narcolepsy: Survey and Discrete Choice Experiment.

INTRODUCTION: Immediate-release sodium oxybate (SXB) has been Food and Drug Administration (FDA)-approved to treat narcolepsy since 2002; in 2020, a mixed-salt oxybates formulation was also approved. Both are taken at bedtime with a second dose taken 2.5-4 h later. A third oxybate option, an investigational extended-release SXB, may soon be available. This study was undertaken to understand clinicians' preferences between these 3 different oxybate treatments. METHODS: Clinicians in active clinical practice for 3-35 years and experience treating patients with narcolepsy were recruited. A 30-min web-based survey quantified narcolepsy disease-state attitudes, treatment perceptions, and satisfaction with oxybates on 9-point scales. A discrete choice experiment (DCE) of 12 choice sets, with 2 hypothetical treatment profiles in each, was used to capture clinician preferences about overall oxybate therapy preference, impact on patient quality of life (QoL), and patient anxiety/stress. Attributes associated with current therapies and those expected to be available in the near future were included in the design. RESULTS: The clinicians surveyed (n = 100) indicated that narcolepsy has a negative impact on patient QoL (mean rating, 7.7) and rated impact on QoL and treatment efficacy as the most important aspects of a narcolepsy treatment (mean rating, 7.3-7.7). Clinicians with experience prescribing oxybates had moderately high satisfaction with SXB and mixed-salt oxybates efficacy (mean ratings, 6.5-6.9) and safety (mean ratings, 6.1-6.7) and lower satisfaction with nightly dosing frequency (mean rating, 5.9 and 6.3, respectively). In the DCE, dosing frequency was the most important attribute driving overall product choice, patient QoL, and reducing patient anxiety/stress (relative attribute importance, 46.1, 41.7, and 44.0, respectively), with once nightly preferred over twice nightly. CONCLUSION: Clinicians indicated a significantly higher preference for the once-at-bedtime dosing schedule versus twice nightly in selecting oxybate therapies overall and when aiming to improve patient QoL or reduce patient anxiety.

Current medications for narcolepsy include immediate-release sodium oxybate and mixed-salt oxybates. People taking these oxybates for narcolepsy take 1 dose at bedtime and must wake up 2.5­4 h later for the second dose. An investigational sodium oxybate, designed as a single bedtime dose, has been tentatively approved by the US Food and Drug Administration. This study used a 30-min web-based survey to learn what clinicians think about narcolepsy and narcolepsy medicines. A discrete choice experiment was used to identify which properties of current/future oxybate medicines are most important in a narcolepsy treatment. In this exercise, relevant properties of current/future oxybate medicines were mixed and matched to create hypothetical medicine profiles. Clinicians selected from these profiles which medication they preferred overall, which would improve patient quality of life, and which would reduce patient anxiety when thinking about taking the treatment. Clinicians were moderately satisfied with the effectiveness and safety of current narcolepsy medications. They strongly preferred oxybate treatments with fewer nightly doses and agreed that waking up for the second oxybate dose causes stress for patients. In the discrete choice experiment, the number of doses each night was the product characteristic that had the biggest impact on clinicians picking a medicine for narcolepsy. This was true for overall medicine choice, choosing a medicine that would improve patient quality of life, and choosing one that would reduce patient anxiety/stress. If granted marketing approval, extended-release sodium oxybate will be a once-at-bedtime option that may overcome challenges with current oxybate therapies.

Efficacy of once-nightly sodium oxybate (FT218) in narcolepsy type 1 and type 2: post hoc analysis from the Phase 3 REST-ON Trial.

STUDY OBJECTIVES: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). METHODS: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. RESULTS: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2. CONCLUSIONS: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy.

