Search

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 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.

Introduction Narcolepsy, particularly type 1 (NT1), is often comorbid with obesity. FT218 (LUMRYZ™) is an investigational once-nightly sodium oxybate (ON-SXB) formulation whose efficacy and safety were shown in the phase 3 REST-ON clinical trial (NCT02720744). Methods REST-ON was a 13-week, randomized (1:1), double-blind, placebo-controlled multicenter study in patients ≥16 years old with NT1/NT2. Stable concomitant stimulant use was permitted. A post hoc analysis of participants in the ON-SXB group experiencing ≥5% weight loss (weight-loss group) was conducted. Results In REST-ON (n=212), mean participant age was 31.2 years (range, 16–72), 67.9% were female, 75.5% were white, 76.4% had NT1, mean baseline BMI was 28.1 kg/m2 (range, 16.9–71.9), and 61.3% were taking stimulants. At week 13, 17.8% (19/107) of participants receiving ON-SXB experienced ≥5% weight loss vs 3.8% (4/105) of participants receiving placebo (P< 0.001). Compared to the REST-ON population, the weight-loss group had similar age and proportion of NT1 diagnosis, a smaller proportion was female, and a higher proportion was white and was taking stimulants. At baseline, mean BMI was 25.6 kg/m2 (range, 20.3–34.0) in the weight-loss group, 47.4% (9/19) were overweight (BMI 25.0–29.9 kg/m2) or obese (BMI >30 kg/m2); none were underweight (BMI < 18.5 kg/m2). At week 13, 31.6% (6/19) remained overweight or obese; none were underweight. Excessive daytime sleepiness was significantly improved from baseline to week 13 (ON-SXB 9 g) in the weight-loss group vs the ON-SXB group without weight loss (Maintenance of Wakefulness test, P< 0.05; Epworth Sleepiness Scale score, P< 0.001). Adverse events of nausea and vomiting were more frequent in the weight-loss group vs the ON-SXB group without weight loss; however, rate of discontinuations owing to AEs in the weight-loss group was approximately half that of the ON-SXB group without weight loss. Conclusion These data expand the body of knowledge regarding weight loss during treatment with sodium oxybate. Given the high proportion of comorbid obesity among people with narcolepsy, the additional benefit of potential weight loss with sodium oxybate may further inform treatment selection. Whereas ON-SXB was effective overall, further exploration of possible increased pharmacologic response in certain subgroups should be evaluated. 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

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.

Introduction Restless legs syndrome (RLS) is a debilitating condition associated with reduced health-related quality of life (HRQoL) and increased resource utilization. Recently, the RESTFUL study demonstrated significant improvement in RLS severity following treatment with a novel non-invasive neuromodulation treatment (Tonic Motor Activation; TOMAC). Our objective was to provide model-based estimates of quality-adjusted life year (QALY) gain and reduction in healthcare utilization that might be expected for the observed changes in symptom severity. Methods The RESTFUL study randomized n=133 subjects 1:1 to active TOMAC treatment and sham control, with change in International Restless Legs Scale (IRLS) scores reported at four weeks at the end of the randomization period. Functional relationships between IRLS and HRQoL and resource utilization were derived from two prior health-economic studies (Happe et al. 2009 and Durgin et al. 2015). Model-projected quality-adjusted life year (QALY) gain and events avoided at a five-year analysis horizon were calculated based on assumption of maintained treatment effect. Results From baseline of 25.2, change in IRLS at four weeks was -7.2 for the active and -3.8 for the sham group (between group difference -3.4, p< 0.01). Based on this effect size, TOMAC was projected to add 0.16 QALYs over 5 years (0.39 when considering reduction from baseline). Based on lower symptom severity, TOMAC was projected to avoid 3.80 (8.05) health care provider visits, 0.29 (0.62) ER visits, and 0.12 (0.26) hospitalizations over 5 years, resulting in a relative risk (RR) of composite healthcare utilization of 0.94 (0.88). Conclusion The findings of this exploratory analysis suggest TOMAC-associated improvements in RLS severity as observed in the RESTFUL study may lead to meaningful improvements in patient quality-of-life and concurrent reductions in healthcare utilization. Further investigation is warranted. Support (if any) Wing Tech Inc. (AMR, KNC, JBP) received consulting fees from Noctrix Health. AR is an investigator in the RESTFUL study.

