bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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 < 12 years), 19 (29.2%) were adolescents (12 to < 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 < 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

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

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

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 >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 >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

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< 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 < 11 min on the MWT and ESS score >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< 0.01), ≥3 endpoints (76.4% vs 43.5%; P< 0.001), and in all 4 endpoints (47.3% vs 14.5%; P< 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

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< 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

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

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)
0644 Comparison of Baseline Narcolepsy Characteristics Among Participant Age Groups: Analysis from REST-ON
Authors: Roth Thomas , Schweitzer Paula , Thorpy Michael , Gudeman Jennifer , Dauvilliers Yves
Published: April 2024

Introduction

Narcolepsy is a chronic disease with symptom onset frequently occurring between the ages of 10–25 years. Efficacy and safety of once-nightly sodium oxybate (ON-SXB; LUMRYZ™) were demonstrated in the phase 3 REST-ON trial. The objective of this post hoc analysis was to compare baseline narcolepsy characteristics among 3 age groups from REST-ON.

Methods

Participants aged ≥16 years with narcolepsy type 1/2 were enrolled in the randomized, double-blind, placebo-controlled REST-ON trial (NCT02720744). Baseline data were trichotomized post hoc by age subgroups (years, youngest: 16–25; middle: 26–34; oldest: 35–72).

Results

The safety analysis included 212 participants who received ≥1 dose of study drug (youngest, n=73; middle, n=70; oldest, n=69). For youngest, middle, and oldest participants, respectively, mean age was 20.6, 29.6, and 44.0 years; 63.0%, 68.6%, and 72.5%, were female. Respective mean baseline values for excessive daytime sleepiness (EDS) measures were similar across the youngest, middle, and oldest age groups (range of group means, mean sleep latency on the Maintenance of Wakefulness Test: 4.5–5.1, 4.6–5.0, 4.9–5.1 minutes; Clinical Global Impression of Severity for sleepiness rating: 4.8–5.3, 5.1–5.3, 5.1 [both treatment arms]; Epworth Sleepiness Scale score: 16.7–16.9, 15.2–17.9, 17.6–18.1). For objective disrupted nighttime sleep (DNS) measures determined by polysomnography, the middle group (range of group means, 58.1–68.2) and oldest group (63.4–66.3) had more sleep stage shifts to lighter stage of sleep/wake compared to the youngest group (50.5–56.3). The oldest group experienced a higher number of nocturnal arousals (range of group means, 83.5–87.2) compared to the middle (77.6–83.2) and youngest groups (65.4–80.7). Subjective DNS measures were similar across age groups (range of group means, visual analog scale [VAS] sleep quality, 1=did not sleep/100=slept very well: 48.3–60.7; VAS refreshing nature of sleep, 1=not refreshed/100=refreshed: 44.2–53.2).

Conclusion

Baseline measures of EDS were similar among age groups of participants with narcolepsy in the REST-ON trial. Objective but not subjective DNS measures were worse in older participants, suggesting DNS may increase with age.

Support (if any)

Avadel Pharmaceuticals
0645 Comparison of Demographics and Baseline Narcolepsy Symptoms Between Participants with NT1 and NT2 from REST-ON
Authors: Dauvilliers Yves , Roth Thomas , Thorpy Michael , Morse Anne , Kushida Clete , Harsh John , Ortiz Luis , Gudeman Jennifer
Published: April 2024

Introduction

Narcolepsy is classified into 2 subtypes: narcolepsy type 1 (NT1; with cataplexy) and 2 (NT2; without cataplexy). Limited data are available regarding subtype differences in clinical characteristics and disease severity. In the phase 3 REST-ON trial, once-nightly sodium oxybate (ON-SXB; LUMRYZ™) demonstrated significant improvement in the 3 coprimary endpoints of change from baseline in mean sleep latency on the Maintenance of Wakefulness test (MWT), Clinical Global Impression of Improvement rating, and weekly cataplexy episodes (all P< 0.001) in patients with NT1 and NT2. This post hoc analysis compared baseline characteristics between participants with NT1 and NT2.

Methods

REST-ON (NCT02720744) participants were ≥16 years of age with NT1 or NT2, excessive daytime sleepiness, and cataplexy (NT1 only). Use of alerting agents was permitted. Randomization (1:1 to ON-SXB or placebo) was stratified by narcolepsy type; the trial population was oversampled for NT1. Baseline characteristics were compared between narcolepsy types.

