bluuebunny/crossref_metadata_2025_split huggingface dataset:
0579 Long-Term Safety of Once-Nightly Oxybate for Narcolepsy: RESTORE Study Interim Analysis of Data
Authors: Stern Thomas , Roy Asim , Shapiro Colin , Harsh John , Ajayi Akinyemi , Ibrahim Sally , Dubow Jordan , Gudeman Jennifer 
Published: May 2023

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&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
0582 Polysomnography Parameters Predict Mean Sleep Latency Test Results Using Machine Learning
Authors: Araujo Matheus , Mora-Munoz Laura , Andrews Noah , Foldvary-Schaefer Nancy 
Published: May 2023

Abstract

Introduction
The mean sleep latency test (MSLT) objectively measures mean sleep latency (MSL) and sleep onset during REM periods (SOREMPs) in the absence of external alerting factors used for diagnoses of central hypersomnolence disorders. Polysomnography (PSG) is routinely performed the night before an MSLT. We explored the use of PSG variables at the individual level to predict MSL and SOREMPs assisted by machine learning methods.

Methods
802 PSG/MSLTs from 796 patients (75% female, age 34 years[SD:12.1], BMI 27.9[SD:7.6], ESS 13.9[SD:4.9]) performed at Cleveland Clinic Sleep Disorder Center from 2012 to 2022 were included. We used 5-fold cross-validation experimental settings where five types of machine learning models (logistic regression, support vector machine, multilayer perceptron, random forest, XGBoost) were trained for two separated binary classification tasks: predict MSL&lt; 8 minutes (343 out of 802) and SOREMP&gt;=2 (234 out of 802). Within each fold, we performed a feature selection analysis on the training set in 39 PSG and demographic variables based on Analysis of Variance (ANOVA) with p &lt; 0.05. A random search approach with 1000 combinations was used for machine learning hyperparameter tuning. The area under the ROC (AUC-ROC) score was used to rank the methods based on the test set of each fold (mean+SD). We retrained the best machine learning configuration in a new single train/test (80%/20%) split to evaluate the top 5 features that were more relevant to the best model by computing their Shapley Additive Explanations values (SHAP).

Results
XGBoost had the best average AUC-ROC for predicting MSL of 0.71 + 0.04. Its most important features out of 14 selected were total recording time, percentage of sleep time, total wake time after sleep onset, non-supine sleep time, and sleep efficiency. Random forest was the best for SOREMP prediction with AUC-ROC of 0.75 + 0.05, and the most important features were REM latency, age, and Epworth Sleepiness Scale score, percentage of time on REM, minimum oxygen saturation, out of 13 selected.

Conclusion
PSG the night prior to MSLT provides predictive information that can be leveraged to anticipate MSLT results on the individual level. This work provides the foundation to better identify patients with central hypersomnolence disorders.

Support (if any)
0583 Prevalence and Incidence of Narcolepsy in the US General Population
Authors: Ohayon Maurice , Cote Marie-Lise 
Published: May 2023

Abstract

Introduction
Narcolepsy is a sleep disorder characterized by cataplexy, hypersomnolence, sleep fragmentation and manifestations of various REM sleep abnormalities. It is a rare orphan disorder and therefore, its prevalence is almost exclusively estimated by derivate from clinical samples. Consequently, the objective of this study was to assess the prevalence of narcolepsy in an US general population representative sample.

Methods
The epidemiological study was carried with 15,927 individuals from 15 US States using the Sleep-Eval system. The longitudinal study was in eight of these 15 states: 12,218 subjects were interviewed by phone during the first wave and 10,931 at the second wave three years apart. Prevalence rates were calculated with the large sample while the Incidence was calculated on the subjects who participated in both interviews (N=10,931). The same interview was completed in both waves. For the purpose of this study, an algorithm was created using the answers provided for each symptom to reach a diagnosis conclusion of Narcolepsy type 1 (NT1) or Narcolepsy type 2 (NT2) according to ICSD3.

Results
NT1 was identified in 0.0126% (95% CI: 0.000%-0.03%) of the whole sample. Prevalence was similar between men and women. NT1 did not differ significantly by age groups although it was slightly higher in individuals younger than 35 y.o. (0.0201% (95% CI: 0.000%-0.06%)) compared to 0.016% (95% CI: 0.000% to 0.047%) in the 35 to 54 y.o. group and none in the oldest group. NT2 was observed in 0.0251% (95% CI: 0.0005%-0.0497%) of the sample. NT2 prevalence was comparable between men and women and among age groups. Overall, 66.7% of narcolepsy individuals in the sample identified by Sleep-Eval were already diagnosed as such by a physician. The incidence rate was also very low at 0.0026% per year.