Introduction There is a large population of patients who have become refractory to first-line treatments for Restless Legs Syndrome, partially due to augmentation to dopamine agonist medications. For patients with refractory RLS, tonic motor activation (TOMAC) is a noninvasive medical device therapy with promising short-term safety and efficacy. Here, we evaluated the response to TOMAC over a longer duration of >24 weeks. Methods In the RESTFUL study, 133 patients with primary moderate-severe refractory RLS were 1:1 randomized to TOMAC or sham control for weeks 1 to 4 followed by open-label TOMAC for weeks 5 to 8. The final 50 participants to complete the RESTFUL study were invited to continue TOMAC treatment for an additional 24 weeks (weeks 9 to 32) in an extension study. Participants were instructed to self-administer one 30-minute TOMAC session bilaterally over the peroneal nerve whenever RLS symptoms presented. Efficacy was assessed by comparing responses from baseline (RESTFUL study entry, week 0) to week 32 on Clinician Global Impressions-Improvement (CGI-I) responder rate, Patient Global Impressions-Improvement (PGI-I) responder rate, and International RLS Study Group Rating Scale (IRLS) total score. Additional analyses compared responses from week 8 (RESTFUL study completion) to week 32. Results Of the 50 eligible participants, 44 consented to the extension study and 42 completed. CGI-I responder rate relative to baseline increased from 64% at week 8 to 76% at week 32. PGI-I responder rate relative to baseline increased from 68% at week 8 to 77% at week 32. IRLS total score reduced from 24.5 at baseline to 17.1 at week 8 to 12.9 at week 32, a reduction of 11.6 points from baseline to week 32. There were no moderate or severe device-related AEs. Conclusion TOMAC resulted in substantial and clinically significant reduction in RLS symptom severity that was maintained through >24 weeks of treatment. Furthermore, there was a trend towards increased efficacy with continued use of TOMAC. These data suggest that TOMAC could represent a potential long-term treatment for the chronic condition of refractory RLS. Support (if any) Funding was provided by Noctrix Health, Inc.

Introduction FT218 (LUMRYZ™) is an investigational once-nightly sodium oxybate (ON-SXB) for treatment of adults with narcolepsy type 1 (NT1) or type 2 (NT2). The efficacy and safety of ON-SXB at doses 6, 7.5, and 9 g in patients with NT1/NT2 were confirmed in the phase 3 REST-ON clinical trial (NCT02720744). RESTORE is an ongoing, open-label extension/switch study to assess long-term safety and tolerability of ON-SXB (NCT04451668). Methods Individuals aged ≥16 years with NT1/NT2 are enrolled in Group A (participants who completed the REST-ON trial with no current oxybate use), Group B (participants who switched from twice-nightly immediate-release oxybates), or Group C (participants who are oxybate-naive). Initial ON-SXB dose is 4.5 g/night for Groups A/C and is the nearest equivalent or closest single dose to their previous nightly dose for Group B. Investigators may alter the nightly dose by 1.5 g/week (maximum, 9 g/night) based on effectiveness and tolerability. Results A total of 184 participants were enrolled (180, ≥1-dose) as of July 1, 2022. Most participants are white (n=150 [83.3%]) and female (n=122 [67.8%]), and mean age is 35 years. Most participants in Groups A/C (n=43/50 [86.0%]) increased from the 4.5-g initial dose and had 2–4 dose adjustments during initial titration (median [range], 3 [0–5]); 47% (17/36) are stable at 7.5 g. The most common initial doses in Group B were 7.5 g (50/130 [38.5%]) and 9 g (47/130 [36.2%]). Most in Group B reaching a stable dose maintained their initial dose (70/118 [59.3%]); 43 increased (36.4%) and 5 decreased (4.2%) their initial ON-SXB dose. In Group B, 49.1% (53/108) had no dose adjustments (median [range], 1 [0–5]) and 83.0% (n=39/47) who started at 9 g maintained this dose. Most common treatment-related adverse events (>3%; safety population [n=180]) are nausea (11.7%), somnolence (6.7%), headache (5.0%), enuresis (5.0), dizziness (3.9%), tremor (3.9%), somnambulism (3.9%), and vomiting (3.3%). Conclusion Most study participants had successful titration of ON-SXB to a therapeutic and tolerable dose within 1 month. If granted final approval by the US Food and Drug Administration, ON-SXB will offer a once-nightly treatment for adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

