Sleep Management Institute

Abstract Introduction Sodium oxybate (SXB) is a central nervous system depressant used to treat narcolepsy and has the potential to cause respiratory depression. Registrational trials of SXB have generally excluded patients with respiratory depression, including those with an apnea hypopnea index (AHI) >15. This post hoc analysis of REST-ON evaluates the effect of once-nightly SXB (ON-SXB) compared to placebo on AHI in individuals with narcolepsy with either no sleep apnea or mild sleep apnea. Methods REST-ON (NCT02720744) was a phase 3, double-blind, placebo-controlled randomized clinical trial. Participants (age ≥16 years) with narcolepsy and AHI < 15 were randomized 1:1 to ON-SXB (week 1, 4.5 g; weeks 2–3, 6 g; weeks 4–8, 7.5 g; weeks 9–13, 9 g) or placebo. AHI was measured using polysomnography at baseline and weeks 3, 8, and 13, and analyzed post hoc. Adverse drug reactions (ADRs) were assessed at each visit. Results Respective mean (min, max) AHI values were similar for the ON-SXB (n=97) and placebo groups (n=93) at baseline (2.7 [0, 15] and 2.8 [0, 13]), week 3 (0.1 [0, 5] and 0.1 [0, 2]), and week 8 (0 [0, 0] and 0 [0, 0]). At week 13, mean (min, max) AHI values were 0 (0, 0) and 0.2 (0, 10) in the ON-SXB and placebo groups, respectively. Least squares mean (LSM) change from baseline in AHI with ON-SXB and placebo was –3.0 and –2.9, respectively, at week 3 (LSM difference [LSMD; 95% CI], –0.11 [–0.46 to 0.24]; P=0.522); –3.0 and –2.9, respectively, at week 8 (LSMD [95% CI], –0.11 [–0.46 to 0.23]; P=0.518); and –3.0 and –2.9, respectively, at week 13 (LSMD [95% CI], –0.12 [–0.46 to 0.23]; P=0.515). In the safety population, 1 (0.9%) and 1 (1.0%) participant in the ON SXB and placebo arms, respectively, experienced ADRs of sleep apnea, and 1 (0.9%) participant receiving ON-SXB reported snoring; all were mild or moderate in severity. Conclusion Treatment with ON-SXB was not associated with worsened AHI at any tested dose. ON-SXB was well-tolerated, as the reported respiratory-related ADRs were minimal, and mild or moderate in severity. Support (if any) Avadel Pharmaceuticals

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 significantly reduced weekly cataplexy attacks from baseline to Week 5 versus placebo in patients with narcolepsy. Here we report the Phase 3 ENCORE trial, assessing long-term efficacy and safety of AXS-12 in participants who completed SYMPHONY. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, remaining participants were randomized 1:1 to continue twice-daily AXS-12 or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. The primary endpoint was change in frequency of cataplexy attacks from randomization to DBRW Week 3. OLE efficacy outcomes included change in weekly frequency of cataplexy attacks, cataplexy response (≥50% reduction), and change in cataplexy-free days. Additional analyses are ongoing. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In SYMPHONY, baseline mean weekly frequency of cataplexy attacks was 31.5. At DBRW randomization, mean weekly frequency of cataplexy attacks was 4.2 (AXS-12) and 6.9 (placebo). Participants randomized to placebo experienced a mean increase of 10.29 weekly cataplexy attacks versus 1.32 for AXS-12, at end of DBRW (p=0.017). In the OLE, weekly frequency of cataplexy attacks decreased by 22.3 (71%) and 24.1 (77%) at 1 and 6 months, respectively. Cataplexy response was achieved by 72% and 82% at 1 and 6 months, respectively. Cataplexy-free days increased from 14.3% to 61% and 70% at 1 and 6 months, respectively. Common adverse events (AEs; ≥5%) during the OLE were nausea and tachycardia (both 5.9%); no new safety signals were detected. Discontinuations due to AEs occurred in 17.6% of participants in the OLE. Conclusion AXS-12 significantly reduced the frequency of cataplexy attacks during the DBRW. AXS-12 was well-tolerated and demonstrated maintenance of efficacy with long-term open-label use. These results align with SYMPHONY, supporting the positive therapeutic impact of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics, Inc.