Results

The safety population included 212 participants (NT1, n=162; NT2, n=50). At baseline, demographic characteristics of participants with NT1 vs NT2 were: mean (SD) age, 32.1 (11.1) vs 28.3 (10.0) years, respectively; sex, 72.8% vs 52.0% female; body mass index, 28.9 (7.5) vs 25.7 (5.6) kg/m2; and use of concurrent alerting agents, 59.2% vs 68.0%. Mean (SD) baseline clinical characteristics in participants with NT1 vs NT2 were: mean sleep latency (MWT), 4.9 (2.9) vs 4.9 (2.9) minutes; Clinical Global Impression rating (CGI-Severity), 5.2 (1.1) vs 4.7 (1.1); ESS scores, 17.6 (4.0) vs 15.4 (3.2); number of sleep stage shifts to lighter stage of sleep or wake measured by polysomnography (PSG), 61.5 (22.2) vs 55.8 (23.5); number of nocturnal arousals by PSG, 81.5 (42.4) vs 73.2 (35.9); sleep quality (visual analog scale [VAS; 1 = did not sleep and 100 = slept very well]), 54.5 (22.0) vs 55.8 (20.8); and refreshing nature of sleep (VAS; 1 = not refreshed and 100 = refreshed), 49.9 (22.6) vs 42.6 (21.6).

Conclusion

Limited data are available comparing NT1 and NT2 populations; these data indicate a similar level of disease severity at baseline.

Support (if any)

Avadel Pharmaceuticals
0657 Understanding the Debilitating Nature of Narcolepsy in Patients’ Own Words: A Social Listening Analysis
Authors: Morse Anne , Lavender Maggie , Horsnell Matthew , Krahn Lois , Ortiz Luis , Cronin Dianna , Schneider Beth , Gudeman Jennifer
Published: April 2024

Introduction

To further characterize the many struggles and unmet needs of people with narcolepsy (PWN), passive social listening was used to explore how PWN describe the condition using their own words.

Methods

MyNarcolepsyTeam is a social network where members can organically share their experiences living with narcolepsy with one another. Following an online survey, organic posts, comments, questions, and answers posted from January 2022 to present were analyzed.

Results

Of 110 survey respondents, 31% reported that the time from symptom onset to diagnosis was ≥10 years. Social listening highlighted both misdiagnoses (eg, depression) and “missed” diagnoses (eg, sleep apnea but not narcolepsy). Almost half (43%) of respondents reported pain as a comorbidity. Social listening revealed the burden of painful comorbidities (eg, fibromyalgia, migraines, neuropathy), which often lead to additional medications and further sleep disruption. While 90% of respondents reported excessive daytime sleepiness, 81% also reported sleep disturbances. Nighttime disruptions experienced by PWN included poor sleep quality, vivid dreams, frequent awakenings, sleep paralysis, and abnormal REM cycles. Structured routines helped improve sleep for some PWN. Additionally, 33% of respondents reporting cataplexy always experienced full body cataplexy; 21% always experienced localized cataplexy; 43% experienced a mix of both, with the remaining answering ‘not sure.’ Social listening highlighted the dangers of cataplexy, including falls/fractures. Organic conversations also brought to bear the full range of emotions that can trigger an attack – from laughter, to being startled, to feeling stressed. In total, 65% of respondents were taking ≥2 medications to treat daytime and/or nighttime narcolepsy symptoms. Organic conversations highlighted the challenges PWN experience managing complex treatment regimens in an attempt to cope with the full spectrum of narcolepsy symptoms.

Conclusion

Insight into how narcolepsy is experienced in patients’ own words and how patients try to mitigate their symptoms will help sleep specialists better understand the challenges and needs of PWN, which can lead to both faster diagnosis and more effective, individualized treatment.