Study Objectives Upper airway stimulation (UAS) therapy is effective for a subset of obstructive sleep apnea (OSA) patients with continuous positive airway pressure (CPAP) intolerance. While overall adherence is high, some patients have suboptimal adherence, which limits efficacy. Our goal was to identify therapy usage patterns during the first 3 months of therapy to enable targeted strategies for improved adherence. Methods Therapy data was retrieved from 2098 patients for three months after device activation. Data included mean and standard deviation (SD) of hours of use, therapy pauses, hours from midnight the therapy was turned ON and OFF, percentage of missing days, and stimulation amplitude. Cluster analysis was performed using Gaussian mixture models that categorized patients into six main groups. Results The six groups and their prevalence can be summarized as Cluster 1A: Excellent Use (34%); Cluster 1B: Excellent Use with variable timing (23%); Cluster 2A: Good Use with missing days and late therapy ON (16%), Cluster 2B: Good Use with missing days, late therapy ON, and early therapy OFF (12%); Cluster 3A: Variable Use with frequent missing days (8%); Cluster 3B: Variable Use with frequent pauses (7%). Most patients (85%) are excellent or good users with mean therapy use >6 hours per night. Conclusions Cluster analysis of early UAS usage patterns identified six distinct groups that may enable personalized interventions for improved long-term management. Differentiation of the patient clusters may have clinical implications with regard to sleep hygiene education, therapy discomfort, comorbid insomnia, and other conditions that impact adherence.

Introduction A growing number of cloud-connected sensors can longitudinally record apnea hypopnea index (AHI) at home. The Ectosense NightOwl is an FDA-approved peripheral arterial tomography device; the Withings Sleep Analyzer mat is an under-mattress sensor with AHI data for retrospective research use (CE marked, not FDA approved). We used these sensors to monitor patients with upper airway stimulation (UAS) therapy during therapy acclimatization and post-titration follow-up and compared sensor AHI to polysomnography (PSG) and home sleep test (HST) AHIs. Methods Enrolled patients underwent UAS implantation as part of regular clinical care and were required to have a smartphone. The Ectosense and Withings sensors were distributed at UAS device activation. Patients were asked to use NightOwl weekly, and Withings provided nightly AHI. Sleep studies (PSG & HST) occurred at 3 and 6-mo post implant. Ectosense & Withings AHI were averaged and correlated against the nearest 3- and 6-month sleep study AHIs. Results Patients were 67% male, aged 57 ± 10 years. Smartphone platforms were 59% Apple iOS, 24% Google Android, and 17% Unknown. As of October 2021, 45 patients have had near-simultaneous Withings and PSG/HST AHI, 35 have had near-simultaneous NightOwl and PSG/HST AHI. The Withings AHI was fairly linear against PSG/HST AHI, adjusted R2 = 0.47, p < 0.0001, (y=10 + 0.82x). Withings AHI < 15 (n=18) had a 90% positive predictive value for a PSG/HST AHI less than 15 (n=20). Ectosense data was less linear and more scattered, adjusted R2 = 0.15, p=0.01, (y=14 + 0.47x). Ectosense AHI < 15 (n=12) had an 80% positive predictive value of a PSG/HST AHI less than 15 (n=15). Conclusion Home-based sensors provide longitudinal SDB data in a home setting and may adequately classify patients with mild sleep apnea, and may have utility for home-based management of UAS patients in the post-implantation period. Support (If Any) Inspire Medical Systems

