bluuebunny/crossref_metadata_2025 huggingface dataset:
0606 Post Market Surveillance from Precision OAT Cases Indicates High Levels of Patient and Provider Satisfaction
Authors: Murphy Mark , Liptak Leonard , Ojeda Yoann
Published: April 2024

Introduction

Post Market Surveillance has emerged as an important tool for assessing the total quality of medical devices, including patient and provider experience and human factors. To prepare for forthcoming medical device directives that require more comprehensive post market surveillance, at least one manufacturer has implemented a program. This scientific abstract reports data from this program.

Methods

Post market surveillance cards from 10,880 patients and 646 individual providers were returned over a 60 month period to the manufacturer, immediately following delivery of each precision oral appliance therapy (OAT) device (ProSomnus Sleep Technologies, Pleasanton, CA, USA).

Results

98% of patients and provider reported a “First time fit” meaning the initial quality of the precision OAT was robust; 2% of precision OAT devices required adjustments or for the device to be remade by the manufacturer. 99% of patients reported being “satisfied” with their precision OAT device upon delivery. And 98% of providers reported being satisfied with the precision OAT device upon delivery to the patient. 100% of providers reported that they, “would recommend the treatment.”

Conclusion

These results contrast with provider satisfaction reported previously for other OSA treatments. A study by Fletcher Spaight of 100 physicians board certified in sleep medicine reported 60% satisfaction for legacy, non-precision OAT devices, and 68% satisfaction for CPAP.Precision OAT devices made from precision, digital manufacturing processes are associated with high levels of satisfaction amongst patients and providers in this large sample size post-market surveillance dataset.

Support (if any)

No support provided for this study The authors disclose their association with ProSomnus sleep technologies, who provided this dataset.
0607 Update on Observational Restrospective Study of the Efficacy of Oral Appliance Therapy for Obstructive Sleep Apnea
Authors: Meskill Sarah , Flores Jacob , Boren Payton , Richardson Sue Ellen , Meskill Gerard
Published: April 2024

Introduction

Obstructive sleep apnea (OSA) affects approximately 15-30% of males and 10-15% of females in North America. While positive airway pressure (PAP) therapy remains the standard in the treatment of OSA, oral appliance therapy (OAT) has emerged as a viable non-invasive alternative. However, there are limited data on OAT efficacy published, and therefore many sleep clinicians question its efficacy. As an update to last year’s presentation, we extended our single-center consecutive chart review to 26 months to evaluate OAT efficacy.

Methods

A manual chart review was performed for records from 11/1/2020 to 12/20/2023. Potential charts were identified in the electronic health record by searching for prescriptions for OAT and orders for home sleep apnea tests (HSAT). If there was a test performed after the prescription was written, the chart was reviewed manually for previous test results and verified that post-OAT testing was conducted. Extracted information included age, BMI, gender, pre-OAT HSAT apnea-hypopnea index (AHI), and post-OAT HSAT AHI. The 4% desaturation criteria for AHI was used in accordance with current Medicare guidelines. A paired t-test was performed after ensuring there were no outliers and a normal distribution.

Results

There were 34 patients included in the analysis: 17 women, 17 men. The average age was 60.2 years (95% CI XXX), and average BMI was 29.5 (95% CI XXX). Prior to intervention, 12 patients had moderate OSA with the rest mild (average pre-OAT AHI 10). After OAT device, 2 patients had more than mild obstructive sleep apnea,18 patients had mild OSA, and the rest (14) did not have residual OSA (average post-OAT AHI 6). The results of the paired t-test showed that the mean AHI was statistically significantly different between the two groups.

Conclusion

The results demonstrate efficacy of OAT in treating OSA. Clinicians should consider OAT as both primary and secondary therapy for mild-to-moderate OSA.