Conclusion
Our results support the fact that narcolepsy is indeed a rare disorder affecting 37.7 individuals per 100,000 inhabitants with a relatively low incidence at 2.6 individuals per 100,000 inhabitants per year. Recognition of the disorder by a physician was relatively high in the United States with 2/3 of the cases being already diagnosed.

Support (if any)
Data analysis study were funded by Tris Pharma and Takeda Pharmaceutical Company.
0584 Sodium Oxybate Treatment Patterns in Narcolepsy Patients: A Propensity Score–Matched Cohort Study Subanalysis
Authors: Krahn Lois , Lipford Melissa , Singh Gajinder Pal , Asfahan Shahir , Moore J Layne , Tippmann-Peikert Maja , Kumar-M Praveen , Ip Wui , Awasthi Samir , Gudeman Jennifer 
Published: May 2023

Abstract

Introduction
Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients.

Methods
Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose.

Results
Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1).

Conclusion
Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen.

Support (if any)
Avadel Pharmaceuticals
0585 A four-week randomized, double-blind, placebo-controlled, phase 2 study of mazindol ER in the treatment of narcolepsy
Authors: Corser Bruce , Stern Thomas , Bogan Richard , Franco Jennifer , Apostol George , Konofal Eric , Morse Anne , Rosenberg Russell , Kushida Clete , Thorpy Michael 
Published: May 2023

Abstract

Introduction
Mazindol is the first partial orexin 2 receptor agonist and triple monoamine reuptake inhibitor in development for the treatment of narcolepsy. A novel extended release (ER) formulation was developed to allow once-daily dosing and may provide a differentiated treatment option. (ClinicalTrials.gov Identifier: NCT04923594).

Methods
Study NLS-1021 was a Phase 2, four-week, double-blind, randomized, placebo-controlled study of mazindol ER (NLS-2) for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy type 1 (NT1) or type 2 (NT2). Efficacy, safety, tolerability, and pharmacokinetics were assessed. Adult subjects diagnosed with NT1 or NT2 and washed out of narcolepsy medications at baseline were randomized 1:1 to receive placebo or 2 mg mazindol ER once-daily for one week followed by 3 mg once-daily for three weeks. The primary efficacy endpoint was the change from baseline at Week 4 in excessive daytime sleepiness using the Epworth Sleepiness Scale (ESS). Secondary efficacy endpoints included improvement in weekly cataplexy attacks and overall disease severity as rated by the investigators (Clinician Global Impression of Severity; CGI-S) and patients (Patient Global Impression of Severity; PGI-S).

Results
Sixty-seven subjects were randomized (n = 33 NLS-2; 34 placebo). The baseline mean [SD] ESS score was 17.9 [2.97] in subjects receiving NLS-2 and 18.0 [3.05] in placebo. NLS-2 met the pre-specified primary endpoint, demonstrating a statistically significant improvement in EDS with a least-squares mean [SE] difference (NLS-2-placebo) of –3.6 [1.33] in the ESS total score at Week 4 (p = 0.0081). Observed mean change from baseline in ESS total score was –7.1 [5.6] for NLS-2 and –3.2 [5.3] for placebo. In NT1 subjects, baseline weekly number of cataplexy episodes was 14.1 [10.8] in subjects receiving NLS-2 (n=11) and 15.0 [10.2] in placebo (n=12). At Week 4, the weekly number of cataplexy episodes was reduced to 4.1 with NLS-2 and to 8.5 with placebo. NLS-2 was generally safe and well-tolerated with no severe or serious adverse events or discontinuations due to adverse events.

Conclusion
In subjects with narcolepsy, NLS-2 significantly improved EDS and the number of cataplexy attacks compared with placebo.

Support (if any)
NLS Pharmaceutics
0593 Functional Outcomes of Sleep Questionnaire in a phase 2 study of mazindol ER in narcolepsy
Authors: Bogan Richard , Stern Thomas , Corser Bruce , Franco Jennifer , Konofal Eric , Apostol George , Morse Anne , Rosenberg Russell , Thorpy Michael , Kushida Clete 
Published: May 2023

Abstract

Introduction
Efficacy secondary outcome measure Functional Outcomes of Sleep Questionnaire, Short Version (FOSQ-10] was collected in the Phase 2 (POLARIS, NLS-1021), multicenter (n=21) study of mazindol ER in adult participants with narcolepsy type 1 (NT1) or type 2 (NT2) (ClinicalTrials.gov Identifier: NCT04923594).