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

Introduction Once-nightly sodium oxybate (ON-SXB; FT218) was evaluated for treatment of narcolepsy in the phase 3 REST-ON trial (NCT02720744). Significant improvement was shown for the three coprimary endpoints mean sleep latency on the Maintenance of Wakefulness test (MWT), Clinical Global Impression of Improvement (CGI-I) rating, and weekly number of cataplexy attacks overall (all P Methods Participants aged ≥16 years were randomized 1:1 to receive ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Mixed-effects models for repeated measures were used to calculate P values for change from baseline vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) for secondary REST-ON endpoints of Epworth sleepiness scale (ESS) score, sleep shifts (ie, the number of shifts from stages N1, N2, N3 and rapid eye movement [REM] sleep to Wake and from N2, N3 and REM sleep to N1), nocturnal arousals (NA), and patient-reported sleep quality and refreshing nature of sleep (100-point visual analog scale). Results Of 190 participants, 145 had NT1 (ON-SXB, n=73; placebo, n=72) and 45 had NT2 (ON-SXB, n=24; placebo, n=21). Improvements with ON-SXB vs placebo were reported for shifts to a lighter stage of sleep (NT1: 6, 7.5, 9 g, all P Conclusion Results of these subgroup efficacy analyses are generally consistent with previously reported REST-ON endpoints and support ON-SXB treatment efficacy in adults with NT1 or NT2. 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 Extended-release once-nightly sodium oxybate (ON-SXB; FT218) is in development for adults with narcolepsy. In REST-ON, significant improvements on the Maintenance of Wakefulness test, Clinical Global Impression of Improvement rating, and number of weekly cataplexy episodes occurred with all analyzed ON-SXB doses vs placebo (week 3, 6-g dose; week 8, 7.5-g dose; week 13, 9-g dose; all P Methods Participants in the double-blind, phase 3 REST-ON (NCT02720744) trial were ≥16 years old, had narcolepsy type 1 or 2, and were randomized 1:1 to ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or placebo. Participants recorded ESS scores and VAS for sleep quality and refreshing nature of sleep (1-100; 1=poor quality/unrefreshing sleep; 100=good quality/refreshing sleep) using electronic diaries. P-values were calculated using a mixed-effects model for repeated measures in the modified intent-to-treat (mITT) population (ie, participants receiving ≥1 dose of study drug having ≥1 efficacy assessment at week 3). Results In the mITT population (n=190; ON-SXB, n=97; placebo, n=93), baseline ESS scores were 16.6 and 17.5 with ON-SXB and placebo, respectively. At week 2, ESS score was significantly improved with ON-SXB vs placebo (P Conclusion Improvement in daytime sleepiness, sleep quality, and refreshing nature of sleep occurred with ON-SXB beginning the first week of treatment. Some patients may experience early narcolepsy symptom relief with ON-SXB. Support (If Any) Avadel Pharmaceuticals

Introduction In the REST-ON trial (NCT02720744), once-nightly sodium oxybate (ON-SXB; FT218) was associated with significant improvement vs placebo for mean sleep latency on the Maintenance of Wakefulness test (MWT) and Clinical Global Impression of Improvement (CGI-I) rating in the overall population (both P Methods Participants (≥16 years of age) with narcolepsy type 1 or 2 were randomized 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. Mixed-effects models for repeated measures calculated P values for change from baseline vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) in ESS score, sleep shifts (ie, number of shifts from N1, N2, N3, and rapid eye movement [REM] sleep to Wake and from N2, N3, and REM sleep to N1), nocturnal arousals (NA), and patient-reported outcomes of sleep quality and refreshing nature of sleep on a 100-point visual analog scale. Results In the modified intent-to-treat population (n=190), 119 participants took concomitant stimulants (ON-SXB, n=66; placebo, n=53); 71 did not take stimulants (ON-SXB, n=31; placebo, n=40). Improvements with ON-SXB vs placebo were reported: ESS (stimulants: all doses, P≤0.01; no stimulants: 6 g, directional improvement; 7.5 g, P Conclusion Data from these post-hoc analyses were consistent with the previously reported results from REST-ON and support the efficacy of ON-SXB for EDS and DNS, as measured by objective and subjective endpoints whether or not stimulants were concurrently used. Support (If Any) Avadel Pharmaceuticals