BACKGROUND: The safety and efficacy of low-sodium oxybate (LXB; Xywav®) were established in a randomized, double-blind, placebo-controlled, phase 3 withdrawal study in adults with narcolepsy with cataplexy; however, the longer-term safety profile has not yet been examined. The aim of the current analysis was to assess the time of onset and duration of common treatment-emergent adverse events (TEAEs) for LXB throughout the open-label optimized treatment and titration period (OLOTTP) and the stable dose period (SDP) portions of the main study, and the subsequent 24-week open-label extension (OLE). METHODS: In a double-blind, placebo-controlled, randomized withdrawal trial of LXB, TEAEs were evaluated during the 12-week OLOTTP, the 2-week SDP, and the subsequent 24-week OLE. Eligible participants were aged 18-70 years with a diagnosis of narcolepsy with cataplexy. At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic-treatment naive; other anticataplectics were tapered and discontinued during the OLOTTP. All participants initiated LXB during week 1 of the OLOTTP, and their dose was individually titrated based on safety and efficacy. Following the main study period, participants entered the OLE after rescreening (re-entry) after discontinuing LXB treatment or directly after completing the main study (rollover). TEAEs were assessed in the safety population as of database lock. TEAE duration was defined as time from TEAE start date to end date (or end of SDP or OLE, if end date was unrecorded). RESULTS: The safety population included 201 participants (SXB alone, n = 52; SXB with other anticataplectics, n = 23; other anticataplectics alone, n = 36; anticataplectic-treatment naive, n = 90). During the OLOTTP/SDP, headache was the most common LXB-emergent TEAE overall (71 events; n = 42 (21%); median (range) duration = 1 (1-147) day), followed by nausea (31 events; n = 26 (13%); median (range) duration = 9 (1-54) days) and dizziness (26 events; n = 21 (10%); median (range) duration = 7 (1-117) days). Among the 74 participants in the OLE, the most commonly reported TEAEs were headache (14 events; n = 7, 9%; peak incidence month 3 (n = 5/72); median (range) duration = 1 (1‒25) day), dizziness (8 events; n = 5, 7%; peak incidence month 1 (n = 3/74); median (range) duration = 26 (1‒181) days), and nasopharyngitis (6 events; n = 6, 8%; peak incidence month 6 (n = 2/69); median (range) duration = 9 (1‒24) days). Overall, study discontinuations attributed to TEAEs were 21/65 (32%) during the OLOTTP and SDP and 3/7 (43%) during the OLE. CONCLUSIONS: In this long-term analysis, the safety and tolerability profile of LXB was generally consistent with the known safety profile of SXB. During the OLOTTP and SDP, most TEAEs occurred early and were generally of short duration. TEAE prevalence decreased throughout the duration of the OLE; the most common TEAEs reported during the OLE were headache, dizziness, and nasopharyngitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03030599 (25 January 2017).

Low-sodium oxybate (LXB) is a medicine for narcolepsy. LXB treats daytime sleepiness and cataplexy (sudden muscle weakness). LXB is like sodium oxybate (SXB) but has 92% less sodium. This study looked at side effects in people taking LXB for many months. Three study periods were looked at in this report. In period 1, people could change their LXB dose for 12 weeks. This was to find their best dose. In period 2, people took that same best dose for 2 weeks. In period 3, some people kept taking LXB for 24 weeks. This was to study the longer-term effects. Everyone knew that they were taking LXB. During periods 1 and 2, the most common side effect was headache. Nausea and dizziness were also common. During period 3, headache was also the most common side effect. Dizziness and nasopharyngitis were also common. Nasopharyngitis is a cold in the nose and throat. In periods 1 and 2, most side effects happened early on. They also ended quickly. Fewer side effects happened in period 3. Among people leaving the study early, 32% left because of side effects during periods 1 and 2. During period 3, 43% left because of side effects. Overall, long-term side effects in people taking LXB were similar to those seen with SXB.

Efficacy and Safety of Lower-Sodium Oxybate in an Open-Label Titration Period of a Phase 3 Clinical Study in Adults with Idiopathic Hypersomnia.

