bluuebunny/crossref_metadata_2025_split huggingface dataset:
0639 Long-term Safety and Timing of Adverse Events with Low-Sodium Oxybate in a Phase 3 Idiopathic Hypersomnia Study
Authors: Bogan Richard , Whalen Marisa , Bronson Stefanie , Fuller Douglas , Macfadden Wayne 
Published: April 2024

Abstract

Introduction
Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. To examine the long-term safety of LXB in this population, this post hoc analysis evaluated treatment-emergent adverse events (TEAEs) over time in a phase 3, double-blind, placebo-controlled, randomized withdrawal trial (NCT03533114), including its open-label extension period.

Methods
Participants were adults with idiopathic hypersomnia. TEAEs were analyzed across all study periods (open-label titration,10–14 weeks; stable-dose, 2 weeks; double-blind randomized withdrawal, 2 weeks; open-label extension, 24 weeks; safety follow-up, 2 weeks) in the analysis population (oxybate-naive participants who took ≥1 dose of study drug; N=148). Onset and duration of common TEAEs (≥5% of participants) were reported in the total population and by baseline medication group (treatment-naive, n=66; taking alerting agents [stimulants or wake-promoting agents], n=82). Duration was defined as the time from when a TEAE started until it was reported as ended. Results are presented using descriptive statistics.

Results
The majority of the most frequently reported TEAEs occurred within the first 5 weeks after study onset. In treatment-naive participants, the most common TEAEs (incidence; median duration) were nausea (n=13 [19.7%]; 7.5 days), headache (n=12 [18.2%]; 3.0 days), dizziness (n=11 [16.7%]; 4.0 days), anxiety (n=7 [10.6%]; 9.0 days), and decreased appetite (n=7 [10.6%]; 15.0 days). In participants taking alerting agents, the most common TEAEs were nausea (n=21 [25.6%]; 7.5 days), headache (n=15 [18.3%]; 2.0 days), vomiting (n=14 [17.1%]; 1.5 days), anxiety (n=10 [12.2%]; 28.0 days), insomnia (n=9 [11.0%]; 7.0 days), and tremor (n=9 [11.0%]; 11.0 days). Common TEAEs were of mild or moderate severity and infrequently led to study discontinuation (≤3.7% of participants each). Nine serious TEAEs occurred in 4/148 (2.7%) participants; none were considered related to study drug or led to study discontinuation.

Conclusion
In this study of LXB in participants with idiopathic hypersomnia, the common TEAEs (≥5% of participants) were consistent with the known safety profile of oxybate, peaked early (generally within 5 weeks), and were mild to moderate in severity, in both treatment-naive participants and participants taking alerting agents.

Support (if any)
Jazz Pharmaceuticals
0648 Phase 3 Randomized Placebo-Controlled Trial of Pitolisant for Excessive Daytime Sleepiness in Prader-Willi Syndrome
Authors: Revana Amee , Seiden David , Rapchak Krystle Davis , Adee Ann , Bauer Eric , Runyan Grant , Nomikos George 
Published: April 2024

Abstract

Introduction
Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by global hypothalamic dysfunction that results in a variety of symptoms including behavioral disturbance, hyperphagia, and excessive daytime sleepiness (EDS). Pitolisant is approved for the treatment of EDS or cataplexy in adults with narcolepsy. In a phase 2, proof-of-concept study, pitolisant showed trends of reduction in EDS relative to placebo in patients with PWS.

Methods
This multicenter, randomized, double-blind, placebo-controlled, phase 3 study will evaluate the efficacy and safety of pitolisant in patients with PWS. The study will enroll patients ≥6 years of age with a genetically confirmed diagnosis of PWS, and have EDS as confirmed by the investigator. Selected exclusion criteria include patients with symptoms or diagnosis of psychosis or schizophrenia, inadequately treated sleep disordered breathing, and moderate or severe hepatic or renal impairment. Eligible patients will be randomly assigned (1:1) to receive pitolisant (weight-based dosing: 8.9-44.5 mg/d) or matching placebo tablets. The 11-week double-blind period will be followed by an optional 52-week open-label extension.