Methods
Adults diagnosed with NT1 or NT2 who were washed out of narcolepsy medications at baseline were included into the study. Patients were treated with mazindol ER (NLS-2) at once-daily 2 mg for one week and once-daily 3 mg thereafter or matching placebo (PBO) on a 1:1 ratio. Throughout the study, FOSQ-10 was assessed and compared vs. PBO scores at baseline. Treatment emergent adverse events (TEAEs) were assessed.

Results
Sixty-seven participants were randomized (NT1 33.3% in NLS-2 group versus 35.3% in PBO). At baseline, the mean [SD] FOSQ-10 score was 23.1 (5.5) for the NLS-2 arm and 23.7 (7.1) for the PBO arm. After four weeks of treatment, there was an increase of 4.1 (9.0) on NLS-2 vs an increase of 0.4 (6.9) on PBO (p = 0.04). Similar magnitude of effect was seen in NT1 patients (D = +4.7, p = 0.08, n = 20) as well as NT2 patients (D = +3.0, p = 0.20, n = 44) No serious adverse events were reported. The most frequently reported TEAEs (&gt;5%) were dry mouth, nausea, decreased appetite and tachycardia.

Conclusion
Mazindol ER resulted in significant improvements of functional outcome measure FOSQ-10 These secondary outcome results support the efficacy of mazindol ER on cataplexy attacks, in NT1 patients, and on sleepiness, in NT1 as well as in NT2 patients.

Support (if any)
NLS Pharmaceutics
0594 Hybrid Decentralized Recruitment Approach to a Rare Disease Registry for Pediatric Patients With Narcolepsy: The CATNAP® Registry
Authors: Nichols Deborah , Macfadden Wayne , Leary Eileen , Gwadry-Sridhar Femida , Owens Judith 
Published: May 2023

Abstract

Introduction
Limited information is available on the natural history, presentation, and management of pediatric narcolepsy. CATNAP® is a retrospective and prospective, longitudinal, multicenter, web-based pediatric narcolepsy registry (NCT04899947). The primary objectives are to improve understanding of the natural history of pediatric narcolepsy, characterize symptom presentation and diagnosis, and understand treatment practices and outcomes. After registry initiation, an innovative decentralized approach was added to adapt to the post-COVID-19 environment and reach additional participants via social media.

Methods
Eligible children/adolescents (&lt; 18 years) with confirmed narcolepsy were recruited. Participants, caregivers, and clinicians, leveraging web-based portals, answered questions on sociodemographic characteristics; diagnostic, medical, and treatment history; comorbidities; and disease progression. Participants continue to answer follow-up questions annually until they reach 25 years of age or decline to participate. Since registry initiation in September 2020, 17 sites have been activated, including a virtual site launched in August 2022. Hybrid decentralized recruitment required a new web interface, Institutional Review Board submissions, and 7-week social media campaign (press release, 5 targeted posts) to accompany the virtual site launch.

Results
A total of 126 participants have been enrolled (signed consent), including 75 participants at 16 physical sites over the first 2 years and 51 participants at the virtual site over 10.6 weeks. Rates of engagement (eg, clicks, likes, and shares) for Instagram (3.2%), LinkedIn (7.2%), and Twitter (2.4%) exceeded “good engagement rate” benchmarks for these platforms. Although the engagement rate for Facebook was below benchmarks (&lt; 2%), the absolute number of “clicks” (29) was the largest among social media platforms in the campaign.

Conclusion
A hybrid recruitment approach for CATNAP demonstrates incorporation of patient-driven considerations into clinical trial design and increases access to future real-world data registries and studies. Decentralization likely increases enrollment and may enable representation from more diverse regions and populations. This is especially important for rare diseases. The CATNAP Registry provides valuable information on the experience and management of pediatric narcolepsy, which will benefit patients and caregivers, inform clinical decision-making, and potentially contribute to development of new treatments. This successful implementation of a hybrid approach with physical and virtual sites could inform design of future registries.

Support (if any)
Jazz Pharmaceuticals
0596 Overlap of Psychiatric Disorders with Central Hypersomnia
Authors: Kaji Sanjay , Workman Kimberly , Stoddart Jeremy , Sundar Krishna 
Published: May 2023

Abstract

Introduction
In sleep clinics, hypersomnia is a frequently encountered condition. While narcolepsy and idiopathic hypersomnia are discrete diagnoses that typically do not have co-existing psychiatric co-morbidities, sleep practitioners often have to address mental illness and/or psychotropic medication needs in these patients with hypersomnia. The reasons for co-occurrence of idiopathic hypersomnia and narcolepsy with psychiatric disorders is not well understood. This study aimed to assess the degree of overlap between psychiatric diagnoses with central hypersomnias and the temporal relationship between the development of hypersomnia and psychiatric conditions.

