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Introduction In the phase 3 REST-ON trial (NCT02720744), participants with narcolepsy type 1 (NT1) treated with once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release formulation, had significant reductions in cataplexy episodes (ON-SXB vs placebo: 4.5 g, P< 0.05 [post hoc]; 6 , 7.5, and 9 g, all P< 0.001). This post hoc responder analysis further characterized improvements in mean weekly cataplexy episodes in trial participants. Methods In REST-ON, participants aged ≥16 years with NT1/NT2 were randomized 1:1 to double-blind ON-SXB or placebo for 13 weeks. Participants took 4.5 g (1 week), 6 g (2 weeks), 7.5 g (5 weeks), and 9 g (5 weeks). Participants with NT1 recorded number of cataplexy episodes per day (0, 1, 2, 3, 4, or ≥5) in a diary. Percentage of participants with ≥25%, ≥50%, ≥75%, and 100% reductions in weekly cataplexy episodes from baseline were compared (ON-SXB vs placebo; Fisher exact test). Results In the modified intent-to-treat population, 145 participants had NT1 (ON-SXB, n=73; placebo, n=72). Baseline mean (SD) number of weekly cataplexy episodes was 18.9 (8.7) for the ON-SXB group and 19.8 (8.9) for placebo. At week 1 (4.5 g), significantly more participants taking ON-SXB had ≥25% reduction in cataplexy (43.8% vs 26.4%; P< 0.05). Significantly more participants receiving ON-SXB had ≥25%, ≥50%, or ≥75% reduction in cataplexy vs placebo at weeks 3, 8, and 13 and complete resolution of cataplexy at weeks 8 and 13 (6-g dose: ≥25%, 68.5% vs 40.3% [P< 0.001]; ≥50%, 38.4% vs 20.8% [P< 0.05]; ≥75%, 23.3% vs 4.2% [P=0.001]; 100%, 2.7% vs 0 [P=NS]; 7.5-g dose: ≥25%, 67.1% vs 43.1%; ≥50%, 53.4% vs 25.0%; ≥75%, 32.9% vs 8.3% [all P< 0.001]; 100%, 6.8% vs 0 [P< 0.05]; 9-g dose: ≥25%, 58.9% vs 41.7% [P< 0.001]; ≥50%, 49.3% vs 26.4% [P< 0.001]; ≥75%, 32.9% vs 15.3% [P< 0.01]; 100%, 11.0% vs 2.8% [P< 0.05]). Conclusion In this post-hoc analysis, ON-SXB 4.5 g significantly reduced cataplexy by week 1. Additionally, ~10% of participants taking ON-SXB 7.5 and 9 g were free of cataplexy episodes. These data may be useful for clinicians when setting expectations of ON-SXB effectiveness for patients with cataplexy. Support (if any) Avadel Pharmaceuticals

Introduction The pivotal phase 3 REST-ON trial (NCT02720744) evaluated the efficacy and safety of once-nightly sodium oxybate (ON-SXB; FT218), an investigational extended-release formulation for treatment of adults with narcolepsy. In REST-ON, ON-SXB met its 3 coprimary endpoints: improvement in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating (% much/very much improved), and number of weekly cataplexy attacks at all doses tested (P< 0.001 vs placebo). The safety profile of ON-SXB was consistent with that of immediate-release (IR) SXB. The ongoing RESTORE trial (NCT04451668) is an open-label/switch study evaluating the safety and tolerability of ON-SXB. Methods Participants aged ≥16 years with narcolepsy type 1 or 2 who completed the REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive are eligible for RESTORE. Initial doses were 4.5 g/night or equivalent/closest to the previous total IR oxybate dose/night for those switching; incremental adjustments (1.5 g/week; maximum dose, 9 g/night) were allowed. Safety data for participants receiving ≥1 dose of ON-SXB as of 01 July 2022 are reported here. Results This analysis includes interim data from 180 participants (REST-ON participants, n=15 [8.3%]; oxybate-naive, n=35 [19.4%]; switch, n=130 [72.2%]). Most participants are white (n=150 [83.3%]) and female (n=122 [67.8%]); mean age is 35 years [range, 16–84]). Most participants who reported an adverse event (AE; n=105 [58.3%]) had AEs that were mild (61.9%) or moderate (32.3%) in severity. Three participants had serious AEs (abscess, deep vein thrombosis, rib fracture and pneumothorax); all were deemed unrelated to ON-SXB and all 3 participants continued in the study. Adverse drug reactions (ADRs; ie, AEs related/possibly related to study drug) were reported by 76 (42.2%) participants with 6 (3.3%) participants discontinuing ON-SXB owing to ADRs. ADRs occurring in ≥3% of participants were nausea (11.7%), somnolence (6.7%), headache (5%), enuresis (5%), somnambulism (3.9%), dizziness (3.9%), tremor (3.9%), and vomiting (3.3%). Conclusion Interim data from the RESTORE study indicate that ON-SXB is generally well tolerated with a low rate of discontinuation owing to ADRs. If granted final FDA approval, ON-SXB will offer adults with narcolepsy a once-at-bedtime oxybate treatment option. Support (if any) Avadel Pharmaceuticals