Purpose: To report the efficacy and safety of lower-sodium oxybate (LXB; Xywav®) during the open-label titration and optimization period (OLT) and stable-dose period (SDP) in a clinical study for the treatment of idiopathic hypersomnia. Patients and Methods: Data were collected during treatment titration and optimization in a phase 3 randomized withdrawal trial in adults (18-75 years of age) with idiopathic hypersomnia who took LXB treatment (once, twice, or thrice nightly, administered orally) in the OLT (10-14 weeks), followed by the 2-week, open-label SDP. Endpoints included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change, Clinical Global Impression of Change, Functional Outcomes of Sleep Questionnaire (FOSQ)-10, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Results: The safety population included 154 participants; the modified intent-to-treat population comprised 115 participants. During open-label treatment, mean (SD) ESS scores improved (decreased) from 15.7 (3.8) at baseline to 6.1 (4.0) at end of SDP, and IHSS scores improved (decreased) from 31.6 (8.3) to 15.3 (8.5). Improvements were also observed during OLT in each individual IHSS item and in FOSQ-10 and WPAI:SHP scores. Thirty-five (22.7%) participants discontinued during OLT and SDP, 22 (14.3%) due to treatment-emergent adverse events (TEAEs) during OLT and SDP. The most frequent TEAEs in the first 4 weeks were nausea, headache, dizziness, and dry mouth; TEAE incidence decreased throughout OLT and SDP (weeks 1-4, n = 87 [56.5%]; weeks 13-16, n = 39 [31.7%]). Conclusion: During open-label treatment with LXB, participants showed clinically meaningful improvements in idiopathic hypersomnia symptoms and in quality of life and functional measures. TEAE incidence declined over LXB titration and optimization.

Clinical considerations for the diagnosis of idiopathic hypersomnia.

Idiopathic hypersomnia is a sleep disorder of neurologic origin characterized by excessive daytime sleepiness, with sleep inertia, long, unrefreshing naps, and prolonged nighttime sleep being key symptoms in many patients. Idiopathic hypersomnia is described in the International Classification of Sleep Disorders, 3rd Edition as a central disorder of hypersomnolence with distinct clinical features and diagnostic criteria; however, confirming the diagnosis of idiopathic hypersomnia is often challenging. Diagnosis of idiopathic hypersomnia is based on objective sleep testing and the presence of associated clinical features but may be difficult for clinicians to recognize and correctly diagnose because of its low prevalence, clinical heterogeneity, and symptoms, which are similar to those of other sleep disorders. The testing required for diagnosis of idiopathic hypersomnia also presents logistical barriers, and reliability of objective sleep measures is suboptimal. The pathophysiology of idiopathic hypersomnia remains unknown. In this review, clinical considerations related to the pathogenesis, diagnosis, and management of idiopathic hypersomnia will be discussed, including perspectives from the European Union and United States.

Randomized, crossover, open-label study of the relative bioavailability and safety of FT218, a once-nightly sodium oxybate formulation: Phase 1 study in healthy volunteers.

OBJECTIVES: Treatment for narcolepsy with sodium oxybate (SXB) has required twice-nightly dosing, at bedtime and 2.5-4 h later. This study evaluated the pharmacokinetics of FT218, an investigational, extended-release, once-nightly formulation of SXB (ON-SXB), vs twice-nightly SXB. METHODS: In this phase 1, open-label study, healthy volunteers were randomized (1:1) to ON-SXB 6 g or twice-nightly SXB (two 3-g doses administered 4 h apart); minimum 3-day washout before crossover. Doses were administered 2 h post-evening meal. Blood samples for pharmacokinetic assessments were collected predose and up to 14 h after the first dose during each treatment period. RESULTS: Twenty-eight participants were enrolled (mean age, 39.6 years; 54% women; 93% white). Mean ± SEM area under the concentration-time curve for ON-SXB was 282.7 ± 30.2  µg·h/mL vs 273.3 ± 27.8 µg·h/mL for twice-nightly SXB. Geometric mean ratio (GMR; 90% CI) was 102.9 (98.0-108.0). Maximum γ-hydroxybutyrate (GHB) plasma concentration (Cmax) was 65.8 ± 4.0 µg/mL for ON-SXB vs 77.1 ± 4.9 µg/mL for twice-nightly SXB (GMR [90% CI], 88.3 [80.5-97.0]). The GMR (90% CI) for GHB plasma concentrations 8 h post dose (C8h) for ON-SXB vs twice-nightly SXB was 61.7 (45.8-83.0). The most frequently reported adverse events were the same for ON-SXB and twice-nightly SXB (nausea, dizziness, somnolence, vomiting). CONCLUSIONS: GHB exposure and Cmax with one 6-g dose of ON-SXB were bioequivalent to those with two 3-g doses of twice-nightly SXB, whereas C8h was lower with ON-SXB. If approved, ON-SXB will provide a single bedtime oxybate option, with clinically relevant pharmacologic exposure during the entire sleep period.

