bluuebunny/crossref_metadata_2025_split huggingface dataset:
0629 The Lehigh Valley Health Network Narcolepsy Cohort: Clinical and Polysomnographic Analysis of 303 Cases
Authors: Chu Irene , Jiang Rena , Rochart Roger , Duka Shae , Vendrame Martina 
Published: April 2024

Abstract

Introduction
Narcolepsy has been associated with several psychiatric, cardiovascular and metabolic disorders. This study aimed to analyze the clinical and polysomnographic characteristics of narcolepsy patients within the Lehigh Valley Health Network (LVHN).

Methods
We performed a chart-review of all narcolepsy cases seen between 2000 and 2022. Bivariate analysis highlighted differences between narcolepsy-type I (NT1) and narcolepsy-type II (NT2).

Results
Among 3.3 million patients, 303 (0.0001%, 9 per 100,000) were diagnosed with narcolepsy (51 with NT1, 252 with NT2), based on ICDS-3 diagnostic criteria. Age at symptom onset was 20.5±6.8 years. Diagnostic delay was 4.1 (2.0-8.9) years. Average Epworth Sleepiness Scale (ESS) was 16.9±2.9. Concomitant symptoms were refreshing naps [226(74.6%)], hypnagogic hallucinations [87(28.7%)], disrupted sleep [86(28.4%)], sleep paralysis [77(25.4%)]. Compared to NT2, NT1 patients had earlier age at diagnosis (24.3±8.0 versus 27.6±9.1, p=0.02), shorter diagnostic gap (3.0 vs 4.6 years, p=0.001), more frequent sleep paralysis [27(52.9%) vs 50(19.8%) p&lt; 0.0001], hygnagogic hallucinations [22(43.1%) vs 65(25.8%), p=0.01], higher ESS (17.6±3.3 versus 16.7±2.8, p=0.04). Comorbid sleep disorders were breathing disorders (17.5%), insomnia (15.5%), restless legs syndrome (3.6%), periodic limb movements (2.3%), and REM parasomnias (1.3%). Migraine was the most common neurological disorder (29.7%). Frequent mood disorders included depression (34.7%) and anxiety (32.3%). Depression was more common in NT2 [11 (21.6%) vs 94 (37.3%) p=0.03]. Hypertension, diabetes, and obesity prevalence were not different between the two groups (overall 24.1%, 8.3%, 12.5% respectively). The most common treatments were modafinil (66.3%), methylphenidate (31.3%), armodafinil (28.1%), dextroamphetamine (28.8%), sodium oxybate (8.7%), pitolisant (4.5%), solriamfetol (5.2%). Review of overnight-polysomnography showed an average sleep efficiency of 93%, sleep latency of 12.3 minutes, REM latency of 98.8 minutes, with no differences between NT1 and NT2. Multiple sleep latency test showed an average sleep latency of 3.7 (2.4-5.0) minutes, and more SOREMPs in NT1 (≥3 in 28 (58.3%) vs 64 (27.1%), p&lt; 0.0001).

Conclusion
This study is one of the largest monocentric studies to date of patients with narcolepsy and confirms the frequent comorbidity of narcolepsy with many other disorders. Specific clinical characteristics and comorbidities may help differentiate NT1 from NT2. Further analysis on this dataset is in progress and will be presented.

Support (if any)
0631 Phase 2, Proof-of-Concept Study of Pitolisant in Prader-Willi Syndrome: Primary and Secondary Efficacy Analyses
Authors: Revana Amee , Bhattacharjee Rakesh , Miller Jennifer , Khanna Priya , Scheimann Ann , Chidekel Aaron , McCandless Shawn , Shelton Althea Robinson , Singh Haramandeep , Norman Daniel , Patel Tarak , Maynard James , Burg Casey , Rapchak Krystle Davis , Seiden David 
Published: April 2024

Abstract

Introduction
Prader-Willi Syndrome (PWS) is a complex genetic disorder with symptoms that include hyperphagia, behavioral disturbances, and excessive daytime sleepiness (EDS). Pitolisant is approved for the treatment of EDS or cataplexy in adults with narcolepsy.

