bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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< 8 minutes (343 out of 802) and SOREMP>=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 < 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

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

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

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

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 (>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

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 (< 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 (< 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

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

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 >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
0600 Subjective reporting of Disrupted Nighttime Sleep and Associated Functional Outcomes in NT1 Youth
Authors: Heckler Gillian , Worhach Jennifer , Scammell Thomas , Maski Kiran
Published: May 2023

Introduction

In people with NT1, Disrupted Nighttime sleep (DNS) can be measured using the Wake/N1 Index, the number of transitions from sleep to wake or N1 sleep per hour of sleep. However, it remains unknown if this DNS measure correlates with sleep quality and daytime symptom burden. We compared the Wake/N1 Index with perceptions of sleep quality in young NT1 patients and healthy controls (HC) and determined its relationships with subjective sleep quality, daytime behavior, and cognition across groups.

Methods

25 HC (mean age 13.4 years) and 23 NT1 participants (mean age 15.8 years) completed a 15-item survey after sleeping a minimum of 6 hours during an in-lab polysomnogram. The survey included questions from validated surveys on habitual sleep quality, fatigue, sleepiness and cognitive function. We dichotomized survey responses into frequent or infrequent concerns. We compared responses using Fisher Exact tests and logistic regression to determine associations with the Wake/N1 Index. NT1 participants could take SSRI/SNRI medication for cataplexy but were weaned off wake-promoting medications and excluded if on an oxybate.

Results

Compared to HC, NT1 participants reported more frequent restless sleep, nighttime moaning/groaning/talking, tossing and turning, and waking more than once during the night (p’s < 0.02) and showed a trend for more leg kicking during sleep (p=0.06). NT1 and HC groups did not differ in falling asleep quickly and returning back to sleep quickly after waking. NT1 subjects reported more frequent fatigue, difficulty keeping thoughts focused, difficulty thinking clearly and making decisions, problems remembering things, and dozing/napping inadvertently. Across groups and controlling for age, the Wake/N1 Index was associated with subjective reporting of waking more than once (OR=3.2) as well as problems with daytime alertness (OR 1.5) and fatigue (OR 1.4).

Conclusion

Young NT1 patients describe DNS as a multi-factorial complaint comprising problems with sleep maintenance, restless sleep, parasomnia-like behaviors, and periodic limb movements. The Wake/N1 Index is associated with perceptions of waking at night as well as daytime alertness and fatigue across groups. This work suggests that Wake/N1 Index could be a useful measure of sleep instability and inform future research on DNS impact on daytime function.

Support (if any)

NIH 5K23NS104267-2, Jazz Pharmaceuticals
0601 An Atypical Cause of Hallucinations in Type 1 Narcolepsy
Authors: Unger Jason , Arora Subodh , Creamer Jennifer , Hediger Lacie
Published: May 2023

Introduction

Narcolepsy is a disorder of hypersomnolence affecting between 1:5000-1:10,000 individuals. Type 1 Narcolepsy can be differentiated from Type 2 Narcolepsy by the presence of cataplexy. Visual hallucinations are reported in 50-80% of T1 Narcoleptics and ~25% of T2 Narcoleptics. This is thought to be a REM-related phenomenon occurring at transitions of sleep and wakefulness. Auditory hallucinations or paranoid delusions are more rare. We report a case of a 17 year old patient who experienced psychotic symptoms after trialing more than one class of stimulants.

Methods

This was primarily a retrospective case review. A subsequent literature search was performed reviewing similar reports of psychosis secondary to medications used to treat Narcolepsy.

Results

The patient is a 17 year old female who was 10 years old at the time of her diagnosis of Narcolepsy T1. At onset, the patient had reported cataplexy and visual hallucinations occurring at the time of sleep onset and wakening. After finding minimal help with stimulants, by age 15 she was maintained on sodium oxybate 6 grams per night for her cataplexy and started modafinil 200mg BID for wakefulness. She then reported new auditory hallucinations and hyperreligiosity and was admitted to inpatient psychiatry where both medications were discontinued. She was subsequently started on extended release methylphenidate and within 2 months had a recurrence of auditory hallucinations and hyperreligiosity resulting in two consecutive inpatient hospitalizations for psychosis.