Introduction Upper airway stimulation (UAS) therapy is an alternative treatment option for select CPAP-intolerant patients with obstructive sleep apnea. Current standard-of-care management uses in-laboratory polysomnography for titration of UAS stimulation amplitude (tPSG) after 3 months of patient self-titration at home. This home monitoring study was designed to evaluate whether tPSG or efficacy home sleep test (eHST) with tPSG by exception for eHST non-responders would have non-inferior apnea-hypopnea index (AHI) outcomes. Methods Enrolled patients underwent UAS implantation as part of regular clinical care and were randomized at the activation visit 1:1 between tPSG or eHST for the 3-month post-activation visit. If eHST results were suboptimal (AHI > 15 events/h or < 50% reduction from baseline AHI) patients underwent tPSG titration at 5 months. Both groups had 2-night eHSTs at 6 months post-activation. The primary endpoint was 6-month AHI equivalence between arms (defined as ± 15 events/h). Secondary endpoints were equivalence of Epworth Sleepiness Score (ESS; ± 2), oxygen desaturation index (ODI; ± 15 events/h), and nightly UAS device usage (± 0.5 h). Results The study randomized 60 patients from August 2020 through September 2021, who were primarily middle aged (57 ± 10 years), male (67%), Caucasian (98%), and overweight (BMI 29 ± 3 kg/m2), with severe OSA (AHI 35 ± 16). Eleven patients withdrew from the study early. As of December 2021, 41 and 36 patients have completed 3- and 6-month follow-up visits, respectively. Six-month visit AHI, ESS, ODI, and device usage data between arms is currently blinded and is expected to be complete by Q2 2021 prior to SLEEP 2022. Conclusion If the study demonstrates equivalent 6-month AHI, ESS, ODI, and usage outcomes, the use of eHST to ascertain therapy efficacy prior to tPSG could be a non-inferior alternative management option to tPSG. Support (If Any) Sponsored by Inspire Medical Systems, Inc.

Introduction Extended-release, once-nightly sodium oxybate (ON-SXB; FT218) is under FDA review for the treatment of adults with narcolepsy. RESTORE, an ongoing, open-label extension/switch study (NCT04451668), evaluates long-term ON-SXB safety and tolerability. This interim analysis assessed dosing titration, tolerability, and study continuation. Methods RESTORE enrolls adults with narcolepsy in 1 of 3 groups: those with prior REST-ON participation but no current oxybate use (Group A), those who switched from twice-nightly oxybates (Group B), and oxybate-naïve patients (Group C). No patients rolled directly from REST-ON to RESTORE. Initial dose for Groups A/C was 4.5 g/night. Group B switched to ON-SXB from stable doses of twice-nightly oxybate to the nearest equivalent single dose. Investigators could increase or decrease dose by 1.5-g increments weekly as needed. Descriptive statistics were used to analyze dose titration and discontinuations. Results At an interim data cutoff date of November 14, 2021, 99 participants were enrolled and had received ≥1 dose of ON-SXB (not currently taking oxybate, n=24; switch, n=75). For Groups A/C, 5 (21%) participants continued the 4.5-g dose, 8 (33%) increased to 6 g, 8 (33%) increased to 7.5 g, and 3 (13%) increased to 9 g by this data cutoff. Most Group B participants received initial ON-SXB doses of either 9 g (n=27) or 7.5 g (n=24). For Group B participants with >1 visit, 41 maintained their initial dose, 20 increased the dose, and 8 increased the dose but then later decreased it. All but 2 Group B participants with initial 9-g doses of ON-SXB maintained this dose. Twenty participants (20%) discontinued study treatment since the first patient enrolled in July 2020; the primary reason was withdrawal of consent (n=3; 3%). Two (2%) discontinued due to adverse reactions: vivid dreams/anxiety/lightheadedness and lack of efficacy (7.5 g); and difficulty breathing (6 g). Two discontinued due to taste/texture (2%); the remainder for miscellaneous reasons (eg, withdrew consent, could not adhere to schedule, left the country, caring for sick parent/child, wanted to get pregnant, using cannabis). Conclusion These interim data indicate that the majority of participants in all groups titrated to therapeutic and tolerable doses of ON-SXB. Support (If Any) Avadel Pharmaceuticals