Methods
In this phase 2, proof-of-concept study (which was not powered to show statistical significance), patients with a confirmed diagnosis of PWS and a score ≥12 on the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) were randomized to receive higher-dose pitolisant, lower-dose pitolisant, or placebo (dose based on age group) for 11 weeks (3-week titration, 8-week stable-dose). The primary efficacy endpoint was change from baseline at Week 11 in ESS-CHAD score. Secondary/exploratory endpoints included the Caregiver Global Impression of Severity (CaGI-S) for EDS, Aberrant Behavior Checklist-2 (ABC-2), and Hyperphagia Questionnaire for Clinical Trials (HQ-CT) (in conjunction with the Food Safe Zone Questionnaire).

Results
Among 65 enrolled patients (50.8% male), 34 (52.3%) were children (6 to &lt; 12 years), 19 (29.2%) were adolescents (12 to &lt; 18 years), and 12 (18.5%) were adults (≥18 years). Overall, mean (SE) change in ESS-CHAD score at Week 11 was greater in the higher-dose (-4.9 [1.23]) and lower-dose (-4.1 [1.06]) pitolisant groups compared with the placebo group (-3.7 [1.13]). There was an unusually large placebo response in the adolescent age group, due to data from a single outlier. Reductions in CaGI-S scores and HQ-CT scores were greater for pitolisant compared with placebo in the children and adult age groups. In children (6 to &lt; 12 years), mean reduction in all ABC-2 domain scores (irritability, social withdrawal, hyperactivity/noncompliance, inappropriate speech, stereotypic behavior) was greater for higher-dose pitolisant compared with placebo. The most common adverse events in pitolisant-treated patients (doses pooled) were irritability (17.4%) and anxiety (13.0%).

Conclusion
Pitolisant reduced EDS in patients with PWS. Pitolisant may also reduce behavioral disturbances and hyperphagia. An upcoming phase 3 clinical trial (TEMPO) will further evaluate the efficacy and safety of pitolisant in patients ≥6 years old with PWS and EDS.

Support (if any)
Harmony Biosciences, LLC
0634 Effects of Solriamfetol on Cognition on Patients with Excessive Daytime Sleepiness Associated with Narcolepsy
Authors: Winter Yaroslav , Mayer Geert , Benes Heike , Burghaus Lothar , Eglit Graham , Abeynayake Iresha , Floam Samantha , Parks Gregory , Kallweit Ulf 
Published: April 2024

Abstract

Introduction
Previous studies indicated that patients with narcolepsy often exhibit neuropsychological deficits. Cognitive domains related to alertness, attention, executive function, and decision-making are predominantly impaired. Solriamfetol (Sunosi®) is a dopamine/norepinephrine reuptake inhibitor and TAAR1 / 5HT1a agonist approved to treat excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Solriamfetol has been shown to improve cognitive performance in a clinical study of OSA patients with cognitive impairment. Here we report neuropsychological outcomes of narcolepsy patients following treatment with solriamfetol in a real-world setting.

Methods
Neuropsychological outcomes were assessed in a subgroup of adult narcolepsy patients in a retrospective observational study (SURWEY), which collected data from physicians in Germany who prescribed solriamfetol for narcolepsy. The test of attentional performance (TAP, subtest “alertness“), Regensburger Word Fluency Test (RWT), Wechsler Memory Scale (WSM-IV, subtest “visual reproduction“), Wechsler Adult Intelligence Scale (WAIS-IV, subtest “coding“), and British Columbia Cognitive Complaints Inventory (BC-CCI) were conducted prior to and 3 months following solriamfetol initiation. Data were analyzed with analysis of variance (ANOVA) repeated measures. Unadjusted linear regression models were fit on change from baseline of each outcome. Adjusted models were fit to evaluate associations between cognitive and ESS changes from baseline.

