Maintenance Of Wakefulness Test Research Articles

The role of microsleeps to estimate sleepiness at the wheel and near-miss accidents in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is considered a risk factor for sleepiness at the wheel (SW) and near-miss accidents (NMA). To date, there are subjective and objective methods such as the Maintenance of Wakefulness Test (MWT) to investigate sleepiness. However, these methods have limitations. Therefore, a new analysis of the MWT was introduced based on the identification of microsleeps (MS). So, we tested MS analysis to improve the discriminative ability of MWT in recognizing individuals at risk for SW and NMA in a population with OSA. The study was conducted on 100 naïve patients with suspected OSA referred to our Sleep Medicine Unit. All patients performed a full-standard polysomnography and MWT. The MWT was analyzed according to standard criteria, and the presence of MS episodes, the mean MS latency and the MS density (the mean absolute or relative number of MS) were assessed. Microsleeps were observed in 100% of alert or sleepy patients and 47% of the fully alert (P <0.0001). Almost 90% of patients reporting NMA showed episodes of MS during MWT. The occurrence of NMA was related to EDS, MS latency and MS density (P <0.001). The discriminative power for the NMA of MS density measures was higher than that derived from latency analysis, particularly in patients without EDS and with a simultaneous mean sleep latency >33 minutes. MS analysis provides objective evidence of sleepiness and, therefore, could improve the discriminative ability of the MWT in recognizing individuals at high risk for accidents.

Comparative efficacy, safety and benefit/risk of alerting agents for excessive daytime sleepiness in patients with obstructive sleep apnoea: a network meta-analysis

Obstructive sleep apnoea (OSA) is a common chronic respiratory disease associated with a high burden of disabilities related to sleepiness and reduced quality of life. Despite first-line treatment with continuous positive airway pressure (CPAP) therapy, many patients experience residual excessive daytime sleepiness (EDS). The aim of this study is to compare the relative efficacy and safety of medications authorised for this indication in Europe and/or the United States (modafinil/armodafinil, solriamfetol, and pitolisant) for OSA. In this systematic review and network meta-analysis, randomised controlled trials (RCTs) that compared the efficacy and safety of authorised medications for adult patients with OSA were identified by literature searches of PubMed, Embase and ClinicalTrials.gov databases (up to 12 June 2024). The primary efficacy endpoint was combined Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSLER)/Maintenance of Wakefulness Test (MWT) Z-scores. Quality of life (QoL), overall and specific cardiovascular safety, and benefit-risk ratios were calculated. The study was registered with PROSPERO: CRD42023434640. Of 4017 studies identified, a total of 20 RCTs involving 4015 patients were included. Analysis of combined subjective (ESS) and objective (OSLER/MWT) efficacy outcome Z-scores showed that solriamfetol (150mg; effect size [ES]=0.66 [95% CI: 0.36, 0.96]), pitolisant (20mg; ES=0.66 [95% CI: 0.44, 0.88]), and modafinil (200mg; ES=0.54: [95% CI: 0.33, 0.74]); 400mg; ES=0.54 [95% CI: 0.42, 0.65]) had a clinically meaningful improvement in efficacy. P-scores ranked placebo, then pitolisant, modafinil 200mg, modafinil 400mg and solriamfetol for overall safety; and pitolisant, then solriamfetol, modafinil 400mg and modafinil 200mg for benefit-risk ratio. Pitolisant, solriamfetol and modafinil had comparable efficacy for maintaining wakefulness in patients with OSA. Pitolisant had a better safety profile and benefit-risk ratio compared with solriamfetol and modafinil. The overall and cardiovascular safety risk ratios suggest that pitolisant might be the best candidate for patients with OSA with multiple cardiovascular comorbidities. Bioprojet.

Efficacy of once-nightly sodium oxybate (FT218) on daytime symptoms in individuals with narcolepsy with or without concomitant alerting agent use: A post hoc analysis from the phase 3 REST-ON trial