Results
Up to 100 patients per group will be enrolled. The primary endpoint will be change from baseline at Week 11 in EDS as measured by the PROMIS-SRI (Patient-Reported Outcomes Measurement Information System - Sleep Related Impairment [Parent Proxy]). The secondary endpoints will include behavioral disturbance as measured by the Aberrant Behavior Checklist-Community domains (irritability, social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech), Caregiver Impression of Severity for EDS, Clinician Global Impression of Severity for EDS, Epworth Sleepiness Scale for Children and Adolescents, and the Hyperphagia Questionnaire for Clinical Trials in conjunction with the Food Safe Zone Questionnaire. Safety assessments will include incidence and severity of adverse events, clinical laboratory tests, vital signs, and 12-lead ECG. The study is expected to start enrolling patients in 2024.

Conclusion
This study is designed to determine whether pitolisant is efficacious in the treatment of EDS in patients with Prader-Willi syndrome and to further characterize its safety profile in this patient population.

Support (if any)
Harmony Biosciences, LLC
0650 Safety and Efficacy of KP1077 in a Phase 2, Double-Blind, Randomized Trial in Patients with Idiopathic Hypersomnia
Authors: Braeckman Rene , Drake Christopher , Gallo Daniel , Vaughn Ben , AbdelFattah Ihab 
Published: April 2024

Abstract

Introduction
KP1077 is under development as an oral medication for the treatment of rare sleep disorders with Excessive Daytime Sleepiness (EDS), including idiopathic hypersomnia (IH). The active ingredient in KP1077 is serdexmethylphenidate (SDX), a prodrug of d-methylphenidate. The objectives of the study were to assess the safety (primary endpoint) and efficacy of KP1077 in patients with IH.

Methods
Adult patients with IH began KP1077 treatment in a 5-week open-label (OL) titration period. Possible dose levels were 80, 160, 240 and 320 mg/day SDX. Patients were randomized to receive their daily dose either once per day (just before going to sleep), or twice per day (half the daily dose just before going to sleep and half shortly after awakening). After the titration period, patients in each treatment group were randomized to placebo or continued KP1077 (optimized dose) during a 2-week double-blind (DB) withdrawal period. Assessments of safety were based on adverse events (AEs), physical examinations, clinical laboratory tests, vital signs, electrocardiograms, sleep quality, and suicidal ideation. Efficacy assessments included the Epworth Sleepiness Scale (ESS) and Idiopathic Hypersomnia Severity Scale (IHSS). Patients rated their difficulty of waking up in the morning with the Sleep Inertia Visual Analog Scale (SI-VAS) and brain fog throughout the day with an exploratory Brain Fog Scale (BFS).

Results
Safety and efficacy in the OL titration phase were evaluated in an interim analysis when 22 patients completed the study (target: ≥48 completers). KP1077 was well-tolerated for both treatments and all dose levels, with most frequent AEs of insomnia, headache, and nausea. Most AEs were mild, not leading to early discontinuation. Meaningful clinical improvements in scores of ESS, IHSS, SI-VAS, and BFS were observed in both treatment groups. Mean total ESS scores decreased by &gt;9 points after 5 weeks of OL treatment. Results from all patients in the both the OL titration and DB withdrawal periods will be presented.

Conclusion
KP1077 was well-tolerated in patients with IH with AEs typical for a central nervous system stimulant. Meaningful clinical improvements of EDS, sleep inertia and brain fog were observed after 5 weeks of OL KP1077.

Support (if any)
Zevra Therapeutics
0653 Caregiver Preferences for Narcolepsy Treatment: A Discrete Choice Experiment
Authors: Ortiz Luis , Morse Anne , Wermter Ellen , Lavender Maggie , Brooks Diana , Gudeman Jennifer 
Published: April 2024

Abstract

Introduction
Once-nightly sodium oxybate extended-release oral suspension (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness and cataplexy in adults with narcolepsy. Currently, a once-nightly oxybate option is not available for pediatric patients with narcolepsy. A discrete choice experiment was conducted among caregivers of pediatric patients with narcolepsy to determine drivers of preferences for oxybate therapy.

Methods
Thirty-minute web-based surveys were provided to adult caregivers of a pediatric (&lt; 18 years old) patient with narcolepsy and prior or current use of twice-nightly SXB. Participants were recruited online or via patient advocacy groups. Two hypothetical product profiles with attributes of twice-nightly SXB and ON-SXB were created for 10 choice sets. For each choice set, participants indicated their preferred product overall, the product they would be more adherent to, and the product that would result in less anxiety or stress for the patient when thinking about taking the medication. A hierarchical Bayesian model was used to analyze the results.