Support (if any)

Avadel Pharmaceuticals
0660 In and Between Nap MSLT Features in Hypersomnia
Authors: Andersen Louise , Brink-Kjaer Andreas , Sum-Ping Oliver , Mignot Emmanuel
Published: April 2024

Introduction

This study aimed to identify novel markers of NT1 using between-nap and in-nap features of Multiple Sleep Latency Test (MSLT) recordings. We hypothesized that sleep-wake instability observed in NT1, alongside quantifiable patterns of sleepiness during wakefulness, may contain biomarkers for differentiating NT1 from other hypersomnia disorders between naps. Further, we wanted to explore if NT1 and NT2 MSLT could be distinguished beyond the common presence of a mean sleep latency below 8 minutes and multiple SOREMPs.

Methods

We analyzed in-between nap periods of MSLT recordings, extracting features describing sleepiness, microsleep patterns, and sleep-stage mixing, in three different sleep centers, based on the hypodensities obtained from U-sleep. 107 features were extracted from 178 patients diagnosed with NT1, NT2, Idiopathic Hypersomnia (IH), and Subjective IH (sIH), most with CSF hypocretin levels available. Second, we trained a model to distinguish NT1 from sIH and to differentiate NT1 from other hypersomnolence disorders, including IH plus NT2. A cross-cohort validation strategy was employed, involving training the model on combinations of two cohorts and validating on the third.

Results

Analysis indicated an increased probability of REM sleep during between-nap periods in the MSLT of NT1 patients, along with a greater prevalence of sleep stage mixing between REM and N1 sleep stages in microsleep episodes. In distinguishing NT1 from NT2, IH, and Subjective IH using features solely from between-nap periods of the MSLT, sensitivity was 0.72, specificity 0.70, and F1-score 0.62 across three validation cohorts. Distinguishing NT1 versus NT2 with between-nap features resulted in sensitivity 0.75, specificity 0.59 and F1-score 0.66 across three validation cohorts. When using features from the in-nap part of the MSLT, NT1 was distinguished from NT2 with sensitivity of 0.75, specificity of 0.82, and F1-score of 0.78 on average across the three validation cohorts.

Conclusion

The findings in this study support the hypothesis that NT1 patients exhibit increased sleepiness and sleep stage mixing during wake periods compared to other hypersomnolence disorders. Further, NT1 and NT2 could be partially distinguished using in-nap features, even so these two groups of subjects have positive MSLTs. This work supports the use of new analytical methods in MSLT.

Support (if any)
0664 Development of a Novel Patient-Reported Outcome Measure of Functional Impacts for Narcolepsy Types 1 and 2
Authors: Romero Heather , Savva Yulia , Crawford Stephen , McPherson Peter , Doll Helen , Howerter Amy , Symonds Tara , Swick Todd , Dauvilliers Yves
Published: April 2024

Introduction

Narcolepsy, a rare, chronic neurologic disorder that affects sleep-wake stability, is associated with detrimental effects on functioning, quality of life, and productivity. There is a need for a fit-for-purpose clinical outcome assessment that captures the functional impacts of narcolepsy in various clinical settings to complement the Narcolepsy Severity Scale. The objective was to develop a new patient-reported outcome (PRO) measure, the Functional Impacts of Narcolepsy Instrument (FINI), for evaluating treatment response in patients with narcolepsy type 1 (NT1) or type 2 (NT2).

Methods

Initial item generation was derived using concept elicitation (patients with NT1, n=21), cognitive debriefing (NT1, n=20; NT2, n=15), and item debriefing with medical experts. A mixed-methods approach was used to determine the final PRO using two independent datasets: a cross-sectional, US observational NT1 study (n=126) and a global Phase 2 study (NT1 and NT2, n=125).

Results

Concept elicitation interviews were conducted with patients with NT1 to understand meaningful symptoms and impacts and generate items deemed relevant by patients and medical experts. The original instrument version was then refined and cognitively debriefed with patients in two stand-alone studies resulting in a 48-item pilot version. 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.” The four a priori factors were expanded to a six-factor structure based on exploratory factor analysis results and confirmed to be multidimensional on Rasch analysis, resulting in a final 28-item version with 6-domains (tiredness, cognitive functioning, cataplexy [for NT1], social activities, everyday activities, and everyday responsibilities) (FINI v1.0). Summary scores for each of 6 domains for NT1 and 5 domains for NT2 were calculated and transformed to a standardized scale from 0 (best health) to 100 (worst health).