Objective/BackgroundExtended-release, once-nightly sodium oxybate (ON-SXB) significantly improved narcolepsy symptoms in participants in the phase 3, randomized, double-blind, placebo-controlled REST-ON trial. This post hoc analysis of REST-ON data evaluated ON-SXB efficacy in participants with or without concomitant alerting agent use. Patients/methodsParticipants with narcolepsy aged >16 years 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. Primary endpoints in this post hoc analysis included change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement (CGI-I) rating, and number of weekly cataplexy episodes. The secondary endpoints were change from baseline in the Epworth Sleepiness Scale (ESS) score and in objective and subjective disrupted nighttime sleep parameters. Post hoc analyses assessed participants with and without alerting agent use across 6-, 7.5-, and 9-g doses. ResultsIn the modified intent-to-treat population, 119 (63 %) were (ON-SXB, n = 66; placebo, n = 53) and 71 (37 %) were not (ON-SXB, n = 31; placebo, n = 40) taking alerting agents. Regardless of alerting agent use, treatment with ON-SXB resulted in significant improvements vs placebo (all doses, P < 0.05) for MWT, CGI-I, and number of weekly cataplexy episodes. Significant improvements in ESS (all doses, P < 0.05) with ON-SXB vs placebo were observed in the alerting agent use cohort. Directional improvements in ESS were reported with all doses in the no alerting agent use group. ConclusionsRegardless of concomitant alerting agent use, ON-SXB improved daytime and nighttime narcolepsy symptoms vs placebo.

Phenotyping patients treated for obstructive sleep apnea with persistent objective impaired alertness or subjective sleepiness

Background and objectivesSleepiness in patients with obstructive sleep apnea (OSA) is associated with accidental and economic burden, as well as cardiovascular risk. Despite OSA treatment, 10–28 % of patients report residual sleepiness. Its determinants, as well as those of objective impaired alertness remain poorly known. In this study, we investigated factors associated with residual subjective sleepiness and objective impaired alertness in patients treated for OSA. MethodsConsecutive OSA treated patients referred for maintenance of wakefulness tests (MWT) at a tertiary university center were recruited between 2017 and 2020. Clinical data and polysomnography parameters were compared between patients with vs without subjective sleepiness (Epworth Sleepiness Scale, ESS≥11) and those with vs without impaired alertness (at least one trial with sleep onset on MWT). A multivariate logistic model was used to assess explanatory variables of MWT and ESS results. ResultsWe included 141 patients, of whom 12.8 % had both subjective sleepiness and objective impaired alertness, 17.7 % objective impaired alertness only and 9.2 % subjective sleepiness only. Self-reported history of car accident/near miss, smoking history and ESS≥11 were significantly associated with objective impaired alertness whereas residual Apnea-hypopnea Index and CPAP use were not. The only significant variable associated with ESS at the time of MWT evaluation was initial ESS. Patients with objective impaired alertness only were more often smokers (52 % vs 19 %, p = 0.01), had a higher body mass index (BMI) (32 vs 29 kg/m2, p = 0.05), and showed lower initial ESS (11 vs 13, p < 0.01). ConclusionsMore than one third of OSA treated patients referred for MWT have objective impaired alertness and/or subjective sleepiness. Our findings highlight the need for a comprehensive medical assessment including accident history, subjective sleepiness and comorbidities. Particular attention should be paid to smoking patients with high BMI, who are at risk of impaired alertness with no report of subjective sleepiness.

The actigraphic evaluation of daytime sleep in central disorders of hypersomnolence: comparison with polysomnography.

The role of actigraphy in central disorders of hypersomnolence (CDH) is expanding but evidence of reliability with polysomnography (PSG) is scarce and provided only during nighttime. We explored the agreement between actigraphy and continuous 24-hour PSG at CDH diagnosis. Forty-four consecutive drug-naïve patients (28 narcolepsy, 16 idiopathic hypersomnia) underwent actigraphy during 24 hours of free-running PSG, during multiple sleep latency test (MSLT) and 13 of them also during maintenance of wakefulness test (MWT). Daytime and nighttime sleep features and MSLT and MWT mean sleep latencies (mSL) were estimated with the actigraphic algorithms by Cole-Kripke (CK) Sadeh, and University of California San Diego (UCSD). Agreement to corresponding PSG measures was assessed with Bland Altman plots. Nighttime-total sleep time (TST) in narcolepsy was significantly underestimated with CK (bias 27.8min, 95%CI 13.7-41.9) and Sadeh (bias 56.7min, 95%CI 38.8/74.5). Daytime-TST was overestimated in IH and narcolepsy with all algorithms (CK: bias -42.2, 95%CI -67/-17.4; Sadeh: bias -30.2min, 95%CI -52.7/-7.7; UCSD bias -86.9min, 95%CI -118.2/-55.6). 24-hour-TST was overestimated by CK and UCSD in IH (CK: bias -58.5min, 95%CI -105.5/-11.5; UCSD: bias -118.8min, 95% CI -172.5/-65), and by UCSD in narcolepsy (bias -68.8min, 95%CI -109.3/-38.2). In the entire cohort, actigraphy overestimated MSLT mSL but not MWT mSL. Conventional actigraphic algorithms overestimate 24-hour TST in IH and underestimate nighttime TST in narcolepsy. These discrepancies call for cautious application of actigraphy in the diagnostic process of CDH and the development of new quantitative signal analysis approaches.