Solriamfetol Titration & AdministRaTion (START) in Patients With Narcolepsy.

PURPOSE: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved (in the United States and European Union) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75-150 mg/d) or obstructive sleep apnea (OSA) (37.5-150 mg/d). This study characterized real-world titration strategies for patients with narcolepsy (with or without comorbid OSA) initiating solriamfetol therapy. METHODS: This virtual, descriptive study included a retrospective medical record review and qualitative survey. US-based physicians prescribing solriamfetol for EDS associated with narcolepsy or OSA participated. Data are reported for patients with narcolepsy with or without comorbid OSA (OSA alone reported separately). On the basis of medical record review, titration strategies were classified de novo (EDS medication naive), transition (switched or switching from existing EDS medication[s] to solriamfetol), or add-on (adding solriamfetol to current EDS medication[s]). The survey included open-ended questions regarding a hypothetical patient-a 32-year-old woman with narcolepsy (Epworth Sleepiness Scale score of 8) treated with 35 mg/d of amphetamine and 6 g per night of sodium oxybate who experiences non-use-limiting adverse events from amphetamine. FINDINGS: Twenty-six physicians participated: 23 provided data from 70 patients with narcolepsy (type 1, n = 24; type 2, n = 46; mean [SD] age, 40 [11] years; 57% female; 6 with comorbid OSA), and 26 responded to the hypothetical patient scenario. From the medical record review, solriamfetol therapy initiation was de novo for 19 of 70 patients (27%), transition for 31 of 70 patients (44%), and add-on for 20 of 70 patients (29%). Efficacy profile of solriamfetol was the primary reason for de novo (12 of 19 [63%]), transition (18 of 31 [58%]), and add-on (19 of 20 [95%]) initiation. Most (86%) initiated use of solriamfetol at 75 mg/d and were stable at 150 mg/d (76%). Most (67%) had 1 dose adjustment, reaching a stable dose over a median (range) of 14 (1-60) days. Physicians most often considered EDS severity (44%) when titrating. Among transitioning patients, 14 of 22 (64%) using wake-promoting agents discontinued their use abruptly, and 5 of 9 (56%) using stimulants were tapered off. At data collection, 90% continued to take solriamfetol. Regarding the hypothetical patient scenario, most physicians (81%) thought solriamfetol was appropriate, highlighting tolerability issues with current treatment and lack of symptom control as drivers for switching; however, 3 physicians (12%) did not think solriamfetol was appropriate, noting current symptoms were not severe enough and/or symptoms could be managed by increasing sodium oxybate dose; 2 (8%) thought it would depend on other factors. Physicians emphasized managing withdrawal symptoms while maintaining EDS symptom control when titrating off a stimulant and starting solriamfetol therapy. IMPLICATIONS: In a real-world study, physicians initiated solriamfetol therapy at 75 mg/d for most patients with narcolepsy, adjusted dosages once, tapered stimulants, and abruptly discontinued therapy with wake-promoting agents.

Solriamfetol Titration and AdministRaTion (START) in Patients with Obstructive Sleep Apnea: A Retrospective Chart Review and Hypothetical Patient Scenario.