Low-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates; Xywav) contains the same active moiety as high-sodium oxybates (SXBs; SXB [Xyrem] and fixed-dose SXB [Lumryz]), with 92% less sodium, and is approved in the United States for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and idiopathic hypersomnia in adults. Patients with narcolepsy have increased cardiovascular risk relative to people without narcolepsy. LXB's lower sodium content is recognized by the United States Food and Drug Administration in the narcolepsy population as clinically meaningful in reducing cardiovascular morbidity compared with SXBs. The Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study (NCT04794491) examined the transition experience of patients with narcolepsy switching from SXB to LXB. Eligible participants were aged 18-80 years with narcolepsy type 1 or 2 on a stable SXB dose/regimen. After 2 weeks, participants transitioned gram-per-gram to LXB for 6 weeks, with opportunity for subsequent titration. Assessments included the Epworth Sleepiness Scale, Patient Global Impression of change, Ease of Switching Medication Scale, and Forced Preference Questionnaire. The study enrolled 62 participants at baseline; 60 transitioned to LXB and 54 completed the study. At baseline and end of the LXB intervention/early discontinuation, respectively, mean total doses were 8.0 and 8.0 g/night; mean Epworth Sleepiness Scale scores were 9.4 and 8.8. Most participants reported improvement (45%) or no change (48%) in narcolepsy symptoms on the Patient Global Impression of change, reported the transition to LXB was "easy" (easy, extremely easy, not difficult at all; 93%) on the Ease of Switching Medication Scale, and preferred LXB compared with SXB (79%) on the Forced Preference Questionnaire, most commonly due to the lower sodium content. Most participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment was maintained on LXB, and most participants preferred LXB to SXB. No new safety or tolerability issues were identified. Registry: ClinicalTrials.gov; Name: An Interventional Safety Switch Study (Segue Study) of XYWAV in Narcolepsy; URL: https://classic.clinicaltrials.gov/ct2/show/NCT04794491; Identifier: NCT04794491. Macfadden W, Leary EB, Fuller DS, Kirby MT, Roy A. Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study. J Clin Sleep Med. 2024;20(9):1467-1477.

Cardiovascular parameters characterizing blood pressure (BP), heart rate (HR), endothelial function and arterial stiffness predict cerebro-cardiovascular events (CCVE) in the general population. Considering the paucity of data in stroke patients, we assessed these parameters as potential predictors of recurrent CCVE at acute stroke stroke. This is a secondary outcome analysis of a prospective observational longitudinal Sleep Deficiency & Stroke Outcome Study (ClinicalTrials.gov Identifier: NCT02559739). The study consecutively recruited acute ischemic stroke patients. Cardiovascular parameters (blood pressure variability [BPV], heart rate variability [HRV], endothelial function, and arterial stiffness) were assessed within the first week post-stroke. Future CCVE were recorded over a 3-year follow-up. Multivariate Cox regression analysis was used to investigate the prognostic value of 48 cardiovascular parameters regarding CCVE risk. Out of 447 recruited patients, 359 were included in this analysis. 20% of patients developed a future CCVE. A high variability of systolic BP (n = 333) and nocturnal HR (non-linear parameters; n = 187) at acute stroke predicted CCVE risk after adjustment for demographic parameters, cardiovascular risk factors and mean BP or HR, respectively. Endothelial dysfunction (n = 105) at acute stroke predicted CCVE risk after adjustment for age and sex, but not after adjustment for cardiovascular risk factors. Diurnal HR and arterial stiffness at acute stroke were not associated with CCVE risk. High blood pressure variability, high nocturnal HRV and endothelial function contribute to the risk for future CCVE after stroke.

Abstract Introduction Mazindol ER (extended-release), the first partial orexin-2 receptor agonist and triple mono-aminergic reuptake inhibitor, has demonstrated efficacy and safety in significantly reducing excessive daytime sleepiness (EDS) and cataplexy attacks in narcolepsy type 1 (NT1) and type 2 (NT2) patients (POLARIS, Study NLS-1021). This efficacy was further studied in an open-labeled extension (OLE) study (ClinicalTrials.gov Identifier: NCT04923594). Methods A multicenter, 6-month, OLE study with 51 narcolepsy patients previously enrolled in a double-blind mazindol ER study. Patients were administered 3mg mazindol ER once daily in the morning. Narcolepsy symptoms and adverse events were recorded. Safety measures included monthly physical and laboratory examinations. The primary efficacy measure was the change from baseline in EDS using the Epworth Sleepiness Scale (ESS). Secondary measures included weekly cataplexy attacks, the overall disease severity as rated by the investigators (Clinician Global Impression of Severity) and patients (Patient Global Impression of Severity). Results Mazindol ER at 3 mg once-daily doses, produced overall improvements in EDS and narcolepsy within 1-2 weeks of starting dosing. Reported improvements included diminished daytime sleepiness (p < 0.001); significant decreases in cataplexy attacks (p < 0.001); and multiple improvements in symptoms severity and function. Adverse events were generally mild and patients showed no evidence of tolerance. Conclusion Mazindol ER is a convenient, safe, well-tolerated and effective treatment for narcolepsy. Its anticataleptic and wake-promoting effects indicate that it may be a new therapeutic option for patients with NT1 or NT2 similar or better than various combinations treatments currently available. Support (if any) NLS Pharmaceutics