Methods
Using the University of Utah EPIC database, patients with diagnoses of idiopathic hypersomnia or narcolepsy encountered over the last decade were identified. Out of the 307 available medical records, only those that met strict criteria for diagnosis of narcolepsy and idiopathic hypersomnia were included. Medical records were reviewed for the presence of psychiatric disorders and psychotropic medication use, and to assess the prevalence of mental illness with central hypersomnia.

Results
Out of 119 patients that met ICSD-2 criteria for central hypersomnia, 37 were diagnosed with narcolepsy type 1 (T1N), 59 with narcolepsy type 2 (T2N) and 23 with idiopathic hypersomnia (IH). There were 69/119 (58%) patients with central hypersomnia that had psychiatric comorbidities with 23/37 (62%) of T1N, 32/59 (54%) of T2N and 14/23 (60%) of IH experiencing psychiatric problems. Approximately 45% were prescribed antidepressants or a mood stabilizer either before, during or after diagnosis of a central hypersomnia. 46% of patients on stimulants alone vs. 23% of patients on sodium oxybate had a concurrent psychiatric diagnoses or psychotropic medication use.

Conclusion
Given the degree of overlap between psychiatric disorders and central hypersomnias, further research is necessary to understand whether this overlap is a result of common neurological substrates driving these disorders or whether the hypersomnia is from comorbid psychiatric disorder or psychotropic medication use. The highest prevalence of psychiatric illness was seen with T1N. Patients with hypersomnia on sodium oxybate had lower rates of psychiatric co-morbidities. Whether these findings point to more optimal diagnosis and treatment of underlying hypersomnia with reduced need for psychotropic medication needs to be understood.

Support (if any)
None
0599 Sleep Stage Transition Patterns Among Youth with CNS Disorders of Hypersomnolence
Authors: Pizza Fabio , Maski Kiran , Zhu Guangyu , Zhang Bo , Scammell Thomas , Plazzi Giuseppe , Behn Cecilia Diniz 
Published: May 2023

Abstract

Introduction
Narcolepsy type 1 (NT1) is associated with frequent sleep stage transitions during nocturnal sleep. In this study, we report the pattern of sleep stage transitions that occurs and its relationship to CSF-orexin levels among pediatric NT1 patients. Furthermore, we study the patterns of sleep stage transitions in patients with Narcolepsy Type 2 (NT2) and Idiopathic Hypersomnia (IH).

Methods
We conducted a retrospective, cross-sectional study of nocturnal polysomnograms (PSGs) of a cohort of patients ages 5-21 years with NT1 (n=160), NT2 (n=24), IH (n=28), and subjectively sleepy controls (n=115) collected at Boston Children’s Hospital, Boston, MA and University of Bologna, Bologna, Italy. We compared the patterns of transitions between different sleep/wake stages during the nocturnal PSG by diagnostic group as well as by CSF-orexin level (low ≤110 pg/ml; normal &gt;110 pg/ml) using chi-square testing that was adjusted for multiple comparisons.

Results
NT1 demonstrated a pattern of transitions from wake and all sleep stages except N3 sleep vs. controls, NT2, and IH with frequent transitions between wake and N1 sleep and less frequent transitions from N1 sleep to N2 sleep. The NT2 group had a distinct pattern of transitions from N1 vs. controls with more frequent transitions to REM sleep and less frequent transitions to N2. The IH group showed a similar pattern of sleep/wake transitions vs. controls. The pattern of transitions for the low CSF orexin group was different for all sleep stages and wake vs. normal level with frequent transitions from N2 sleep and REM sleep to wake and N1 sleep.

Conclusion
Young NT1 patients have a unique pattern of transitions between sleep/wake states. These findings are further confirmed by CSF orexin level. NT2 patients have a pattern of sleep stage transitions more similar to controls with the exception of the transitions from N1 sleep suggesting dysregulation of this light sleep stage. In contrast, the IH group shows patterns of transitions between sleep stages and wake that are similar to controls. Overall, results support differing sleep phenotypes demarcating these patients with severe daytime sleepiness.

Support (if any)
National Institutes of Health grant 5K23NS104267-2 to K.M