Introduction Sodium oxybate (SXB) is a standard-of-care treatment for adults with narcolepsy. Existing oxybate formulations are immediate release (IR), requiring patients to awaken for a second dose 2.5–4 hours after the first bedtime dose. Once-nightly SXB (ON-SXB; FT218), an investigational extended-release formulation, replaces this middle-of-the-night dosing with a once-at-bedtime regimen. RESTORE (NCT04451668) is an open-label/switch study evaluating the safety/tolerability of ON-SXB and patient preferences for ON-SXB or IR oxybate. Methods RESTORE includes 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. Initial doses for participants switching from IR oxybate are equivalent/closest to the previous total dose/night; incremental adjustments (1.5 g/week; maximum, 9 g/night) are allowed. A nocturnal adverse event (AE) questionnaire about switch participants’ IR oxybate experience in the previous 3 months was completed at baseline. Switch participants completed the preference questionnaire after 3 months of ON-SXB treatment. Results Data available from preference questionnaires (n=78) and nocturnal AE questionnaires (n=130) were analyzed at the interim data cutoff (01 July 2022). Most common AEs thus far were nausea, headache, and somnolence. The once-nightly dosing regimen was preferred by 93.6% (73/78) of participants. The second nightly IR oxybate dose was unintentionally missed in the previous 3 months by 65.4% (85/130) of switch participants; 80.2% (73/91) who intentionally and/or unintentionally missed the second dose felt worse the next day. Participants who took their second nightly IR oxybate dose >4 h after the first dose (51/130 [39.2%]) reported being somewhat, quite a bit, or extremely groggy/unsteady the next morning (26/51 [51.0%]). Inconvenience of the second dose was reported by 70.8%. Other issues related to the second dose were anxiety (29.2%) and the need to be woken by someone else (23.1%). In the past 3 months, 118 participants (90.8%) arose from bed after waking to take the second dose; 9 of these participants reported having fallen, with 5 reporting injuries. Conclusion These interim RESTORE data demonstrate patient preference for once-at-bedtime dosing of ON-SXB and indicate treatment burden associated with twice-nightly IR oxybate. Support (if any) Avadel Pharmaceuticals

Mesh-based 3-dimensional (3D) shape generation from a 2-dimensional (2D) image using a convolution neural network (CNN) framework is an open problem in the computer graphics and vision domains. Most existing CNN-based frameworks lack robust algorithms that can scale well without combining different shape parts. Also, most CNN-based algorithms lack suitable 3D data representations that can fit into CNN without modification(s) to produce high-quality 3D shapes. This paper presents an approach that integrates a variational autoencoder (VAE) and a generative adversarial network (GAN) called 3 dimensional variational autoencoder signed distance function generative adversarial network (3D-VAE-SDFGAN) to create a 3D shape from a 2D image that considerably improves scalability and visual quality. The proposed method only feeds a single 2D image into the network to produce a mesh-based 3D shape. The network encodes a 2D image of the 3D object into the latent representations, and implicit surface representations of 3D objects corresponding to those 2D images are subsequently generated. Hence, a signed distance function (SDF) is proposed to maintain object inside-outside information in the implicit surface representation. Polygon mesh surfaces are then produced using the marching cubes algorithm. The ShapeNet dataset was used in the experiments to evaluate the proposed 3D-VAE-SDFGAN. The experimental results show that 3D-VAE-SDFGAN outperforms other state-of-the-art models.

Introduction Available, immediate-release oxybate products for narcolepsy require patients to awaken for a second dose 2.5-4 h after the first to cover a full night of sleep. The investigational, extended-release once-nightly sodium oxybate (ON-SXB; FT218) eliminates this middle-of-the-night dosing. This interim analysis from the ongoing RESTORE study (NCT04451668) assessed patient preferences for ON-SXB versus twice-nightly sodium oxybate (SXB) and experiences with the second nightly SXB dose in patients who switched from twice-nightly SXB to ON-SXB. Methods Participants enrolled in the open-label extension/switch study (RESTORE) were aged ≥16 y with a confirmed diagnosis of narcolepsy type 1 or 2 from the phase 3 REST-ON trial or receiving stable doses of twice-nightly SXB for ≥1 month. Initial ON-SXB doses for switch patients were equivalent/closest to their previous total nightly SXB dose. Patient preference questionnaires were completed by switch patients 3 months after switching and nocturnal adverse event (AE) questionnaires at baseline. Results At an interim data cutoff date of November 22, 2021, 46 participants completed patient preference questionnaires; 93.5% (43/46) preferred ON-SXB to twice-nightly SXB. Nocturnal AE questionnaires were completed by 76 switch participants. In the 3 months before switching to ON-SXB, 62% (47/76) had unintentionally missed their second twice-nightly SXB dose, with 86% experiencing worse narcolepsy symptoms the next day. Forty percent (30/76) reported taking their second twice-nightly SXB dose >4 h after the first dose, with 47% reporting being somewhat, quite a bit, or extremely groggy/unsteady the next morning. For 76% (58/76), taking a second nighttime dose was somewhat, quite a bit, or extremely inconvenient. Additionally, 91% (69/76) reported that they had arisen from bed after the second dose; of these, 5 reported associated falls, and 3 had injuries. Anxiety (25%) and the need for someone else to wake them (21%) were also reported. One participant reported that the medication was missing when they awoke for the second dose. Conclusion These interim data indicate that individuals with narcolepsy and prior experience taking SXB prefer ON-SXB to twice-nightly SXB. Treatment burden from the second nightly SXB dose may be alleviated with ON-SXB. Support (If Any) Avadel Pharmaceuticals