Conclusion

The FINI is a modular, domain-specific assessment of functional impacts that is fit-for-purpose for patients with NT1 (FINI) and NT2 (FINI-NT2). It has demonstrated good content validity and psychometric methods support scoring and interpretation. The FINI can be used to generate evidence in clinical trials or practice for functional recovery in patients with NT1 and NT2.

Support (if any)

Funded by Takeda
0666 Idiopathic Hypersomnia in the Sleep Apnea Population
Authors: Molin Nicole , DeKloe Jefferson , Doghramji Karl
Published: April 2024

Introduction

Hypersomnia in OSA can have a significant impact on patient’s quality of life. While hypersomnia tends to improve with treatment, there remains a portion of patients where this persists. This can often be attributed to inadequately controlled OSA, however the prevalence of idiopathic hypersomnia (IH) within the adequately treated OSA population remains unknown. With the emergence of new management strategies for IH, this becomes important to assess. We aim to evaluate the prevalence of patients with adequately treated OSA at risk for idiopathic hypersomnia using the idiopathic hypersomnia severity scale.

Methods

Surveys were administered to patients with OSA on CPAP demonstrating compliance of at least 80%. Surveys included IHSS, insomnia severity scale (ISI) and Epworth sleepiness scale (ESS). Patients were included if they used CPAP >6h/night, had an ISI< 14, no prior diagnosis of central hypersomnia and not on stimulant medication. IHSS >22 was considered high risk for IH based on prior validation studies.

Results

54 patients met inclusion criteria; 7 (13%) were high risk for IH, 4 (57%) of which had ESS< 10. Age, sex, race, ethnicity and CPAP use were similar between high and low risk patients. Patients with IHSS>22 (high risk) had significantly higher BMI (p< 0.05).

Conclusion

Of patients who have adequately controlled OSA and are compliant with CPAP, our data suggests that 13% of them may be at high risk for idiopathic hypersomnia. Of these patients 57% of them would not have been identified using ESS alone. This may be related to the symptom specific questions included on the IHSS such as those related to sleep inertia, total sleep time etc. While further testing with PSG/MSLT is needed to confirm a diagnosis of IH, which is currently being offered to the high risk patients, this preliminary data suggests that increased screening for IH in this population may be beneficial.

Support (if any)
0670 Patterns of Nocturnal Sleep Disruption: Differentiating IH from NT2 Using Cluster Analysis
Authors: Cairns Alyssa , Mysliwiec Vincent , Hanif Umaer , Trotti Lynn Marie
Published: April 2024

Introduction

Disambiguation of type 2 narcolepsy (NT2) from idiopathic hypersomnia (IH) is notably challenging, given the absence of biomarkers and testing (MSLT) limitations. The utility of nocturnal sleep features for diagnostic differentiation of NT2 vs. IH has yielded some promising findings. However, data are limited by the reliance on the MSLT to define CNS subtypes, yielding critical weaknesses in generalizability and inference. The goals of this study were to (1) quantify and qualify patterns of sleep disruption in patients being evaluated for hypersomnia, agnostic of MSLT outcomes [blinded] and (2) evaluate congruence between nocturnal endotypes and unblinded MSLT outcomes/diagnoses.

Methods

This study used BioSerenity’s archival database of patients being evaluated for hypersomnia with in-lab PSG-MSLT. A total of N=697 PSGs met inclusion criteria. Records were scored by senior RPSGTs and spectral power was computed on raw tracings using FFT with Welch’s method. Data for each 30-s epoch were exported for tabulation summary variables, state sequences, and transition indices. Data were ingested into a statistical program for unsupervised cluster analysis.

Results

A two-step unsupervised cluster analysis was performed on 18 PSG features; 5 were retained for cohesion: # wake-REM sequences, sleep-wake and REM transition indices, WASO, and arousal index (p<.001). The model identified 3 clusters of patients with homogeneous patterns of sleep disruption. Cluster 1 (n=88) had notably disrupted sleep and REM, cluster 2 (n=210) had sleep (not REM) disruption with WASO, and cluster 3 (n=399) had well-consolidated sleep. A multinomial logistic regression indicated similar MSLT outcomes for clusters 1 and 3 (p=.385), whereas cluster 2 had the fewest >2 MSLT REMs (17% vs. 27%; p<.001) and longest MSL (8.7 min vs. 7.1 min; p<.001).