Abstract Introduction Tonic motor activation (TOMAC) is a noninvasive medical device therapy that has been shown to reduce symptoms of refractory restless legs syndrome (RLS). Here, we evaluated the effects of TOMAC on subjective sleep quality. Methods One hundred and thirty-three adults with primary moderate-severe refractory RLS were 1:1 randomized to TOMAC or sham control for 4 weeks. Participants were instructed to self-administer a 30-minute TOMAC session bilaterally over the head of the fibula to electrically stimulate the peroneal nerve whenever RLS symptoms presented. Sleep quality was assessed through prespecified analysis of changes to Medical Outcomes Study Sleep Scale (MOS-Sleep) Sleep Problems Index I (MOS-I) and II (MOS-II) scores from baseline to Week 4. Post hoc t-tests were conducted on each MOS-Sleep item included in the MOS-I or MOS-II. Results MOS-I score changed by -11.8 points (48.5 to 36.7) for TOMAC and -2.8 points for sham (44.5 to 41.7), a difference of -9.0 points (p< 0.001). MOS-II score changed by -13.7 points (52.5 to 38.9) for TOMAC and -4.0 points for sham (48.3 to 44.3), a difference of -9.7 points (p< 0.001), which exceeds the proposed minimal clinically important difference (MCID) of 6 points. Post hoc analysis demonstrated statistically significant reductions in trouble falling asleep (item #7; -34.0% for TOMAC vs. -5.8% for sham; p< 0.01) and trouble staying awake during the day (item #9; -33.6% for TOMAC vs. -2.1% for sham; p< 0.05), which exceeded the standard MCID threshold of 30% relative to baseline. Conclusion For adults with refractory RLS, TOMAC improved subjective sleep quality, sleep latency, and daytime somnolence relative to sham control. Each of these improvements represented clinically important improvements. These data demonstrate that TOMAC can provide meaningful improvements to sleep quality and daytime functioning for patients with refractory RLS. Support (if any) Funding was provided by Noctrix Health, Inc.

<h3>Objective:</h3> This study aims to assess patient preference for once- vs twice-nightly oxybate dosing regimens and experiences with the second dose of twice-nightly, immediate-release (IR) oxybate. <h3>Background:</h3> IR oxybates require patients with narcolepsy to awaken for a second dose 2.5–4 hours after the bedtime dose. RESTORE, an ongoing open-label/switch study (NCT04451668), evaluates long-term safety/tolerability of investigational, extended-release once-nightly sodium oxybate (FT218; ON-SXB). <h3>Design/Methods:</h3> Participants aged ≥16 years with narcolepsy type 1 or 2 who completed the phase 3 REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive were eligible. For those switching to ON-SXB, initial doses were equivalent/closest to the previous total IR oxybate dose/night; adjustments were allowed in 1.5-g increments/week. Switch participants completed the nocturnal adverse event (AE) questionnaire about their IR oxybate experience at baseline and preference questionnaire 3 months after switching to ON-SXB. Safety and dose titration data are presented separately. <h3>Results:</h3> RESTORE enrollment completed 30June2022. At the interim data cutoff (01July2022), 78 switch participants completed preference questionnaires; 130 completed nocturnal AE questionnaires. Preference for the ON-SXB dosing regimen was stated by 93.6% (73/78) of participants. On the nocturnal AE questionnaire, 65.4% (85/130) unintentionally missed their second IR oxybate dose in previous 3 months; of participants who intentionally and/or unintentionally missed the second dose, 80.2% (73/91) felt worse the next day. Second nightly IR oxybate doses were taken &gt;4 h after the first by 39.2% (51/130); 51.0% (26/51) were somewhat to extremely groggy/unsteady the next morning. The second dose was rated somewhat to extremely inconvenient for 70.8%. Second-dose-related anxiety (29.2%) and need for someone to wake them (23.1%) were also reported. Most (90.8% [118/130]) arose from bed when waking for the second dose; 9 had falls and 5 reported injuries. <h3>Conclusions:</h3> These data indicate patient preference for once-at-bedtime dosing and reveal the treatment burden of twice-nightly IR oxybate. <b>Disclosure:</b> Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Harmony biosciences. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Eisai . Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Inspire. The institution of Dr. Roy has received research support from Jazz . The institution of Dr. Roy has received research support from Inspire. The institution of Dr. Roy has received research support from Avadel. Dr. Harsh has nothing to disclose. Akinyemi Ajayi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceutical. Akinyemi Ajayi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceutical. Dr. Stern has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel Pharmaceutical. Dr. Stern has received intellectual property interests from a discovery or technology relating to health care. Dr. Seiden has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Dr. Seiden has received stock or an ownership interest from Avadel Pharmaceuticals. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Miss Gudeman has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Miss Gudeman has stock in Avadel Pharmaceuticals.