Results
Caregivers (n=75) of pediatric patients with narcolepsy participated; 88% of patients cared for were age 10–15 years, 80% of caregivers had a household income of $60,000–$120,000, and 96% of patients currently used twice-nightly SXB. Caregivers indicated that the most important attribute driving overall product choice was dosing frequency (relative attribute importance [RAI], 23.7), with once-nightly preferred over twice-nightly dosing (relative preference weight [RPW], ±45.1), followed by treatment efficacy at the highest dose (RAI, 21.7). The most important attribute driving adherence was the efficacy of the drug at the highest dose (RAI, 25.7), followed by dosing frequency (RAI, 21.6), with once-nightly preferred over twice-nightly dosing (RPW, ±31.3). The most important attributes associated with less anxiety/stress were efficacy of the drug at the highest dose (RAI, 24.6) and side effects (RAI, 18.7).

Conclusion
Among caregivers of pediatric patients with narcolepsy, efficacy and dosing frequency were identified as the most important attributes driving preference for overall treatment choice and adherence; efficacy and side effects were important for reducing patient anxiety/stress. If approved by the US FDA for pediatric patients, ON-SXB will eliminate the chronic, middle-of-the night disruption impacting patients and caregivers.

Support (if any)
Avadel Pharmaceuticals.
0655 Novel Design Elements to Evaluate Sleep Architecture and Outcomes in an Idiopathic Hypersomnia and Narcolepsy Study
Authors: Plante David , Nichols Deborah , Steininger Teresa , Fuller Douglas , Whalen Marisa , Akerman Sarah , Macfadden Wayne 
Published: April 2024

Abstract

Introduction
Although the efficacy and safety of low-sodium oxybate (LXB, Xywav®) in the treatment of idiopathic hypersomnia and narcolepsy are well established, opportunities remain to better understand its impact on sleep architecture and other daytime/nighttime outcomes important to patients and clinicians. Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) is a phase 4, prospective, multicenter, single-arm, open-label interventional study designed with novel methodology and expert input to evaluate the impact of LXB on excessive daytime sleepiness, polysomnographic (PSG) sleep parameters, and functional outcomes in adults with idiopathic hypersomnia or narcolepsy (type 1 or 2).

Methods
DUET includes a screening period (with a 2-week washout for participants taking oxybate at study entry), 1-week baseline period (off-treatment), 2- to 8-week titration period (for flexible LXB dosing adjustments based on participants’ needs), 2-week stable-dose period, 1- to 2-week end-of-treatment period (on LXB), and safety follow-up (after 2 weeks). To more comprehensively understand the impact of LXB on sleep architecture and other daytime/nighttime outcomes, novel design elements were integrated into the study. Input from an expert advisory board helped refine the study design and ensure that the most relevant elements for patients and clinicians were incorporated into the final DUET protocol. Responses from a premeeting survey of advisors focused on eligibility criteria, suitability of endpoints, newly created questionnaires, and analyses and were discussed during a 4-hour workshop with the study sponsor.

Results
Advisors were 6 clinicians with expertise in treating patients with idiopathic hypersomnia and narcolepsy and/or with expertise in PSG. Novel design aspects discussed and incorporated into the protocol included PSG conducted with ad libitum sleep duration, objective evaluation of sleep inertia using the Psychomotor Vigilance Test, a new questionnaire for capturing clinician-reported dosing to better understand dosing rationale, evaluation of motor activity during sleep (with PSG), and evaluation of dysautonomia using the Orthostatic Hypotension Questionnaire.

Conclusion
DUET is the first prospective evaluation of the impact of LXB on sleep architecture (PSG) in patients with idiopathic hypersomnia or narcolepsy. Results from these novel elements will provide patients and clinicians with additional information regarding the impact of LXB on nighttime/daytime symptomatology.

Support (if any)
Jazz Pharmaceuticals
0656 Severe Air Pollution as a Possible Triggering Factor for Kleine-levin Syndrome
Authors: Heshmati Arezou 
Published: April 2024

Abstract

Introduction
Kleine-Levin Syndrome (KLS) is a rare neurological disorder characterized by recurrent episodes of hypersomnia, altered behavior, and cognitive disturbances. We report a case where severe air pollution seemingly acted as a trigger for a KLS episode in a patient with a history of viral-triggered and alcohol-associated episodes.