Study Objectives To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial. Methods Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments. Results In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105). For the three coprimary endpoints and Epworth Sleepiness Scale, all three doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement versus placebo (all p < 0.001). For ON-SXB 9 g versus placebo, increase in mean sleep latency was 10.8 versus 4.7 min (Least squares mean difference, LSMD [95% CI], 6.13 [3.52 to 8.75]), 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76 to 11.23]), change in mean weekly number of cataplexy attacks was –11.5 versus –4.9 (LSMD [95% CI], –6.65 [–9.32 to –3.98]), and change in Epworth Sleepiness Scale was –6.5 and –2.7 (LSMD [95% CI], –6.52 [–5.47 to –2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis. Conclusions ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose. Clinical Trial Registration ClinicalTrials.gov: NCT02720744, https://clinicaltrials.gov/ct2/show/NCT02720744.

Introduction Sleep disorders in the pediatric clinical setting are often overlooked and under-screened. The study compared a set of clinical behavior questions and physiological risk factors with potential to increase the risk for sleep disorders within children. Methods A retrospective archive from electronic medical records was analyzed from 695 pediatric patients, 7-14 years old, that visited a pediatric clinic from March-November of 2019. Children or their parents reported on the presence of eight behavioral and physiological factors on the Kids Sleep Screener Questionnaire (KSSQ), which were used as potential risk factors for sleep disorders. The propensity of daytime sleepiness was measured using the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Univariate analysis was performed to find frequencies to summarize the risk factors. Chi square test was used to test for associations between risk factors and ESS-CHAD. Multiple logistic regression (MLR) was used to predict different combinations of factors with ESS-CHAD. Odd ratios (ORs) and 95% CI were used to quantify the level of association. Receiver operating characteristic (ROC) with area under the curve analysis was used to compare three MLR models. Results The risk factors were positively (p Conclusion The Kids Sleep Screener Questionnaire is a potential tool to predict sleep disorder. Further studies are warranted to explore the behavior and physiological risk factors with potential to increase the risk for sleep disorders. Support (If Any)

Introduction Disturbed nocturnal sleep (DNS) is a common symptom in patients with narcolepsy, characterized by fragmented sleep, including frequent brief nightly awakenings. Sodium oxybate (SO) is an effective treatment for narcolepsy; however, currently available formulations must be taken twice nightly. FT218 is an investigational once-nightly controlled-release formulation of SO. Here, we evaluated the efficacy of FT218 on polysomnographic (PSG) measures of DNS and number of arousals (NAs) in patients with narcolepsy types 1 and 2. Methods This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with narcolepsy aged ≥16 years were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks. Secondary endpoints included PSG measurements of DNS (defined as shifts to wake/N1 from N1, N2, N3, and REM) and NAs (defined per AASM Scoring Manual guidelines [v2.6]). Results Patients receiving FT218 had significant improvements vs placebo in DNS; the LS mean difference between FT218 and placebo was −22.63 for 9.0 g (week 13), −17.70 for 7.5 g (week 8), and −11.00 for 6.0 g (week 3) (all P Conclusion FT218 at all evaluated doses showed significant reduction in DNS and number of NAs vs placebo for all doses of FT218 evaluated. FT218 was generally well tolerated; the most common adverse events were consistent with known SO side effects. FT218 could offer a new once-nightly treatment option for DNS in patients with narcolepsy as demonstrated by PSG measures. Support (if any) Avadel Pharmaceuticals.

Introduction Sodium oxybate (SO) is an effective treatment for patients with narcolepsy; however, currently available SO formulations require twice-nightly dosing. The purpose of this study was to evaluate efficacy and safety of FT218, an investigational once-nightly controlled-release SO formulation, for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy types 1 (NT1) and 2 (NT2). Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Coprimary endpoints were mean sleep latency (minutes) on maintenance of wakefulness test (MWT), Clinical Global Impression-Improvement (CGI-I) of sleepiness, and weekly number of cataplexy attacks (NCAs; NT1 only). Results A total of 212 patients were randomized and received study treatment (FT218, n=107; placebo, n=105). FT218 showed significant (P Conclusion All evaluated doses of FT218 showed significant improvement vs placebo in mean sleep latency on MWT, CGI-I, and weekly NCAs. FT218 was generally well tolerated and the most common adverse events were consistent with known side effects of SO. Support (if any) Avadel Pharmaceuticals.

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P