Conclusion

Psychosis induced by medications for Narcolepsy has been reported in the literature where sodium oxybate and stimulants are the most common offending agents. Symptoms primarily related to modafinil or armodafinil are less frequently described. Most medications used to treat Narcolepsy may directly or indirectly act on dopamine pathways, which in theory have the propensity to lead to psychotic symptoms. Small studies of patients with Narcolepsy have reported psychosis in less than 1-2% of Modafinil users. Larger meta-analyses of patients with both Narcolepsy and Schizophrenia, have not found an increased likelihood for uncontrolled psychotic symptoms while on modafinil. Further case studies are needed to elucidate the relationship between stimulants and risk of psychosis in Narcolepsy patients.

Support (if any)
0602 Burden of Narcolepsy in Japan: A Nationwide Real-world Database Study from The Perspectives of Direct Medical Cost and Comorbidity
Authors: Kamada Yuta , Imanishi Aya , Chiu Shih-Wei , Yamaguchi Takuhiro
Published: May 2023

Introduction

In Japan, narcolepsy is not currently covered by a medical expense assistance program (e.g., System of Medical Payment for Services and Support for Persons with Disabilities). The people living with narcolepsy in Japan have been speaking up against current situation. However, to the best of our knowledge, reports about economic burden (direct + indirect) and comorbidity are limited in Japan. The study objectives were to reveal the burden of narcolepsy from the perspectives of direct medical cost and comorbidity, and also to compare it to epilepsy as a benchmark, which is covered by the above program.

Methods

Patients diagnosed with narcolepsy (>1 ICD-10code [G47.4]) were identified from April 2017 to March 2022 using an employment-based health insurance claims data compiled by JMDC Inc. Patients with epilepsy (>2 ICD-10code [G40]) were 1:4 matched for age, sex, insurance status, and observation period. Direct medical cost (including inpatient, outpatient, and medication) and comorbidity were analyzed. The 95% confidence intervals (CI) for differences of two diseases were calculated by bootstrapping (direct medical cost) or conditional logistic regression model (comorbidity). The protocol was approved by the Ethics Review Committee of the Tohoku University Graduate School of Medicine.

Results

We identified 4,594 patients with narcolepsy (sex; 58.7% males, age; 35.2 ± 12.7 years) and 18,376 patients with epilepsy (sex; 58.7% males, age; 35.8 ± 12.2 years). Overall annual direct medical cost per person was 349,188 JPY (narcolepsy) and 521,495 JPY (epilepsy). The difference was -172,307 JPY (95%CI; -199,793JPY to -146,567 JPY). Sleep apnea syndrome (odds ratio; 7.37, 95% CI; 6.52 to 8.33), ADHD (3.21, 2.86 to 3.61), and obesity (1.51, 1.22 to 1.87) were more prevalent in narcolepsy than in epilepsy, while developmental disorders (0.34, 0.27 to 0.41), fracture (0.78, 0.68 to 0.90), and high blood pressure (0.78, 0.71 to 0.86) were less prevalent.

Conclusion

This study showed direct medical cost and comorbidity of narcolepsy in Japan, which helps future discussion on the medical expense assistance program for people living with narcolepsy. Further research is needed to show the indirect economic burden to clarify the burden of narcolepsy.

Support (if any)

Eisai Co., Ltd.
0603 Characterization of Patients Who Had ≥5% Weight Loss With FT218 (Once-Nightly Sodium Oxybate): Post Hoc Analysis From REST-ON
Authors: Roth Thomas , Morse Anne , Bogan Richard , Roy Asim , Dubow Jordan , Gudeman Jennifer , Dauvilliers Yves
Published: May 2023

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
0607 Improvement in Sleep Latency With FT218 (Once-Nightly Sodium Oxybate): Analysis From the Phase 3 REST-ON Clinical Trial
Authors: Thorpy Michael , Shapiro Colin , Kushida Clete , Ohayon Maurice , Dubow Jordan , Gudeman Jennifer
Published: May 2023