Methods
We present a case of a 17-year-old girl with a history of anxiety and migraine headaches, effectively managed with a stable dose of Lexapro 20 mg per day. The patient experienced multiple episodes of Kleine-Levin Syndrome (KLS) following viral infections and alcohol consumption. However, the fourth episode was distinct, as it coincided with extreme air pollution in New York City. On the day that her symptoms started the Air Quality Index was reported to be above 480 technically off the chart. While there were no other known triggers for this fourth episode and the duration of the fourth episode was similar to the previous three ones.

Results
This case sheds light on potential environmental triggers for KLS and highlights the importance of understanding individual susceptibilities within this rare disorder.

Conclusion
This case emphasizes the need for a comprehensive approach to understanding KLS triggers, including environmental factors. The possibility of severe air pollution acting as a trigger adds a new dimension to our understanding of this enigmatic disorder. Further research is required to elucidate the relationship between air pollution and KLS, potentially offering insights into preventive strategies and tailored interventions for susceptible individuals.

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0669 Oxidative Stress in Hypersomnia Patients: Correlation with Sleep Onset REM Period
Authors: Honda Makoto , Kojima Takashi , Kodama Tohru 
Published: April 2024

Abstract

Introduction
Glutathione is the most abundant cell antioxidants. The ratio of reduced and oxidized glutathione (GSH, GSSG) has been used as a marker for oxidative stress and reduced glutathione levels contributes to the onset and progression of many diseases. In sleep research field, oxidative stress has been studied mostly in sleep apnea syndrome and sleep deprivation but not in hypersomnia. Since GSSG is one of the sleep promoting substances, we hypothesized that oxidative stress contributed to the pathophysiology of hypersomnia and examined the relationship between glutathione and sleep variables in sleepy subjects.

Methods
Participants were patients visiting outpatient clinic for sleep disorders in Koishikawa Tokyo Hospital, Institute of Neuropsychiatry and underwent diagnostic PSG-MSLT from June 2020 to Nov 2023. Written informed consents were obtained. We selected 280 patients (25.6±9.3 years old, f/m=148/132) without medication at sleep study and slept more than 5.5 hours during nocturnal PSG. Fasting blood samples were collected at 7am before MSLT and RBC fraction were stored at -80 degree until use. RBC were deproteinized with perchloric acid and supernatant after centrifugation was measured by HPLC-ECD with boron-doped diamond electrode. GSH proportion of the total glutathione [GSH/(GSH+GSSG)] were calculated and correlation with sleep variables and ESS score were investigated. To adjust possible confounders, regression analyses were performed using Logit transformed GSH proportion as objective variable.

Results
We found that GSH proportion showed negative correlation with age (P&lt;.001) and sex differences (lower in female). We also found that GSH proportion showed positive correlation with presence/absence of SOREMP on MSLT(P=.007) and negative correlation with ESS score (P=.046). Correlation with SOREMP remained significant after adjusting the HLA -DQB1*06:02 status.

Conclusion
Our data showed that those with higher oxidative stress have higher ESS score and those without SOREMP on MSLT showed higher oxidative stress. Subgroup analysis showed that those without SOREMP and HLA-DQB1*06:02 have higher oxidative stress compared to others. SOREMP on MSLT is a diagnostic marker for Narcolepsy type 1 but SOREMP can be observed in general population. Our data could provide biochemical basis for the occurrence SOREMP.

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0672 Sleepiness, Psychomotor Vigilance and Cognition in People with OSA Adherent to PAP Therapy
Authors: Ruiz-Perez Elena , Junco Barbara , Dib Salim , Agudelo Christian , Mclntosh Roger , Wallace Douglas , Rothberg Paola , Ramos Alberto 
Published: April 2024

Abstract

Introduction
Residual excessive daytime sleepiness (EDS) is common in people with obstructive sleep apnea (OSA) using positive airway pressure (PAP) regularly, and has been associated with reduced functional outcomes.We examined the association of EDS using the psychomotor vigilance test (PVT) and cognition in patients with OSA adherent to PAP. We hypothesized that objective sleepiness is associated with worse cognitive function.