Support (if any)
0608 No Adverse Effects from Expiratory Positive Expiratory Pressure (EPAP) Enhanced Mandibular Advancement Device (MAD)
Authors: Metwali Rami Al , Conflitti Antonella , Reiter Hilary , Sharma Sat
Published: April 2024

Introduction

The ExVent is an optional accessory to the O2Vent Optima mandibular advancement device (MAD) and provides oral Expiratory Positive Airway Pressure (EPAP). Oral EPAP with the ExVent is designed to provide upper airway support via similar mechanisms of action of nasal EPAP devices in commercial distribution, e.g., passive dilatation of the airway, which reduces flow limitation. Nasal EPAP devices are in commercial distribution as stand-alone therapies for the treatment of OSA. The oral EPAP provided by the ExVent accessory augments the OSA therapy provided by the O2Vent Optima. Long-term complications and adverse effects associated with this combination therapy are not known, but require further study.

Methods

We conducted a retrospective survey of all patients who received O2Vent Optima mandibular advancement device and oral expiratory positive pressure accessory (ExVent) in Canada and Australia from 2019 to November 2022. A study investigator contacted the participants via telephone, obtained consent and collected data on: demographics, duration of use, frequency of use, complications and adverse events.

Results

Out of the patient database of 480 subject, 168 (35%) participated. 31 (18%) stopped using the appliance. Out of 137 (81%) subjects, 118 (86%) were still using the ExVent Accessory, 92% medium strength (Yellow). Mean age 52±7 yrs, 76% Male. Mean duration of use 2.7±0.9 years, 91% for most nights, 86% for >6 hours/night. 56% used morning aligner and 74% performed regular jaw exercises. After 4 weeks of use, excessive salivation was occasional (12%), tooth and jaw pain occasional (8%), tooth movement none (0%). Gum /tongue bruises reported in none (0%). TMJ pain/stiffness reported (5%). Change in bite or occlusion leading to discontinuation none (0%), temporary chewing difficulties (24%), dry mouth none (0%). Difficulty with insertion/removal of ExVent valve none (0%), difficulty breathing in none (0%), Malfunctioning/dislodgement of ExVent valve reported in none (0%). Participants reportedly loved their device (94%) and benefited from ExVent (100%).

Conclusion

This retrospective study demonstrated that majority of patients prescribed EPAP enhanced MAD with O2Vent Optima and ExVent accessory were compliant. There were no significant complications and only minor adverse effects were observed with the combination therapy.

Support (if any)

Centre for Sleep and Chronobiology, Toronto, ON, Canada
0612 Adenotonsillectomy During Childhood Does Not Elevate the Likelihood of Adulthood Overweight
Authors: Goldbart Aviv D , Abuhasira Ran , Even-Tsur Jacov , Shiloh Adi , Tarasiuk Ariel
Published: April 2024

Introduction

Adenotonsillectomy for pediatric obstructive sleep apnea (OSA) might not promote healthy body weight in the short term, as overweight children could still experience accelerated weight gain and increased risk of obesity. Limited data exists regarding the long-term effect of adenotonsillectomy on body mass index (BMI) as individuals enter their third decade of life. Our study investigated BMI twenty years following adenotonsillectomy or watchful waiting (WW).

Methods

Between 1998 and 2000, we enrolled 260 children with OSA, as defined in our previous study (PMID: 14754948). Among them, 132 had undergone adenotonsillectomy, 127 WW, and one participant died from cardiac arrest. All patients have been members of Clalit Health Services (CHS), Israel's largest healthcare organization, for over 25 years. CHS offers compulsory healthcare coverage via the National Health Insurance Law and employs a unified medical record system. Polysomnography records were obtained from the sole pediatric Sleep-Wake Laboratory in southern Israel. In June 2023, we received adulthood anthropometric data from the original study participants' electronic medical records.