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< 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< 0.05), 8 (7.5 g; 10.5% vs 1.3%; P< 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< 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< 0.001]; 9 g: ≥5 min, 66.2% vs 37.2% [P< 0.001]; ≥10 min, 50.0% vs 19.2% [P< 0.001]; ≥15 min, 32.4% vs 10.3% [P< 0.01]; ≥20 min, 17.6% vs 6.4% [P< 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, >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
0612 Understanding Narcolepsy Treatments From the Patient’s Perspective: A Survey of People Living With Narcolepsy
Authors: Ortiz Luis , Morse Anne , Krahn Lois , Lavender Maggie , Horsnell Matthew , Cronin Dianna , Schneider Beth , Gudeman Jennifer
Published: May 2023

Introduction

Individuals with narcolepsy were surveyed to better understand desired treatment outcomes and how those outcomes map to commonly experienced symptoms, treatment awareness, and medication usage.

Methods

In February 2022, an email invitation to a 27-question online survey was sent to US members of MyNarcolepsyTeam, a social network of >9,800 members.

Results

In total, 110 members completed the survey. The most frequently mentioned desired treatment goals aligned with the most commonly reported symptoms: being able to stop sleeping during the day (77%); increased energy (62%); improved memory (36%); improved productivity (29%); improved sleep continuity (22%); and for patients with narcolepsy type 1, reducing cataplexy (28%). A common theme was desire for a medication that would treat the underlying cause and not just improve specific symptoms. In one patient’s own words: “I want to see treatments that target the root problem of poor nighttime sleep rather than just being a band-aid for [excessive daytime sleepiness] EDS, like stimulants are.” Only a small percentage of respondents (13%) were not currently taking any type of medication to address narcolepsy symptoms. 64% were currently taking ≥2 medications to address both the daytime and nighttime symptoms. Most commonly mentioned current treatments were dextroamphetamine-amphetamine (30%), modafinil (22%), melatonin (16%), armodafinil (15%), venlafaxine (14%), and oxybate (14%). Notably, 33% of patients taking sodium oxybate chose sleeping through the night as a desired outcome. Most common sources for learning about treatments were narcolepsy-specific websites (53%), MyNarcolepsyTeam specifically (45%), the patient’s doctor (42%), scientific articles (42%), and advocacy groups (37%).

Conclusion

Patients experience a wide range of both daytime and nighttime symptoms and seek relief from both sets of symptoms including EDS (93%), fatigue (79%), cognitive challenges (74%), as well as sleep disruptions (63%). As a result, the majority need multiple medications. Understanding the experiences and needs of people with narcolepsy provides significant opportunities for clinicians to support, educate, and treat their patients holistically. Additionally, content readily available on the internet, whether it is narcolepsy-specific content or social networks, helps patients proactively discuss options with their clinician.

Support (if any)

Avadel Pharmaceuticals
0614 Characterizing Sleep in Early-Morning Shift Workers at Risk for Shift Work Disorder
Authors: Zitting Kirsi-Marja , Gilmore Katherine , Elkhadem Alexandria , Shaw Samantha , Deminico Marena , Lockyer Brandon , Quan Stuart , Wang Wei , Issa Nicolas , Williams Jonathan , Duffy Jeanne , Czeisler Charles
Published: May 2023

Introduction

Shift work is increasingly common in our 24/7 society and can cause sleep disturbances and excessive sleepiness. Roughly 10-43% of shift workers are diagnosed with shift work disorder (SWD), characterized by excessive sleepiness accompanied by reduced sleep duration and/or insomnia. While more individuals work early morning shifts (shift start 3-6AM) compared to overnight shifts, few studies have investigated this population. The aim of this study was to characterize sleep in a population of early-morning shift workers.

Methods

We characterized sleep in early-morning shift workers (18-65yrs) from New England who were screened for a clinical trial of a wake-promoting agent. Pre-screening consisted of the Epworth Sleepiness Scale (ESS) and a Shift Work Disorder Questionnaire (SWD); screening consisted of the Pittsburg Sleep Quality Index Questionnaire Questionnaire (PSQI) ; a physical exam including an ECG, CBC, urinalysis, and comprehensive metabolic panel; a home sleep test (HST), a Monitored Wakefulness Test (MWT); a physician evaluation of their excessive sleepiness (Clinical Global Impression [CGI]); and a self-evaluation regarding how sleepiness affected their everyday life (Patient Global Impression [PGI]). Only data from consented individuals who met the initial inclusion criteria of being high risk for SWD were included in the analysis.