Results
Prior to initiation of solriamfetol, patients (N=52) showed cognitive deficits in BC-CCI (9.1±5.6), impaired alertness in TAP (263.8±26.0 ms with warning signal and 265.5±26.0 ms without), and psychomotor and visual speed in the subset “coding“ of WAIS-IV (6.8±1.6). After 3 months of solriamfetol treatment, assessment outcomes were compared to baseline values and BC-CCI improved by 39.4% (5.6±2.9), alertness increased by 10.5% (TAP: 236.0±17.7 ms with warning signal and 237.6.5±17.7 ms without), and the coding subtest improved by 34.3% (9.2±1.8). No reductions in word fluency or memory were observed prior to or 3 months following solriamfetol initiation. The ESS scores improved by 3.8±2.1. Reduction in EDS was not associated with improvement in any cognitive domain.

Conclusion
Data from this observational study demonstrates that solriamfetol has potential to improve cognitive function in patients with narcolepsy-associated cognitive impairment. This improvement was independent from its effect on EDS.

Support (if any)
Axsome Therapeutics, Jazz Pharmaceuticals, Pharmanovia
0635 Modafinil vs Amphetamine-dextroamphetamine for Idiopathic Hypersomnia & Narcolepsy Type 2: A Non-inferiority Trial
Authors: Trotti Lynn Marie , Blake Tyler , Hoque Romy , Rye David , Sharma Surina , Bliwise Donald 
Published: April 2024

Abstract

Introduction
Despite recent introduction of several FDA-approved treatments for narcolepsy, clinical management of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) still relies heavily on treatment with modafinil and amphetamines. While modafinil has a strong recommendation for use in these disorders by the American Academy of Sleep Medicine, clinical trial evidence regarding efficacy of amphetamines is scarce.

Methods
We performed a 12-week, randomized, fully-blinded, non-inferiority trial to determine if amphetamine-dextroamphetamine was non-inferior to modafinil in people with IH and NT2. Eligible participants were randomized 1:1 to modafinil (starting 100 mg once daily, titrating as tolerated to maximum 200 mg twice daily) or amphetamine-dextroamphetamine (starting 10 mg once daily, titrating as tolerated to maximum 20 mg twice daily). The primary outcome was Epworth change from baseline. Secondary outcomes included Patient Global Impression of Change (PGI-C, for overall severity, sleepiness, sleep inertia, cognitive symptoms), the Hypersomnia Severity Index (HSI), and the Sleep Inertia Questionnaire (SIQ). Outcomes were collected at baseline, weeks 4, 8, and 12, with last observation carried forward in the case of missing responses or dropouts.

Results
44 participants were randomized and took at least one dose of medication (75% with IH, 84% women, mean age 35.4 +/- 8.9). Although change in Epworth scores was similar between the two medications (5.0 +/- 2.7 points improved for modafinil group, 4.4 +/- 4.7 for amphetamine-dextroamphetamine), non-inferiority of amphetamine-dextroamphetamine was not demonstrated. However, amphetamine-dextroamphetamine was shown to be non-inferior to modafinil for several secondary outcomes, including PGI-C for cognitive symptoms and sleep inertia, change in HSI, and change in SIQ. Participants experiencing at least one adverse event was similar between groups (77.3% for each medication); dropouts due to adverse events were numerically but not statistically higher in the modafinil group (32% for modafinil, 9% for amphetamine-dextroamphetamine, p=0.13).

Conclusion
Amphetamine-dextroamphetamine is non-inferior to modafinil across a variety of disease measures included as secondary outcomes, but may not be non-inferior for sleepiness as measured by the Epworth. Depending on patient symptoms, this study provides evidence in support of amphetamine-dextroamphetamine.