Conclusion

This data-driven approach produced 3 distinct groups of nocturnal features that, in theory, were compatible with the conceptual distinction of NT2 from IH. However, MSLT outcomes of NT2 and IH did not reflect a differential pattern of cluster membership. While further data are needed to evaluate the clinical utility of nocturnal sleep/REM features in predicting outcomes, PSG features of sleep/REM disruption, when adjudicated against MSLT outcomes, may provide nuance to guide interpretation and additional testing.

Support (if any)

Jazz Pharmaceuticals (IST-19-11124)
0673 The Burden of Living with Narcolepsy : Patient Perspectives from In-Depth Qualitative Interviews
Authors: Doane Michael , O'Connor Meaghan , Lauher-Charest Miranda , Waldman Laura Tesler , Williams Wilbur
Published: April 2024

Introduction

Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness, among other symptoms. This rare condition may be associated with negative impacts to patients’ lives, including impaired mental and physical health, increased stigma, and difficulty obtaining an education or maintaining employment. Previous studies that have identified the burden associated with narcolepsy have largely relied on quantitative methods (e.g., surveys), providing limited insights into the patient experience. This study used qualitative, in-depth interviews to characterize the burden of narcolepsy.

Methods

Participant recruitment included convenience and snowball sampling. Sixty-minute individual interviews were conducted online by trained qualitative researchers. Interviewers used a concept elicitation approach with a semi-structured interview guide to elicit descriptions of patients’ experiences. Interview transcripts were coded and thematically analyzed using inductive and deductive approaches.

Results

Twenty-two adults with narcolepsy (type 1 [NT1] =12; type 2 [NT2=10]) participated in this study (average age: NT1=35; NT2=44). Most identified as female (NT1=83%; NT2=70%) and white (NT1=75%; NT2=60%). Approximately half of participants were employed (NT1=58%; NT2=50%). Average time since diagnosis was 7 years for NT1 and 11 years for NT2. Participants described several ways that narcolepsy has negatively impacted their lives. All or nearly all participants cited impacts on: work and school activities (e.g., trouble concentrating on tasks, forgetting information, falling asleep during meetings or conversations; NT1=100%; NT2=100%), mental health (e.g., depression, frustration, anxiety, embarrassment, lack of motivation; NT1=100%; NT2=90%), and instrumental activities of daily living (e.g., home maintenance, cooking/preparing meals, driving; NT1=92%; NT2=100%). Most participants also described negative impacts on their relationships with family, friends, and romantic partners (e.g., reduced time spent with children, strain on marriage; NT1=83%; NT2=80%) and activities of daily living (e.g., eating, bathing, dressing/grooming, toileting; NT1=92%; NT2=60%).

Conclusion

Results from this study demonstrate the wide breadth of impacts narcolepsy has on patients’ lives and, in so doing, helps to fill a gap in the literature by providing rich insights into the patient experience of narcolepsy.

Support (if any)

This study was sponsored by Alkermes, Inc. and conducted in partnership with QualityMetric. The authors thank Megan Patsch for her contributions.
0677 Winding down for the Night: Changes in Thalamocortical Connectivity Before Bed Are Associated with Deeper Sleep
Authors: Killgore William , Henderson-Arredondo Kymberly , Jankowski Samantha , Patel Salma , Hildebrand Lindsey , Huskey Alisa , Negelspach David , Grandner Michael A , Reich-Fuehrer Melissa Melissa , Franca Gabriela , Wellman Camryn , Dailey Natalie
Published: April 2024

Introduction

According to the arousal hypothesis, insomnia is often the result of excessive cognitive and somatic arousal during the sleep period. Individuals with insomnia show greater cortico-thalamic functional connectivity during waking hours than healthy sleepers. However, prior studies have only examined such connectivity at a static time point without considering dynamic changes in cortico-thalamic connectivity in the hours prior to sleep. Here, we examined the association between changes in cortico-thalamic connectivity across the 4-hours prior to sleep and subsequent overnight sleep parameters measured by polysomnography (PSG) among individuals with insomnia.