Results

158 early-morning shift workers met the pre-screening criteria and began the screening process. Most worked in retail, healthcare, maintenance, or transportation, and worked five shifts (65%) and 40+ hours (72%) per week, with a duration of 8.8±1.9 hours. 41 were screened out for abnormal findings on the PE, ECG, or screening blood/urine tests; 26 were screened out for previously un-diagnosed OSA or PLMD; 4 were ineligible for other reasons; 7 were excluded after their MWT due to long sleep latency, 20 were lost to follow-up/withdrew and 60 completed screening and met inclusion criteria. Their average (±sd) age was 37±11 years, 45% women, PSQI score 7.5±2.7, sleep duration 5.6±1.0, ESS=16.3±3.1, CGI=4.2±0.9, PGI=3.6±1.1.

Conclusion

Early-morning shift workers at an increased risk for SWD report short and disturbed sleep, excessive sleepiness, and a negative impact of sleepiness on their quality of life. Many have undiagnosed OSA and PLMD.

Support (if any)

Axsome Therapeutics, Jazz Pharmaceuticals, Brigham and Women’s Hospital Center for Clinical Investigation.
0616 The rest-activity rhythm and its association with metabolic syndrome in midlife adults
Authors: Jeon Bomin , Moon Chooza
Published: May 2023

Introduction

Metabolic syndrome (MetS) in middle-aged adults increases a risk of cardiovascular disease in their older ages. The rest-activity rhythms disruptions have been linked to metabolic dysfunctions. However, there are limited data for the association between rest-activity rhythms and MetS in middle-aged. The purpose of this analysis was to compare rest-activity rhythms between midlife adults with MetS and those without MetS.

Methods

This study was a secondary analysis of data from Midlife in the United States (MIDUS 2): Biomarker Project, 2004-2009 cohort. The rest-activity rhythms were described by four parameters: the mesor, the amplitude, the acrophase, and the goodness-of-fit (R2), generated from Cosinor analysis using Actiwatch activity monitor data. Metabolic syndrome was defined as having three or more the following traits: the waist circumference ≥85cm in women and ≥102cm in men, the triglyceride level ≥150mg/dL, the high-density lipoprotein < 50mg/dL in women and < 40mg/dL in men, the blood pressure ≥130/85 mmHg, the fasting blood sugar level ≥100mg/dL. Student T-test were conducted.

Results

The sample (N=302; mean age 54.7 years [range 34 – 83]; 55.3% female; 97.3% White; 72.8) consists of 60.9% of persons with MetS (n=184) and 39.1% of those without MetS (n=118). The MetS group was older and more likely to be male than the non-MetS group (all p<.05). The MetS group had statistically lower mesor (mean 221.7 vs. 246.1; p=.005) and amplitude (mean 183.1 vs. 207.9; p=.004) than the non-MetS group. R square (0.58 vs. 0.62; p=.004) was significantly lower in the MetS than the non-MetS group. However, acrophase was not associated with MetS.

Conclusion

Midlife adults, those with MetS had lower levels of average activity and lower amplitude of rest-activity rhythms than those with non-MetS. The circadian rest-activity rhythms were significantly fragmented in those with MetS than with those non-MetS. Our findings suggest that the disrupted rest-activity rhythm could be a modifiable factor to manage MetS in midlife.