<h3>Objective:</h3> The objective of RESTORE (NCT04451668) is to assess the long-term safety and tolerability of once-nightly sodium oxybate (ON-SXB; FT218), an investigational extended-release formulation. Interim safety data are reported; dose titration and patient preference data are presented separately. <h3>Background:</h3> In the pivotal phase 3 REST-ON trial (NCT02720744), ON-SXB met its 3 coprimary efficacy endpoints for treatment of adults with narcolepsy (<i>P</i>&lt;0.001 vs placebo) and had a safety profile consistent with that of immediate-release (IR) SXB. RESTORE is an ongoing open-label extension/switch study. <h3>Design/Methods:</h3> Participants aged ≥16 years with narcolepsy type 1/2 who completed the REST-ON trial, were on stable-dose IR oxybate for ≥1 month, or were oxybate-naive were eligible to enroll in RESTORE. Initial ON-SXB doses are equivalent/closest to previous total nightly dose of IR oxybate (switch participants) or 4.5 g/night (other participants); weekly ON-SXB dose adjustments were allowed at 1.5 g/week increments (maximum, 9 g/night). Safety data for participants who received ≥1 dose of ON-SXB as of 01July2022 are reported. <h3>Results:</h3> This analysis includes 180 individuals (REST-ON participants, n=15 [8.3%]; oxybate-naive, n=35 [19.4%]; switch, n=130 [72.2%]; white, n=150 [83.3%]; female, n=122 [67.8%]; mean age, 35 y [range, 16–84]). Adverse events (AEs) were reported by 105 (58.3%) participants. Serious AEs were recorded in 3 participants (abscess; deep vein thrombosis; rib fracture and pneumothorax); all were deemed unrelated to ON-SXB and did not result in study discontinuation. Seventy-six (42.2%) participants reported an adverse drug reaction (ADR), ie, AE related/possibly related to ON-SXB. The most common ADRs (≥3%) were nausea (11.7%), somnolence (6.7%), headache (5%), enuresis (5%), somnambulism (3.9%), dizziness (3.9%), tremor (3.9%), and vomiting (3.3%). Six (3.3%) participants discontinued due to ADRs. <h3>Conclusions:</h3> Thus far in RESTORE, ON-SXB is generally well tolerated, and no new safety signals have been observed. If approved, ON-SXB will offer a once-nightly oxybate treatment option for adults with narcolepsy. <b>Disclosure:</b> Dr. Stern has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avadel Pharmaceutical. Dr. Stern has received intellectual property interests from a discovery or technology relating to health care. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Harmony biosciences. Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Eisai . Dr. Roy has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Inspire. The institution of Dr. Roy has received research support from Jazz . The institution of Dr. Roy has received research support from Inspire. The institution of Dr. Roy has received research support from Avadel. Colin Shapiro has nothing to disclose. Dr. Harsh has nothing to disclose. Akinyemi Ajayi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceutical. Akinyemi Ajayi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceutical. The institution of Dr. Ibrahim has received research support from Avadel. The institution of Dr. Ibrahim has received research support from NIH. Dr. Seiden has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Dr. Seiden has received stock or an ownership interest from Avadel Pharmaceuticals. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Miss Gudeman has received personal compensation for serving as an employee of Avadel Pharmaceuticals. Miss Gudeman has stock in Avadel Pharmaceuticals.

PurposeCurrent US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment.Patients and MethodsAdults with self-reported physician-diagnosed narcolepsy for ≥1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model.ResultsSeventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P<0.05).ConclusionAmong the choices presented, dosing frequency was the most important attribute for overall product choice, likelihood to take medication exactly as directed, and reducing anxiety/stress. The ON-SXB blinded profile was significantly preferred over twice-nightly SXB.