Methods

Twenty participants (12 female; age=26.9, SD=6.6 years) with insomnia symptoms completed two serial resting-state functional connectivity (rsFC) MRI sessions in the early evening (1900-2000 and 2100-2200 hrs.) followed by PSG monitored sleep from 2300 to 0700 in a controlled sleep laboratory. Sleep parameters, including time in wake, N1, N2, N3, total sleep time (TST), sleep efficiency (SE), and rapid eye movement (REM) sleep were entered into a series of seed-to-voxel whole-brain analyses using the CONN Toolbox (v21.a). The seed region comprised bilateral thalami as defined by the Automated Anatomical Labeling Atlas. The correlation between the change in cortico-thalamic connectivity and subsequent time in each sleep stage was calculated. Data were analyzed with peak threshold of p<.005 (uncorrected) and p<.05 False-Discovery-Rate (FDR) cluster correction.

Results

Greater declines in cortico-thalamic connectivity prior to bedtime were associated with significantly more N3 sleep (i.e., anticorrelated connectivity to left orbitofrontal cortex, middle frontal gyrus, putamen, insula, and medial prefrontal/paracingulate gyrus), and more REM sleep (i.e., anticorrelated connectivity to the left lateral occipital cortex). Interestingly, greater cortico-thalamic connectivity to the bilateral visual cortex and frontal pole during this same pre-sleep period was associated with more time in stage N2 sleep. Changes in connectivity were not associated with wake, N1, TST, or SE.

Conclusion

Among individuals with insomnia, greater declines in cortico-thalamic connectivity, particularly regions associated with emotion, interoception, and sensory-motor processes, predicted more time in slow-wave sleep, also known as the ‘deep sleep’ stage. Findings support the arousal hypothesis and suggest that interventions that facilitate cortico-thalamic gating may prove useful in facilitating sleep and treating insomnia.

Support (if any)

USAMRAA: W81XWH2010173
0681 Circadian Rest/activity Rhythms Are Associated with Cognitive Flexibility Among Older Adults with Insomnia
Authors: Pfaeffle Claire , Wilkens Kristine , Zhao Zhiwei , Verceles Avelino , Johnston Christine , Jones Ashley , Chen Shuo , Rogers Valerie , Spira Adam , Buysse Daniel , Wickwire Emerson
Published: April 2024

Introduction

Circadian rest/activity rhythms (RARs) are associated with cognitive function among older adults. Reports of poor cognitive function are common among individuals with insomnia. We examined the association of circadian RARs with performance in multiple cognitive domains among older adults with insomnia.

Methods

Older adults with insomnia were recruited from a tertiary academic medical center. Participants wore an actigraph and completed concurrent sleep diaries for up to 14 days. We derived nonparametric circadian RARs including relative amplitude (RA), interdaily stability (IS), intradaily variability (IV), maximum ten-hour activity (M10) and minimum five-hour activity (L5). Secondary parametric RARs included amplitude, acrophase, and midline statistics of rhythm (MESOR). Cognitive function was measured via the Brief Test of Adult Cognition by Telephone as well as in-home computerized administration of the psychomotor vigilance test, Stroop Test, and a Task-switching test. Cognitive testing results were grouped into eight a priori-defined domains (attention, inhibition, cognitive flexibility, episodic verbal memory, working memory, reasoning, executive function, processing speed). Composite domain scores were calculated by averaging the z-scores for all individual tests within that domain. Finally, a series of 64 linear regression models were tested to determine the association between circadian RAR parameters and cognitive domains. All models were adjusted for age, sex, education, and total sleep time. We used the Benjamini-Hochberg procedure for correcting false discovery rate (BH-FDR) to correct for multiple comparisons.

Results

The final sample included 30 older adults with insomnia (67% women, mean age=68.0 [SD 6.58] years) who self-identified as White (80%), Black (17%) and American Indian (7%) race. Greater IS (t=2.82, p=0.011), RA (t=2.59, p=0.018), and L5 (t = 2.61, p=0.017) were associated with greater cognitive flexibility. Of parametric RARs, greater amplitude (t = 2.53, p=0.020) and acrophase (t=2.67, p=0.015) were also associated with greater cognitive flexibility. No other significant associations were observed for any cognitive domain.

Conclusion

Circadian RARs were associated with cognitive flexibility but not other cognitive domains. These findings highlight the potential importance of circadian RAR parameters among older adults with insomnia and provide further support for cognitive flexibility as a key cognitive outcome among older adults with sleep problems.

Support (if any)

Merck Investigator Studies Program (#59170).