Weight Loss With Once-nightly Sodium Oxybate for the Treatment of Narcolepsy: Analysis From the Phase III Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) Trial

Individuals with narcolepsy are more likely to be obese than the general population. Changes in weight-related measures with extended-release, once-nightly sodium oxybate (ON-SXB) and characteristics of participants with ≥5% weight loss were assessed in a Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) trial post hoc analysis. REST-ON (NCT02720744) was a Phase III, double-blind, placebo-controlled, multicenter, randomized clinical trial. Participants aged ≥16 years with narcolepsy type 1 (NT1) or NT2 received ON-SXB or placebo for 13 weeks (week 1, 4.5 g; weeks 2-3, 6 g; weeks 4-8, 7.5 g; and weeks 9-13, 9 g). Weight and body mass index were measured at baseline and study end. Weights were similar between groups at baseline (mean [SD]; ON-SXB, 81.2 [20.8] kg; N = 107 [NT1, n = 80; NT2, n = 27]; placebo, 82.1 [22.5] kg; N = 105 [NT1, n = 82; NT2, n = 23]). At week 13 (9 g), mean (SD) weight decreased 1.3 (3.6) kg with ON-SXB and increased 0.2 (2.6) kg with placebo; 17.8% (19/107; NT1, n = 14; NT2, n = 5) of participants receiving ON-SXB had ≥5% weight loss versus 3.8% receiving placebo (4/105; NT1, n = 3; NT2, n = 1; P = 0.001). At week 13, least squares mean (SE) body mass index change from baseline was ‒0.51 (0.13) kg/m2 with ON-SXB and 0.08 (0.13) kg/m2 with placebo (least squares mean difference [95% CI], -0.59 [-0.95 to -0.23] kg/m2; P = 0.001). Excessive daytime sleepiness improved for both groups with ON-SXB, the ≥5% weight-loss subgroup exhibited larger improvement in the Maintenance of Wakefulness Test and Epworth Sleepiness Scale versus the other subgroup (weight loss <5%, no change, or weight gain) (Maintenance of Wakefulness Test, P = 0.019; Epworth Sleepiness Scale score, P < 0.001). Narcolepsy is often associated with obesity, which may increase cardiometabolic risks. ON-SXB, an effective treatment for excessive daytime sleepiness and cataplexy, may be preferred in overweight or obese individuals to provide a more tailored treatment approach. NCT02720744.

Improvement in sleep latency with extended-release once-nightly sodium oxybate for the treatment of adults with narcolepsy: Analysis from the phase 3 REST-ON clinical trial

BackgroundIn the REST-ON clinical trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved with extended-release once-nightly sodium oxybate (ON-SXB) vs placebo (P < 0.001) in participants with narcolepsy. This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness. MethodsParticipants with narcolepsy aged ≥16 years were randomized 1:1 to receive ON-SXB (4.5 g, week 1; 6 g, weeks 2–3; 7.5 g, weeks 3–8; and 9 g, weeks 9–13) or placebo. Mean sleep latency on the MWT was measured across 5 trials of ≤30 min each. Post hoc assessments included percentage of participants whose sleep latency improved ≥5, ≥10, ≥15, and ≥20 min and with a mean sleep latency of 30 min. ResultsSignificantly more participants receiving ON-SXB vs placebo experienced increased mean sleep latency ≥5 min (all doses P < 0.001), ≥10 min (all doses P < 0.001), ≥15 min (6 and 7.5 g, P < 0.001; 9 g, P < 0.01), and ≥20 min (6 g, P < 0.01; 7.5 g, P < 0.001; 9 g, P < 0.05). More participants receiving ON-SXB had mean sleep latency of 30 min vs placebo (6 g, 5.7 % vs 0 %, respectively [P < 0.05]; 7.5 g, 10.5 % vs 1.3 % [P < 0.05]; 9 g, 13.2 % vs 5.1 % [P = 0.143]). ConclusionsSignificantly more participants who received ON-SXB experienced increased mean sleep latency ≥5 to ≥20 min; at the 2 highest doses, >10 % remained awake for the entirety of the MWT. ON-SXB offers a once-at-bedtime treatment option for adults with narcolepsy.