Support (if any)
American Academy of Sleep Medicine Foundation, National Institutes of Health (UL1TR002378, NS111280)
0636 Assessing Usability of Once-Nightly Sodium Oxybate Extended-Release Oral Suspension for Narcolepsy
Authors: Lavender Maggie , Wermter Ellen , Ortiz Luis , Morse Anne , Horsnell Matthew , Gudeman Jennifer 
Published: April 2024

Abstract

Introduction
Sodium oxybate, available in once-nightly and twice-nightly formulations, is indicated for treatment of cataplexy or excessive daytime sleepiness in narcolepsy. Once-nightly sodium oxybate extended-release oral suspension (ON-SXB; LUMRYZ™) may alleviate potential dosing challenges associated with immediate-release twice-nightly formulations. Human factors validation testing was conducted to confirm safe use of ON-SXB, using the product packaging, mixing cup, and Instructions for Use (IFU).

Methods
Two summative studies evaluated simulated usability of ON-SXB in individuals (16–65 years of age) with narcolepsy, who were categorized as either experienced (having current or previous experience self-administering SXB) or naive (no current or previous experience). Both studies were conducted in lab settings modeled after a home bedroom environment. Study 1 (S1) assessed all critical and noncritical tasks related to storage, preparation, administration, and disposal of ON-SXB. After S1, IFU updates were implemented for additional risk control. Study 2 (S2) assessed tasks associated with these updates. Tasks were evaluated through observed performance or participant responses to a labeling comprehension activity.

Results
Of the S1 participants enrolled (mean [range] age, 37.0 [16–57] years; female, 77%), 77% (24/31) successfully prepared and administered the full ON-SXB dose. Critical use errors included failure to administer dose at bedside (experienced, 8/15; naive, 12/16) and preparing &gt;1 dose packet (experienced, 1/15; naive, 1/16). Multiple critical use errors occurred during the label comprehension activity, which S1 participants attributed to difficulty in locating certain safety-critical warnings in the labeling. Using these data, the IFU was updated. In S2, 87% (26/30) of participants (mean [range] age, 35.8 [17–64] years; female, 83%) successfully prepared and administered the dose. Fewer S2 participants encountered critical errors observed in S1 (not administering dose at bedside [experienced, 4/15; naive, 5/15] and preparing &gt;1 dose packet [none]), indicating that IFU updates effectively reduced the associated use risks. Only 2 use errors, which occurred with naive participants and were related to product storage, occurred in the S2 label comprehension activity.

Conclusion
Validation to confirm that individuals with narcolepsy can follow labeled instructions for safe use and self-administration of oxybates is important and has been conducted with ON-SXB.

Support (if any)
Avadel Pharmaceuticals
0637 Composite Response with Once-Nightly Sodium Oxybate: Symptom Improvement in Participants with Narcolepsy Type 1
Authors: Ortiz Luis , Roth Thomas , Morse Anne , Thorpy Michael , Harsh John , Kushida Clete , Gudeman Jennifer , Dauvilliers Yves 
Published: April 2024

Abstract

Introduction
A novel once-nightly formulation of sodium oxybate (ON-SXB; LUMRYZ™) was investigated in patients with narcolepsy type 1 (NT1) and 2 (NT2) in the phase 3 REST-ON trial (NCT02720744). ON-SXB treatment resulted in statistically significant improvements vs placebo for the coprimary endpoints of 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 attacks, as well as the secondary endpoint of improved excessive daytime sleepiness (EDS) using the Epworth Sleepiness Scale (ESS; all P&lt; 0.001 vs placebo). The objective of this post hoc analysis was to assess the proportion of participants with NT1 achieving clinically significant improvement on a composite of these endpoints.

Methods
Participants (aged ≥16 years with NT1 or NT2) who had continuing presence of EDS (sleep latency &lt; 11 min on the MWT and ESS score &gt;10) and continuing cataplexy (average of 8 episodes/week) were randomized 1:1 to 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. Clinically significant improvement thresholds per the 2021 American Academy of Sleep Medicine Clinical Practice Guidelines for each endpoint were defined as follows: MWT (2-min improvement), CGI-I (1-point improvement), cataplexy (25% decrease), or ESS (2-point improvement) and examined for each dose.