Introduction Upper airway stimulation (UAS) therapy is effective for a subset of obstructive sleep apnea (OSA) patients with CPAP intolerance. While overall adherence is high, some patients have suboptimal adherence to UAS, which limits effectiveness. Our goal was to identify UAS therapy usage patterns during the first three months of therapy that affect adherence. Methods We retrieved anonymized UAS therapy usage data from 2,091 individuals stored in a cloud-based monitoring system during the first three months after device activation. We aggregated adherence data including mean and standard deviation (SD) of nightly hours of use, therapy pauses, hours from midnight when the therapy was turned ON and OFF, and percentage of missing days. We computed the difference of the stimulation amplitude between the first and last day. We performed cluster analysis with Gaussian mixture models and computed the centroids of each cluster highlighting their main differences. Results We identified six distinct clusters of UAS usage patterns. Clusters 1A (34% of the total cohort) and 1B (23%) had excellent therapy usage with 7.23h and 7.14h on days of use, respectively; with 1B distinguished by increased night-to-night variability. Clusters 2A (16%) and 2B (12%) had good mean therapy use of 6.63h and 6.21h, respectively, but their usage patterns were distinguished by a higher percentage of missing days (8% missing days in 2A and 23% in 2B) and less favorable therapy timing with an average therapy ON time after midnight. Clusters 3A (8%) and 3B (7%) were characterized by the lowest nightly use at 6.16h and 5.50h, respectively, and the highest night-to-night variability. 3A was further distinguished by the highest percentage of missing days (34%) while 3B was characterized by the frequent therapy pauses (mean 4.1 pauses per night) and the least increase in stimulation amplitude across the first 90 days. Conclusion Cluster analysis of UAS usage patterns identified six distinct groups that may enable custom interventions for improved long-term management. Differentiation of these groups may have clinical implications on conditions (e.g. therapy discomfort, comorbid insomnia, poor sleep hygiene) that impact adherence. Support (If Any)

Introduction Patients with narcolepsy are more likely to be obese compared with healthy controls. FT218 is an investigational once-nightly sodium oxybate formulation for the treatment of narcolepsy. Here, we report on changes in weight-related clinical values with FT218 treatment in patients with narcolepsy. Methods This was a randomized, double-blind, placebo-controlled multicenter study in patients with narcolepsy ≥16 years old. Patients were not excluded based on baseline weight or body mass index (BMI). 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). Weight and BMI were measured at baseline and study end. LS mean difference in BMI between FT218 and placebo was analyzed using analysis of covariance. Results A total of 107 patients received FT218 and 105 patients received placebo. At baseline, mean (SD) weight was 81.2 (20.8) kg in the FT218 treatment group and 82.1 (22.5) kg in the placebo treatment group. At end of study (week 13), mean (SD) weight was 80.9 (21.9) kg in the FT218 treatment group and 82.25 (21.6) in the placebo treatment group. At week 13, mean (SD) change in weight from baseline was –1.29 (3.6) kg for FT218 and 0.19 (2.6) kg for placebo; 17.5% of patients receiving FT218 vs 3.8% of patients receiving placebo had ≥5% weight loss. At baseline, mean (SD) BMI was 28.1 (7.8) kg/m2 in the FT218 treatment group and 28.2 (6.6) kg/m2 in the placebo treatment group. At study end (week 13), LS mean (SE) change from baseline in BMI was ‒0.51 (0.13) kg/m2 for patients receiving FT218 and 0.08 (0.13) kg/m2 for patients receiving placebo (LS mean difference [95% CI], ‒0.59 [‒0.95 to ‒0.23]; P=0.001). FT218 was generally well tolerated. Conclusion Patients receiving FT218 experienced a significantly greater decrease in weight and BMI vs placebo. These results suggest that treatment with once-nightly FT218 may provide weight-related benefit for patients with narcolepsy and comorbid weight gain. Support (if any) Avadel Pharmaceuticals

Introduction FT218 is an investigational, once-nightly, controlled-release formulation of sodium oxybate for the treatment of narcolepsy. The purpose of this post hoc analysis of the REST-ON study was to evaluate the effect of FT218 on measures of excessive daytime sleepiness (EDS) in patients with narcolepsy subtypes 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 stratified by narcolepsy subtypes and 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). Assessments of EDS included mean sleep latency (minutes) on maintenance of wakefulness test (MWT) and Clinical Global Impression-Improvement (CGI-I) in sleepiness. Results A total of 190 patients were included in the modified intent-to-treat population (NT1: FT218, n=72; placebo, n=73; NT2: FT218, n=21, placebo, n=24). Patients with NT1 or NT2 receiving FT218 had significant improvement in MWT. LS mean difference in mean sleep latency (minutes) vs placebo for NT1 was 5.97 for 9.0 g (week 13), 7.02 for 7.5 g (week 8), and 4.89 for 6.0 g (week 3; all P Conclusion FT218 had similar efficacy on EDS at evaluated doses in NT1 and NT2, with improvement in MWT and CGI-I greater than placebo. FT218 may provide effective treatment for EDS in patients with narcolepsy, with or without cataplexy. Support (if any) Avadel Pharmaceuticals.