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.

Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture.

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent.

Recommendations for clinical management of excessive daytime sleepiness in obstructive sleep apnoea - A Delphi consensus study.

STUDY OBJECTIVE: Excessive daytime sleepiness is common with obstructive sleep apnoea and can persist despite efforts to optimise primary airway therapy. The literature lacks recommendations regarding differential diagnosis and management of excessive daytime sleepiness in obstructive sleep apnoea. This study sought to develop expert consensus statements to bridge the gap between existing literature/guidelines and clinical practice. METHODS: A panel of 10 international experts was convened to undertake a modified Delphi process. Statements were developed based on available evidence identified through a scoping literature review, and expert opinion. Consensus was achieved through 3 rounds of iterative, blinded survey voting and revision to statements until a predetermined level of agreement was met (≥80 % voting "strongly agree" or "agree with reservation"). RESULTS: Consensus was achieved for 32 final statements. The panel agreed excessive daytime sleepiness is a patient-reported symptom. The importance of subjective/objective evaluation of excessive daytime sleepiness in the initial evaluation and serial management of obstructive sleep apnoea was recognised. The differential diagnosis of residual excessive daytime sleepiness in obstructive sleep apnoea was discussed. Optimizing airway therapy (eg, troubleshooting issues affecting effectiveness) was addressed. The panel recognised occurrence of residual excessive daytime sleepiness in obstructive sleep apnoea despite optimal airway therapy and the need to evaluate patients for underlying causes. CONCLUSIONS: Excessive daytime sleepiness in patients with obstructive sleep apnoea is a public health issue requiring increased awareness, recognition, and attention. Implementation of these statements may improve patient care, long-term management, and clinical outcomes in patients with obstructive sleep apnoea.

Long-Term Treatment of Narcolepsy and Idiopathic Hypersomnia with Low-Sodium Oxybate.

Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient's life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.

Narcolepsy and idiopathic hypersomnia are disorders that make people feel very sleepy. Low-sodium oxybate (LXB) is a medicine for these disorders. Doctors think LXB works on parts of the brain that keep people awake. LXB may quiet those brain parts down at night by reducing their electrical activity, which helps people sleep better. LXB wears off by the morning, so people can wake up normally and feel more alert the next day. LXB has less sodium (which is part of salt) than a medicine called sodium oxybate. Sodium oxybate has been used for narcolepsy for more than 20 years. LXB has several benefits. First, LXB may be healthier than medicines that contain a lot of sodium, such as a high-sodium oxybate. This is because sodium can increase blood pressure and risk of heart disease. Second, LXB can be taken twice each night for narcolepsy, or once or twice each night for idiopathic hypersomnia. This depends on a person's lifestyle, how well the medicine is working, and side effects. Third, people taking LXB are more able to work and do other activities and have better quality of life. Finally, people taking LXB may lose weight. This can help overweight or obese people.

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.

Long-term efficacy and safety of tonic motor activation for treatment of medication-refractory restless legs syndrome: A 24-Week Open-Label Extension Study.

STUDY OBJECTIVES: To evaluate long-term efficacy and safety of tonic motor activation (TOMAC) for treatment of medication-refractory moderate-to-severe primary restless legs syndrome (RLS). METHODS: In the parent study (RESTFUL), adults with refractory RLS were randomized to active TOMAC or sham for 4 weeks followed by 4 weeks of open-label active TOMAC. In the extension study, earlier RESTFUL completers comprised the control group (n = 59), which was followed for 24 weeks with no TOMAC intervention, and later RESTFUL completers compromised the treatment group (n = 44), which received 24 additional weeks of open-label active TOMAC followed by no intervention for 8 weeks. The primary endpoint was Clinician Global Impressions-Improvement (CGI-I) responder rate at week 24 compared to RESTFUL entry. RESULTS: CGI-I responder rate improved from 63.6% (95% CI, 49.4 to 77.9%) at RESTFUL completion to 72.7% (95% CI, 58.2 to 83.7%) at week 24 for the treatment group versus 13.6% (95% CI, 7.0 to 24.5%) at week 24 for the control group (p < 0.0001). Mean change in International RLS Rating Scale (IRLS) score improved from -7.4 (95% CI, -5.6 to -9.2) at RESTFUL completion to -11.3 points (95% CI, -8.8 to -13.9) at week 24 for the treatment group versus -5.4 (95% CI, -3.7 to -7.2) at week 24 for control group (p = 0.0001). All efficacy endpoints partially reverted during cessation of treatment. There were no grade 2 or higher device-related adverse events. CONCLUSIONS: TOMAC remained safe and efficacious for >24 total weeks of treatment with partial reversion of benefits upon cessation. CLINICAL TRIAL: Extension Study Evaluating NTX100 Neuromodulation System for Medication-Refractory Primary RLS; clinicaltrials.gov/ct2/show/NCT05196828; Registered at ClinicalTrials.gov with the identifier number NCT05196828.

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial.

STUDY OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). METHODS: RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. RESULTS: A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = .00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = .00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. CONCLUSIONS: TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population. CLINICAL TRIAL: Noninvasive Peripheral Nerve Stimulation for Medication-Refractory Primary RLS (The RESTFUL Study); clinicaltrials.gov/ct2/show/NCT04874155; Registered at ClinicalTrials.gov with the identifier number NCT04874155.