Results
Mean age of participants with NT1 was 32.1 years, 72.8% were female, and 76.5% were white. The modified intent-to-treat population included 145 participants with NT1 (ON-SXB, n=73; placebo, n=72). At week 13 (9 g), more participants treated with ON-SXB vs placebo had clinical improvement in ≥2 endpoints (87.3% vs 62.9%; P&lt; 0.01), ≥3 endpoints (76.4% vs 43.5%; P&lt; 0.001), and in all 4 endpoints (47.3% vs 14.5%; P&lt; 0.001). Similar results were observed at all doses.

Conclusion
These data support the robust clinical efficacy of ON-SXB, a once-at-bedtime oxybate for treatment of cataplexy or EDS in adults with narcolepsy, using multiple disease state metrics compared with placebo.

Support (if any)
Avadel Pharmaceuticals
0640 Magnitude of Improvement in Excessive Daytime Sleepiness with the Once-at-Bedtime Oxybate for Narcolepsy
Authors: Kushida Clete , Thorpy Michael , Morse Anne , Harsh John , Ortiz Luis , Roth Thomas , Dauvilliers Yves , Gudeman Jennifer 
Published: April 2024

Abstract

Introduction
Safety and efficacy of once-nightly sodium oxybate (ON-SXB; LUMRYZ™) were investigated in the phase 3 REST-ON trial (NCT02720744). Results demonstrated statistically significant improvements in the secondary endpoint of excessive daytime sleepiness (EDS) measured using the Epworth Sleepiness Scale (ESS; P&lt; 0.001 vs placebo) at all doses tested beginning at week 2 (post hoc analysis, ON-SXB 6 g vs placebo at week 2). The objective of this post hoc analysis was to assess the magnitude of improvement in the patient-reported outcome of EDS following treatment with ON-SXB.

Methods
Participants aged ≥16 years with narcolepsy type 1 (NT1) or 2 (NT2) were randomized 1:1 to 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. Median (interquartile range [IQR]) ESS scores were assessed for each dosing period.

Results
Mean age of participants was 31.2 years, 68% were female, 75.5% were white, and 76.4% had NT1. The modified intent-to-treat population included 190 participants (ON-SXB, n=97; placebo, n=93). Baseline median (IQR) ESS scores were 17 (14−19) for ON-SXB and 18 (15−21) for placebo. At week 1, median (IQR) ESS scores were 16 (12−18) for ON-SXB 4.5 g vs 17 (13−20) for placebo. At week 3 (ON-SXB 6 g), median (IQR) ESS scores were 14 (10−18) vs 17 (14−20) for placebo. At week 8 (ON-SXB 7.5 g), median (IQR) ESS scores were 12 (8−16) vs 15.5 (12−20) for placebo. At week 13, median (IQR) ESS scores for ON-SXB 9.0 g were 9.5 (6.0−15.0) vs 15 (11−19) for placebo.

Conclusion
Treatment with ON-SXB resulted in clinically meaningful improvements in EDS with doses ≥6 g, as median ESS scores were within the range considered normal (≤10) at the end of the trial. ON-SXB is considered an effective intervention in treatment of EDS for patients with narcolepsy with a once-at-bedtime dose.

Support (if any)
Avadel Pharmaceuticals
0641 Population Pharmacokinetic and Exposure-Response Analyses Supporting Individualized Dosing of Oxybate
Authors: Zhou Honghui , Wu Liviawati , Chen Cuiping 
Published: April 2024

Abstract

Introduction
Low-sodium oxybate (LXB; Xywav®) and high-sodium oxybate (SXB; Xyrem®) are approved for the treatment of cataplexy or excessive daytime sleepiness in patients aged ≥7 years with narcolepsy; LXB is also approved for idiopathic hypersomnia in adults. LXB and SXB dosing are individually titrated for optimal efficacy/tolerability. To inform dosing individualization, population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted to identify factors influencing oxybate PK variability and assess relationships between exposure and efficacy/safety.