Revised European guidelines for the accreditation of sleep medicine centres.

The accreditation of sleep centres aims to ensure high-quality diagnosis and management of sleep centres. European accreditation standards were introduced in 2006, and were aimed at centres offering inpatient polysomnography and vigilance tests (Mean Sleep Latency Test and Maintenance of Wakefulness Test). Since then, the practice of sleep medicine has evolved, with greater use of ambulatory polysomnography and polygraphy. As a result, in many sleep centres, actual clinical practice, although of a high standard, is no longer in accordance with the published guidelines. The current criteria have been revised with the introduction of level-based criteria. Level 1 and 2 centres offer full diagnostic testing in a laboratory-based setting. Level 1 practices will usually be university affiliated, and have a full teaching and active research role. Level 3 and 4 practices may offer both inpatient and ambulatory testing. Level 3 practices perform polysomnography, while level 4 practices (usually monodisciplinary and focussed on sleep apnea) perform polygraphy only. The role of the medical and paramedical team, training, appropriate equipment, patient care pathways and patient management according to national/European recommendations is underlined for accreditation at each level. It is anticipated that the guidelines will be reviewed and if necessary revised after 4 years.

Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in children: guidance from the American Academy of Sleep Medicine.

Maski KP, Amos LB, Carter JC, Koch EE, Kazmi U, Rosen CL. Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in children: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2024;20(4):631-641.

Eyelid Closure Behavior of Patients with Idiopathic and Nonorganic Hypersomnia, Narcolepsy-Cataplexy, and Healthy Controls in the Maintenance of Wakefulness Test.

Differential diagnosis of central disorders of hypersomnolence remains challenging, particularly between idiopathic (IH) and nonorganic hypersomnia (NOH). We hypothesized that eyelid closure behavior in the maintenance of wakefulness test (MWT) could be a valuable biomarker. MWT recordings of patients with IH, NOH, narcolepsy-cataplexy (NC), and healthy sleep-deprived controls (H) were retrospectively analyzed (15 individuals per group). For each MWT trial, visual scoring of face videography for partial (50-80%) and full eyelid closure (≥80%) was performed from "lights off" to the first microsleep episode (≥3 s). In all groups, the frequency and cumulative duration of periods with partial and full eyelid closure gradually increased toward the first microsleep episode. On the group level, significant differences occurred for the latency to the first microsleep episode (IH 21 min (18-33), NOH 23 min (17-35), NC 11 min (7-19), H 10 min (6-25); p = 0.009), the ratio between partial and full eyelid closure duration (IH 2.2 (0.9-3.1), NOH 0.5 (0-1.2), NC 2.8 (1.1-5), H 0.7 (0.4-3.3); p = 0.004), and the difference between full and partial eyelid closure duration in the five minutes prior to the first microsleep episode (∆full - partial eyelid closure duration: IH -16 s (-35 to 28); NOH 46 s (9-82); NC -6 s (-26 to 5); H 10 s (-4 to 18); p = 0.007). IH and NOH significantly differed comparing the ratio between partial and full eyelid closure (p = 0.005) and the difference between ∆full - partial eyelid closure duration in the five minutes prior to the first microsleep episode (p = 0.006). In the MWT, eyelid closure behavior (∆full - partial) in the period prior to the first microsleep episode could be of value for discriminating NOH from other etiologies of excessive daytime sleepiness, particularly IH.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1

BackgroundNarcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.MethodsWe conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2–selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.ResultsOf the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and −2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were −12.2 in the 30-mg group, −13.5 in the 90-mg group, −15.1 in the 180-mg group, and −2.1 in the placebo group (difference vs. placebo, −10.1 in the 30-mg group, −11.4 in the 90-mg group, and −13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy’s law criteria occurred in 3 patients.ConclusionsIn a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)

0573 Application of AASM Clinical Significance Thresholds to Once-Nightly Sodium Oxybate for Improvement in Narcolepsy Symptoms