Safety and pharmacodynamics of a single infusion of danavorexton in adults with obstructive sleep apnea experiencing excessive daytime sleepiness despite adequate use of CPAP.

BACKGROUND: Sleep disruptions experienced by patients with obstructive sleep apnea (OSA) can lead to excessive daytime sleepiness (EDS) and significantly impact patients' quality of life. EDS may persist despite use of continuous positive airway pressure (CPAP) therapy. Small molecules that target the orexin system, which has a known role in sleep-wake regulation, show therapeutic potential for the treatment of EDS in patients with hypersomnia. This randomized, placebo-controlled, phase 1b study aimed to investigate the safety of danavorexton, a small-molecule orexin-2 receptor agonist, and its effects on residual EDS in patients with OSA. METHODS: Adults with OSA aged 18-67 years with adequate CPAP use were randomized to one of six treatment sequences of single IV infusions of danavorexton 44 mg, danavorexton 112 mg, and placebo. Adverse events were monitored throughout the study. Pharmacodynamic assessments included maintenance of wakefulness test (MWT), Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance test (PVT). RESULTS AND CONCLUSION: Among 25 randomized patients, 16 (64.0%) had treatment-emergent adverse events (TEAEs) and 12 (48.0%) had TEAEs considered related to treatment, all mild or moderate. Seven patients (28.0%) had urinary TEAEs: three, seven, and none while taking danavorexton 44 mg, danavorexton 112 mg, and placebo, respectively. There were no deaths or TEAEs leading to discontinuation. Improvements in mean MWT, KSS, and PVT scores were observed with danavorexton 44 mg and 112 mg vs placebo. These findings show that danavorexton can improve subjective and objective measures of EDS in patients with OSA and residual EDS despite adequate CPAP use.

Safety and pharmacodynamics of a single infusion of danavorexton in adults with idiopathic hypersomnia.

STUDY OBJECTIVES: Idiopathic hypersomnia (IH) is a chronic disorder characterized by excessive daytime sleepiness unexplained by another disorder or drug/medication use. Although the orexin system plays a role in sleep-wake regulation, orexin A levels in the cerebrospinal fluid are normal in people with IH. This phase 1b, randomized, placebo-controlled, crossover study aimed to investigate the safety, pharmacokinetics, and pharmacodynamics of danavorexton, a small-molecule orexin-2 receptor agonist, in adults with IH. METHODS: Adults with IH aged 18-75 years were randomized to one of two treatment sequences of single intravenous infusions of danavorexton 112 mg and placebo. Pharmacodynamic endpoints included the maintenance of wakefulness test (MWT), the Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance task (PVT). Adverse events were monitored throughout the study period. RESULTS: Of 28 randomized participants, 12 (44.4%) had a treatment-emergent adverse event (TEAE) and 10 (37.0%) had a TEAE considered related to study drug, most of which were mild or moderate. Four participants (18.2%) had urinary TEAEs while receiving danavorexton, all of which were mild in severity. There were no deaths or TEAEs leading to discontinuation. Improvements in MWT, KSS, and PVT scores were observed with danavorexton compared to placebo. Following drug administration, a mean sleep latency of 40 min (maximum value) was observed during the MWT within 2 h of danavorexton infusion in most participants. CONCLUSIONS: A single infusion of danavorexton improves subjective and objective excessive daytime sleepiness in people with IH with no serious TEAEs, indicating orexin-2 receptor agonists are promising treatments for IH. Clinical Trial: Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04091438.

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.

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.

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.

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.

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.

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.

Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy.

STUDY OBJECTIVES: Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). METHODS: Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. RESULTS: Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). CONCLUSIONS: Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. CLINICAL TRIAL REGISTRATION: NCT03030599.

Effects of Solriamfetol on Quality-of-Life Measures from a 12-Week Phase 3 Randomized Controlled Trial.

Rationale: Excessive daytime sleepiness in patients with obstructive sleep apnea is associated with substantial burden of illness.Objectives: To assess treatment effects of solriamfetol, a dopamine/norepinephrine reuptake inhibitor, on daily functioning, health-related quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness as additional outcomes in a 12-week phase 3 trial (www.clinicaltrials.gov identifier NCT02348606).Methods: Participants (N = 476) were randomized to solriamfetol 37.5, 75, 150, or 300 mg or to placebo. Outcome measures included the 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. A mixed-effects model with repeated measures was used for comparisons with placebo.Results: Demographics, baseline disease characteristics, daily functioning, health-related quality of life, and work productivity were similar across groups. At Week 12, increased functioning and decreased impairment were observed with solriamfetol 150 and 300 mg (mean difference from placebo [95% confidence interval]) on the basis of Functional Outcomes of Sleep Questionnaire total score (1.22 [0.57 to 1.88] and 1.47 [0.80 to 2.13], respectively), overall work impairment (-11.67 [-19.66 to -3.69] and -11.75 [-19.93 to -3.57], respectively), activity impairment (-10.42 [-16.37 to -4.47] and -10.51 [-16.59 to -4.43], respectively), physical component summary (2.07 [0.42 to 3.72] and 1.91 [0.22 to 3.59], respectively), and mental component summary (150 mg only, 2.05 [0.14 to 3.96]). Common adverse events were headache, nausea, decreased appetite, and anxiety.Conclusions: Solriamfetol improved measures of functioning, quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness. Safety was consistent with previous studies.Clinical trial registered with www.clinicaltrials.gov (NCT02348606).