Support (if any)

Partially supported by the University of Iowa Institute for Clinical and Translational Science (NIH/ ACTS KL2TR002536) and University of Iowa Center for Advancing Multimorbidity Science (NIH/ NINR P20 NR018081). Contents are solely the responsibility of the authors.
0617 Tracking circadian phase for personalized schedules: A precise medical approach to reduce circadian misalignment in shift workers
Authors: Neuenschwander Eva , Spector Tori , Kalmbach David , Sagong Chaewon , Drake Christopher , Cheng Philip
Published: May 2023

Introduction

Night shift workers experience symptoms of excessive sleepiness and insomnia due to misalignment between the work schedule and their circadian clock. Circadian misalignment can be corrected using exposure to bright light delivered in accordance with a phase response curve. Given the high variability of circadian phase in night shift workers, using a one-schedule-fits-all approach to light therapy might result in significant error (e.g., phase shifts in the wrong direction). Instead, a personalized light exposure schedule should result in more consistent and precise phase shifts. This randomized controlled trial compared personalized and non-personalized light schedules in shifting circadian phase in night shift workers.

Methods

Individuals with shift work disorder (ICSD-3 diagnostic criteria) were randomized into two conditions: personalized light therapy, or non-personalized light therapy control. Personalized light schedules were based on estimates of dim light melatonin onset (DLMO) derived from mathematical modeling of activity data collected via an Apple Watch. Estimates were confirmed with in-lab DLMO. Light schedules were delivered through a mobile app (SHIFT) that updated in accordance with real-time estimates of DLMO. Participants were provided a light box as a source of bright light at night and light blocking glasses. Phase shifts were determined based on in-lab DLMO measured before and after treatment.

Results

Those who received personalized light therapy treatment achieved a larger phase delay (Mean = 7.37 hours, SD = 3.03 hours) compared to those in the non-personalized light therapy control group (Mean = 0.84 hours, SD = 3.46 hours), t(5) = 2.501, p = 0.05.

Conclusion

Preliminary results suggest that personalized light therapy may be a more effective treatment to correct circadian misalignment in night shift workers by delivering treatment according to each individual’s unique circadian phase. This has implications for improving the symptoms of shift work disorder and quality of life for this population.

Support (if any)

Support for this study was provided from the National Institute of Health R41HL163783 and the American Academy of Sleep Medicine Foundation (245-SR-21) awarded to Dr. Philip Cheng.
0619 Comparative analysis of different methods of assessing worker fatigue
Authors: de Mello Marco , Guerreiro Renato , Brant Valdenio , da Silva Flávia Rodrigues , Barreto Amaury , Santarelli Rodrigo , Biasibetti Isadora , Andrade Tonia Chaves , Silva Andressa
Published: May 2023

Introduction

Fatigue at work causes reduced functional capacity that is experienced during the workday, is associated with sleep deprivation and impairs decision making. Fatigue can be estimated in a self-reported way, through the Psychomotor Vigilance Test (PVT), postural balance and core body temperature (CBT) that correlate with performance. Interest in fatigue assessment should focus on identifying risk conditions. Thus, the objective of the study is to present comparative results of 4 different methods used to estimate fatigue.

Methods

This study was approved by Research Ethics Committee (protocol CAAE nº 97394818.6.0000.5149). The sample consisted of 47 volunteers, who worked as truck operators, in a fast reverse rotational shift (4x1) with a workload for each shift of 6 hours, including a 12-hour break between shifts. All workers were submitted to fatigue assessment by postural sway using the Sonômetro for 15 days, in addition to assessments for 5 days such as CBT monitoring, 5 minutes of PVT and karolinska sleepiness scale (KSS). The gamma distribution with the identity function was considered for data analysis through the method of generalized linear models.

Results

CBT measurements were compared from the first to the sixth hour between shifts, no significant differences were observed . Of the variables evaluated by PVT, only the 10% faster presented worse results in the night shift (00:00 to 06:00). The KSS showed no differences between the evaluated times. The result of the pairwise comparisons indicated that there are differences in postural sway by SONOMETRO, being greater at the beginning of the shift 00:00 to 06:00, in relation to the shift 12:00 to 18:00. In the middle and at the end of the shift, a difference was found between the shift 00:00 to 06:00 and all others.

Conclusion

Among the presented methods, the SONOMETER and a single variable of PVT (10% faster), identified differences in the levels of fatigue. It is up to managers to identify the method that best suits the objective of the assessment, as well as the local culture and conditions. Thus, the combined use of different risk and fatigue assessment and management methods may favor the identification and management of worker fatigue.

Support (if any)