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release treatment, was evaluated for the treatment of narcolepsy in adults in the phase 3 REST-ON clinical trial (NCT02720744). The 3 co-primary endpoints, mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement rating, and weekly number of cataplexy attacks (NCA), and the secondary endpoint of Epworth Sleepiness Scale (ESS) score were significant for ON-SXB vs placebo at weeks 3 (6-g dose), 8 (7.5-g dose), and 13 (9-g dose; all P&amp;lt; 0.001). These data were published after the cutoff for inclusion in the American Academy of Sleep Medicine (AASM) clinical practice guidelines for narcolepsy treatment; thus, REST-ON results were analyzed according to AASM clinical significance thresholds (CSTs). Methods Individuals with narcolepsy type 1/2 and age ≥16 years were randomized 1:1 to receive double-blind ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or matching placebo. For each dose (6 g, week 3; 7.5 g, week 8; and 9 g, week 13), least-squares mean (LSM) difference from placebo was calculated for change from baseline in mean sleep latency on the MWT, ESS score, and percentage reduction in NCA. As defined in the 2021 AASM guidelines, CSTs were the following changes vs placebo: MWT, ≥2-minute increase; ESS, ≥2-point decrease; and cataplexy, ≥25% decrease in NCA. Results 190 participants (ON-SXB, n=97; placebo, n=93) were in the modified intent-to-treat population. On the MWT, difference in LSM change from baseline was 5.0, 6.2, and 6.1 minutes for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM change from baseline ESS scores were −2.1, −3.2, and −3.9 for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM percentage reduction in NCA were 26.0%, 34.2%, and 36.1% for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Conclusion Clinically significant improvement in excessive daytime sleepiness and cataplexy per AASM-established criteria was met with ON-SXB 6, 7.5, and 9 g doses. If FDA approved, ON-SXB will provide a once-nightly treatment for improving EDS and cataplexy in adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

0607 Improvement in Sleep Latency With FT218 (Once-Nightly Sodium Oxybate): Analysis From the Phase 3 REST-ON Clinical Trial

Abstract Introduction In the phase 3 REST-ON trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved vs placebo with investigational, extended-release once-nightly sodium oxybate (FT218 [ON-SXB]; P&amp;lt; 0.001). This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness (EDS). Methods Participants (≥16 years) with narcolepsy type 1/2 were randomized 1:1 to double-blind ON-SXB or placebo. Doses were 4.5 g week 1, 6 g weeks 2‒3, 7.5 g weeks 4‒8, and 9 g weeks 9‒13. Mean sleep latency on the MWT was measured in 5 trials up to 30 minutes each at baseline and weeks 3, 8, and 13. Percentage of participants with improvement of ≥5, ≥10, ≥15, and ≥20 minutes from baseline and with mean sleep latency=30 minutes were assessed. Two-sided P values were calculated using Fisher exact test. Results The modified intent-to-treat population included 190 participants (ON-SXB, n=97; placebo, n=93). At baseline, mean (SD) sleep latency was as follows: ON-SXB, 5.0 (3.1) minutes; placebo, 4.7 (2.6) minutes. More participants receiving ON-SXB vs placebo had mean MWT=30 minutes at weeks 3 (6 g; 5.7% vs 0%; P&amp;lt; 0.05), 8 (7.5 g; 10.5% vs 1.3%; P&amp;lt; 0.05), and 13 (9 g; 13.2% vs 5.1%; P=0.14). A significantly greater percentage of participants receiving ON-SXB vs placebo had improved mean sleep latency ≥5 to ≥20 minutes over baseline at all doses (6 g: ≥5 min, 57.5% vs 25.0%; ≥10 min, 35.6% vs 9.1%; ≥15 min, 18.4% vs 3.4%; ≥20 min, 10.3% vs 1.1% [all P&amp;lt; 0.01]; 7.5g: ≥5 min, 63.2% vs 28.2%; ≥10 min, 43.4% vs 11.5%; ≥15 min, 31.6% vs 3.8%; ≥20 min, 15.8% vs 1.3% [all P&amp;lt; 0.001]; 9 g: ≥5 min, 66.2% vs 37.2% [P&amp;lt; 0.001]; ≥10 min, 50.0% vs 19.2% [P&amp;lt; 0.001]; ≥15 min, 32.4% vs 10.3% [P&amp;lt; 0.01]; ≥20 min, 17.6% vs 6.4% [P&amp;lt; 0.05]). Conclusion Clinically significant improvements in EDS occurred with 6-, 7.5-, and 9-g doses of ON-SXB. At the 2 highest doses, &amp;gt;10% of participants remained awake for the entire MWT. If ON-SXB is granted FDA approval, adults with narcolepsy will have a once-nightly treatment to improve EDS. Support (if any) Avadel Pharmaceuticals