INTRODUCTION: Solriamfetol (Sunosi™), a dopamine/norepinephrine reuptake inhibitor, is approved (USA and EU) to treat excessive daytime sleepiness (EDS) in adults with obstructive sleep apnea (OSA) (37.5-150 mg/day). Real-world research on solriamfetol initiation is limited. The objective of this study was to describe dosing and titration strategies used when initiating solriamfetol and to assess whether and how patient factors affected these strategies. METHODS: This descriptive study, featuring a quantitative retrospective patient chart review and hypothetical patient scenario, enrolled US-based physicians prescribing solriamfetol for EDS associated with OSA and/or narcolepsy. Initiation of solriamfetol was classified as: (1) de novo (EDS medication-naive); (2) transition (switched/switching from existing EDS medication[s] to solriamfetol), or (3) add-on (adding solriamfetol to current EDS medication[s]). Study fielding occurred 3-19 June 2020. Data were summarized descriptively. RESULTS: Twenty-six physicians participated in the study, of whom 24 provided data from 50 patients with OSA (mean ± standard deviation [SD] age, 51.9 ± 9.1 years; 62% male). Mean apnea-hypopnea index at diagnosis indicated that most patients had severe OSA and 92% were adherent to positive airway pressure therapy. EDS was primarily moderate (56%) or severe (36%). Solriamfetol initiation was de novo for 44% of patients, transition for 52%, and add-on for 4%. Efficacy (including the need for better efficacy) was the primary reason for the initiation of solriamfetol as de novo (82%), transition (58%), and add-on (100%) therapy. Starting doses were predominantly 37.5 mg/day (48%) or 75 mg/day (48%); stable doses were typically 75 mg/day (56%) or 150 mg/day (40%). Most patients (64%) adjusted dosages once, reaching stable doses over a median (range) of 14 (1-74) days. Physicians considered EDS severity (32% of patients) when titrating, but more commonly no specific patient factors caused them to alter their titration (44% of patients). Physicians abruptly discontinued wake-promoting agents (WPAs; 17/18, 94%) and stimulants (6/9, 67%) for transitioning patients. The hypothetical patient scenario showed that physicians discontinuing prior WPAs commonly considered the current dose (23%) and potential adverse events (15%). Most patients (96%) were stable on solriamfetol at data collection. CONCLUSIONS: In a real-world study, most physicians initiated solriamfetol at 37.5 or 75 mg/day and titrated to 75 or 150 mg/day for patients with EDS associated with OSA, adjusted dosages once, and abruptly discontinued prior WPAs. At data collection, most patients remained on solriamfetol.

Changes in Cataplexy Frequency in a Clinical Trial of Lower-Sodium Oxybate with Taper and Discontinuation of Other Anticataplectic Medications.

BACKGROUND: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy. OBJECTIVE: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications. METHODS: Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study. RESULTS: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics. CONCLUSIONS: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics. TRIAL REGISTRATION: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599.

People with narcolepsy are often sleepy during the day. They may also have sudden muscle weakness (known as cataplexy). Lower-sodium oxybate (LXB) is a narcolepsy medicine that is similar to sodium oxybate (SXB) but has 92% less sodium. A recent study found that treatment with LXB was better at reducing how often people with narcolepsy had sleepiness and cataplexy than no medicine at all (NCT03030599). This paper is about the first 12 weeks of that study, when all the people taking part in the study first tried LXB to check that they were being given the right amount. In people who only took LXB, cataplexy happened less often over time. Some people were already taking other medicines to treat their cataplexy (such as antidepressants), so they were asked to slowly stop those medicines while taking LXB. In those people, cataplexy happened more often at first as they stopped taking antidepressants and then less often later on. The increase in cataplexy when antidepressants were stopped was smaller in people who switched from SXB to LXB. This study shows that many people getting treatment for narcolepsy can switch to LXB without their cataplexy becoming worse.

Effect of FT218, a Once-Nightly Sodium Oxybate Formulation, on Disrupted Nighttime Sleep in Patients with Narcolepsy: Results from the Randomized Phase III REST-ON Trial.