Methods
This cross-sectional study included participants aged ≥40 years, from an academic sleep disorder center using PAP therapy for ≥6 months with a minimum use of 6 hours per night. Exclusions were diagnosis of dementia, cognitive impairment, stroke, and sleep disordersincluding narcolepsy, parasomnias and PMLD. Demographics, medical history, behavioral data including the Epworth Sleepiness Scale (ESS), were gathered through questionnaires and medical records.Cognitive data was collected using NeuroTrax™, assessing attention, executive function, memory, processing speed, and global cognition. Linear regression analyses were performed between cognitive domains and PVT outcomes (lapses ≥500ms and average reaction time (RT)).

Results
The cohort included 31 participants (71% Hispanic-Latino, 29% women) with mean age 61 (SD=8.95), and mean AHI 33.13 (SD=22.05). PVT data indicated an average RT of 404.30 ms and an average number of lapses (≥ 500 ms) at 8.20. Cognitive assessments revealed scores for global cognition (m= 103.25, SD=10.83), verbal memory (m= 97.76, SD= 12.50), executive function (m= 106.42, SD= 11.82), attention (m= 101.72, SD= 10.54), and information processing speed (m= 101.66, SD=21.05). Pearson’s test showed a correlation between lapses (≥ 500 ms) and memory (r = -0.44; p = 0.008), and average RT with age (r = 0.46; p = 0.006). No correlation was found between lapses (≥ 500 ms) and ESS (r = 0.21; p = 0.26) or average RT and ESS (r = 0.045; p = 0.81). Linear regression analysis, adjusting for age, showed an association between lapses with worse memory function (β= -0.86, p = 0.017), as well as average RT with worse information processing speed (β = -0.089, p = 0.049). Other cognitive domains were not associated with the PVT.

Conclusion
In people with OSA optimally adherent to PAP, objective sleepiness was associated with worse memory function and information processing speed.

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0674 The Functional Impacts of Narcolepsy Instrument Differentiates Patients with Narcolepsy from Healthy Controls
Authors: Crawford Stephen , Romero Heather , Savva Yulia , McPherson Peter , Doll Helen , Howerter Amy , Swick Todd 
Published: April 2024

Abstract

Introduction
The Functional Impacts of Narcolepsy Instrument (FINI) is a fit-for-purpose patient-reported outcome (PRO) measure developed for the assessment of patients with narcolepsy type 1 (NT1) or type 2 (NT2). To provide a baseline for interpretation in future interventional trials, comparative scores for the FINI domains were obtained from a cohort of healthy volunteers included in a United States observational study.

Methods
Healthy volunteers without excessive daytime sleepiness (EDS; ≤10 on the Epworth Sleepiness Scale [ESS] at screening) or any associated medical disorder were eligible for inclusion. Participants received a link to complete a cross-sectional online survey that included a 23-item, 5-domain form of the FINI (excluding cataplexy items) and additional selected quality of life reference questionnaires (SF-36 and EQ-5D). FINI items evaluate narcolepsy/EDS symptoms and impacts on daily functioning. All items have a 7-day recall period on a 5-point Likert scale of frequency from “never” to “always” or severity from “not at all” to “very much.” For each domain, an average item score is calculated and standardized to a 0–100 scale. Lower scores indicate better health/functioning. Responses were compared to patients with NT1 and NT2 from an observational study (n=126) and a phase 2 trial (NCT04096560; n=125).

Results
Thirty-one healthy volunteers (45.2% female) completed the survey. Participants had a mean age of 44.8 years and a median (range) ESS score of 4.0 (0–10.0) at baseline. FINI domain scores ranged from 10.0 to 22.2 in healthy volunteers, significantly lower than values reported for patients with narcolepsy in observational and phase 2 studies (46.2 to 67.9). Similar patterns were observed for reference PROs, with better quality of life/health status reported for healthy controls than for narcolepsy samples. Mean (SD) FINI domain values for healthy volunteers were: Tiredness: 22.2 (19.8); Cognitive Functioning: 10.0 (10.5); Social Activities: 16.1 (17.1); Everyday Activities: 12.9 (10.7); and Everyday Responsibilities: 11.6 (15.8).

Conclusion
Mean FINI domain scores from healthy volunteers can serve as normative thresholds and provide a benchmark for comparison of FINI responses reported by patients with narcolepsy, allowing for the evaluation of treatment effects in clinical trials.

Support (if any)
Funded by Takeda