0551 Predicting Daytime Alertness Impairment in Obstructive Sleep Apnea

Abstract Introduction Obstructive sleep apnea (OSA) reduces daytime alertness leading to social and occupational impairment. The Maintenance of Wakefulness Test (MWT), a gold-standard test for daytime alertness, is time-consuming and not routinely available in clinical practice. We examined EEG-based and clinical parameters derived from diagnostic polysomnography (PSG) as predictors of alertness impairment in adults with OSA. Methods Eighty-two participants with untreated OSA on diagnostic PSG (apnea hypopnea index, AHI ≥5/hour), enrolled in a two-center clinical trial were included. The day following PSG, each participant completed four 40-minute MWT and four 10-minute Psychomotor Vigilance Tests (PVT). The outcomes were MWT mean sleep latency (MSL) and PVT lapses (reaction time ≥500 milliseconds, square root transformed). Three multiple linear regression models were used: 1. “standard predictors” (total sleep time, TST, percent REM and slow wave sleep, AHI, time &amp;lt; 90% oxygen saturation, and arousal index), 2. “novel predictors” derived by spectral analysis and averaged across right and left central EEG (normalized EEG power, odds ratio product; ORP parameters, and spindle characteristics), and 3. combined standard and novel predictors. Age, sex, and body mass index (BMI) were included in each model, and backward elimination (step AIC) was used for models 2 and 3. Results Participants were middle-aged (mean ± standard deviation, SD 53.5±8.7 years), with moderate OSA (AHI 33.8±18.2) and daytime sleepiness (Epworth Sleepiness Scale 11.7±3.9), and 86% were men. The adjusted r2 for MSL were: model 1=0.09, model 2=0.16, and model 3=0.27, and PVT lapses were: model 1=0.09, model 2=0.31, and model 3=0.34. For MSL, the significant predictors in model 3 included TST (t-statistic -3.59, p=0.0007), REM% (2.51, p=0.01), ORP-9 (2.95, p=0.004), ORP NREM (-3.15, p=0.002), spindle frequency (-2.95, p=0.004), and normalized EEG power (-2.59, p=0.01). For PVT lapses, model 3 predictors included 2.25-2.5 ORP% (-2.91, p=0.005), normalized EEG power (3.22, p=0.002), spindle power (-4.30, p&amp;lt; 0.0001), spindle frequency (2.83, p=0.006), and sex (men vs. women, -2.56, p=0.01). Conclusion We have identified several novel PSG EEG-based predictors of impaired daytime alertness in OSA that will improve occupational evaluation and prognostication in OSA after future validation. Support (if any) National Institutes of Health, UM1-HL112856, UL1TR001422, and UL1TR002003.

Efficacy of Once-Nightly Sodium Oxybate (FT218) in Narcolepsy Type 1 and Type 2: Post Hoc Analysis From the Phase 3 REST-ON Trial.

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). Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5g, week 1; 6g, weeks 2-3; 7.5g, weeks 4-8; and 9g, 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. 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<0.001) and NT2 (6 and 9g, P<0.05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, P<0.001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (P<0.001), nocturnal arousals (P<0.05), and ESS scores (P≤0.001) were reported for NT1 with directional improvements for NT2. 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.

0579 Long-Term Safety of Once-Nightly Oxybate for Narcolepsy: RESTORE Study Interim Analysis of Data

Abstract 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&amp;lt; 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

0603 Characterization of Patients Who Had ≥5% Weight Loss With FT218 (Once-Nightly Sodium Oxybate): Post Hoc Analysis From REST-ON

Abstract 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&amp;lt; 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 &amp;gt;30 kg/m2); none were underweight (BMI &amp;lt; 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&amp;lt; 0.05; Epworth Sleepiness Scale score, P&amp;lt; 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

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

BackgroundSleep 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. MethodsAdults 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 conclusionAmong 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.

Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.

Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. None.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1mg kg-1 , and p < 0.001 at 1mg kg-1 and 10mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1mg kg-1 and 3mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n=18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8min with danavorexton 44 mg and 30.2min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p=0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.