BACKGROUND: Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release formulation require patients to awaken 2.5-4 h after their bedtime dose to take a second dose. A novel extended-release, once-nightly sodium oxybate formulation (ON-SXB; FT218) is under US Food and Drug Administration review for the treatment of adults with narcolepsy. OBJECTIVE: A phase III trial of ON-SXB in individuals with narcolepsy type 1 (NT1) or 2 (NT2) [the REST-ON trial; NCT02720744] has been conducted and the primary results reported elsewhere. Secondary objectives from REST-ON were to assess the efficacy of ON-SXB on disrupted nighttime sleep; the results of this analysis are reported here. METHODS: In the double-blind, phase III REST-ON trial, patients aged ≥ 16 years were randomly assigned 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Secondary endpoints included polysomnographic measures of sleep stage shifts and nocturnal arousals and patient-reported assessments of sleep quality and refreshing nature of sleep at 6, 7.5, and 9 g; post hoc analyses included changes in time spent in each sleep stage, delta power, and assessments in stimulant-use subgroups for prespecified endpoints. RESULTS: In total, 190 participants (n = 97, ON-SXB; n = 93, placebo) were included in the efficacy analyses. All three ON-SXB doses demonstrated a clinically meaningful, statistically significant decrease vs placebo in the number of transitions to wake/N1 from N1, N2, and rapid eye movement (REM) stages (all doses p < 0.001) and the number of nocturnal arousals (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g). Sleep quality and refreshing nature of sleep were significantly improved with all three ON-SXB doses vs placebo (p < 0.001). Post hoc analyses revealed a significant reduction in time spent in N1 (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g) and REM (all p < 0.001) and increased time spent in N3 with ON-SXB vs placebo (all p < 0.001), with a significant increase in delta power (p < 0.01 ON-SXB 6 g; p < 0.05 7.5 g; p < 0.001 9 g) and increased REM latency (ON-SXB 7.5 g vs placebo; p < 0.05). Significant improvements in disrupted nighttime sleep were observed regardless of concomitant stimulant use. CONCLUSIONS: The clinically beneficial, single nighttime dose of ON-SXB significantly improved disrupted nighttime sleep in patients with narcolepsy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02720744.

Calcium, Magnesium, Potassium, and Sodium Oxybates Oral Solution: A Lower-Sodium Alternative for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy.

Lower-sodium oxybate (LXB) is an oxybate medication approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy 7 years of age and older in the United States. LXB was developed as an alternative to sodium oxybate (SXB), because the incidence of cardiovascular comorbidities is higher in patients with narcolepsy and there is an elevated cardiovascular risk associated with high sodium consumption. LXB has a unique formulation of calcium, magnesium, potassium, and sodium ions, containing 92% less sodium than SXB. Whereas the active oxybate moiety is the same for LXB and SXB, their pharmacokinetic profiles are not bioequivalent; therefore, a phase 3 trial in participants with narcolepsy was conducted for LXB. This review summarizes the background on oxybate as a therapeutic agent and its potential mechanism of action on the gamma-aminobutyric acid type B (GABAB) receptor at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. The rationale leading to the development of LXB as a lower-sodium alternative to SXB and the key efficacy and safety data supporting its approval for both adult and pediatric patients with narcolepsy are also discussed. LXB was approved in August 2021 in the United States for the treatment of idiopathic hypersomnia in adults. Potential future developments in the field of oxybate medications may include novel formulations and expanded indications for other diseases.

Current Understanding of Narcolepsy 1 and its Comorbidities: What Clinicians Need to Know.

Narcolepsy is a chronic neurologic disorder associated with the dysregulation of the sleep-wake cycle that often leads to a decreased quality of life and results in a considerable health burden. There is often a delay to diagnosis of narcolepsy, mainly due to the lack of recognition of this disorder. One of the main factors hindering the diagnosis of narcolepsy is the association of comorbidities, which include other sleep disorders, psychiatric disorders, cardiovascular disorders, and metabolic disorders. The signs and symptoms of these comorbidities often overlap with those of narcolepsy, and some of the medications used for their treatment may obscure the symptoms of narcolepsy, leading to a delay in diagnosis. This review is targeted to clinicians unaccustomed to working with sleep disorders and aims to increase recognition and improve the management of narcolepsy.

Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study.

BACKGROUND: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia. METHODS: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete. FINDINGS: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study. INTERPRETATION: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. FUNDING: Jazz Pharmaceuticals.

Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy.

STUDY OBJECTIVES: This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment. METHODS: Participants (obstructive sleep apnea [OSA], n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups. RESULTS: Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity. CONCLUSIONS: Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606. CITATION: Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy. J Clin Sleep Med. 2022;18(1):235-244.