Methods
For narcolepsy, a 2-compartment PPK model with Michaelis-Menten clearance was fit to plasma concentration-time data from prior LXB and SXB clinical studies. For idiopathic hypersomnia, an LXB PPK model was refined based on the narcolepsy model. The PPK model-derived oxybate exposures (eg, AUC) were employed in ER analyses using response data from randomized parallel-group (RPG; SXB only; maintenance dose was not optimized) and randomized withdrawal (RWD; LXB and SXB; maintenance dose was optimized) studies.

Results
In the narcolepsy PPK model, the interindividual variabilities associated with key clearance and absorption parameters were 42.9%–83.8%, and in the idiopathic hypersomnia PPK model, the interindividual variabilities were 52.7%–57.9%. In both PPK models, food delayed oxybate absorption; greater body weight was associated with wider distribution and higher clearance. In ER analyses from RPG narcolepsy studies, all efficacy endpoints (eg, placebo- and baseline-corrected cataplexy frequency and Epworth Sleepiness Scale [ESS] score) exhibited improvements (ie, decreases) that had a significant relationship with higher oxybate exposure (AUC); no other covariates (eg, age, race, sex, body weight) were significant. In RWD studies, ER relationships for cataplexy change (narcolepsy only) and ESS score (narcolepsy and idiopathic hypersomnia) were flat, indicating that there is a range of effective concentrations and that different patients require different doses to achieve an optimal response. Adverse events associated with oxybate exposure included nausea, vomiting, and enuresis.

Conclusion
PPK analyses identified substantial interpatient variability of oxybate PK, and ER analyses demonstrated interindividual variability in response to oxybate treatment. Together, these modeling analyses highlight the need for individually optimized oxybate dosing in narcolepsy or idiopathic hypersomnia to achieve the appropriate dose and associated exposure for an optimal clinical response.

Support (if any)
Jazz Pharmaceuticals
0642 Real-world Experience Switching from Twice Nightly to Once Nightly Oxybate Therapy in the Treatment of Narcolepsy
Authors: Meskill Gerard , Boren Payton , Flores Jacob , Meskill Sarah 
Published: April 2024

Abstract

Introduction
Narcolepsy is a chronic neurologic condition of excessive daytime sleepiness (EDS), disturbed nocturnal sleep, and REM dissociation. In 2002, Xyrem (sodium oxybate) was approved by the U.S Food and Drug Administration (FDA) for treatment of EDS and cataplexy in narcolepsy. In 2023, the FDA approved Lumryz, a once-nighty sodium oxybate, citing its major contribution to patient care “due to its once nightly dosing because, in treating a sleep disorder, it is best to eliminate or minimize nocturnal arousals.” However, little information exists on the real-world experience of switching patients from an established twice-nightly agent to Lumryz.

Methods
In a large narcolepsy practice in Sugar Land, TX, patients were given the option to switch from their current twice nightly oxybate (Xywav or Xyrem) to Lumryz. Age, current therapy, reason for switching, dose difference, and tolerance were extracted from the medical record.

Results
Twenty-one patients elected to switch: 18 female and 3 male, mean age of 31.2 years with 10 of the patients taking Xywav. The most common reason (38%) for wanting to switch was inability to wake up for the second dose. Of the 21 patients that switched, 20 had follow-up after a change in oxybate product. Of those 20, 16 (80%) preferred the new once-nightly agent. The most common reason for failure was shorter total sleep time with Lumryz with increasing EDS.

Conclusion
In this real-world experience of switching patients from twice-nightly to once-nightly oxybate, the majority of those who elected to switch were successful and remained on Lumryz.

Support (if any)