Results

Both groups had moderate OSA and showed no differences in their initial BMI z-scores, which were -0.2 ± 1.6 and 0.1 ± 1.4 (p = 0.5) for the WW and adenotonsillectomy groups. The twenty-year follow-up indicated similar BMIs of 26.0 ± 5.8 (kg/m2) for the WW group and 25.5 ± 6.4 (kg/m2) for the adenotonsillectomy group (p = 0.5). However, children with baseline BMI z-scores ≥ median, especially females (p < 0.05), exhibited higher BMIs after 20 years. Following accounting for sex, apnea-hypopnea index, and socioeconomic status, it was found that adenotonsillectomy did not elevate the risk of being overweight (BMI ≥ 26) in the third decade of life. Females had a higher likelihood of being overweight (OR = 2.22, 95% CI: 1.10-4.58), as did individuals with childhood BMI z-scores ≥ median (OR = 4.67, 95% CI: 2.39-9.82).

Conclusion

Childhood adenotonsillectomy does not increase the risk of being overweight. High BMI z-scores correlate with an increased risk of adult overweight, unaffected by adenotonsillectomy. Adenotonsillectomy does not impact future BMI, highlighting the importance of promoting a healthy childhood lifestyle to prevent adult obesity.

Support (if any)

Israel Science Foundation grant No 164/2018
0614 Comparison and Outcomes of Adenotonsillectomy for Obstructive Sleep Apnea in Children with Achondroplasia
Authors: Ascencio Claudio Gomez , Wani Anna , Mitchell Ron
Published: April 2024

Introduction

Achondroplasia, a genetic disorder arising from a FGFR3 mutation, is typically detected perinatally, and affects 1 in 40,000 children. The diagnosis of achondroplasia has many associated medical complications, one of which is obstructive sleep apnea (OSA). The objective was to compare demographics between children with achondroplasia and OSA with the general pediatric population with OSA, as well as present treatment outcomes for children with achondroplasia.

Methods

Retrospective chart review of 22 children with achondroplasia and OSA. A sample of 141 children with OSA without achondroplasia was used as a control. Parameters from polysomnography (PSG) were recorded and analyzed. Values before and after adenotonsillectomy (T&A) were compared for the achondroplasia group, while baseline values were compared between the control group and achondroplasia group.

Results

In the achondroplasia group, 12 children who were treated with T&A were included. In the control group, 141 children were included. In the T&A achondroplasia group, 0 children had mild OSA, 1 had moderate OSA, and 10 had severe OSA. In the comparative group 16 had mild OSA, 11 had moderate OSA, and 114 had severe OSA. The achondroplasia population had a much younger age at T&A compared to the control population (p-value < 0.001.) Obstructive Apnea-Hypopnea index, a marker of OSA severity, trended toward being higher in the achondroplasia group (p-value = 0.06). The lowest SpO2 saturation was not significantly different in the achondroplasia group. When comparing baseline data in the achondroplasia population with respective T&A outcomes, both oAHI (p-value < 0.05) and SpO2 (p-value < 0.05) were significantly improved.

Conclusion

Patients with achondroplasia and OSA have an earlier age of onset compared to children without achondroplasia. For these patients, treatment with adenotonsillectomy shows a significant improvement in OSA severity. Future research needs would be to increase sample sizes, establish a standard treatment for OSA in children with achondroplasia, and also establish improvement and treatment frequency by OSA severity. There is also a need to compare the improvement of OSA in children undergoing other interventions and compare these to the general pediatric population.

Support (if any)
0615 DISE-Cryotherapy a Novel Treatment for Patients with Obstructive Sleep Apnea
Authors: saleh Abdelbaset , Mohamed Fatmah , Hussein Mona , Awadalla Nabil , Mohammadien HamdyA
Published: April 2024

Introduction

Drug induced sleep endoscopy (DISE) can provide valuable information about the level (VOTE), pattern and degree of upper airway obstruction in patients with obstructive sleep apnea (OSA). Integrating DISE with cryotherapy can provide a novel and successful treatment for OSA patients. The objective of this study was to examine safety and efficacy of a novel DISE-Cryotherapy technique in treating OSA.

Methods

A prospective single-arm interventional trial was done after institution review board approval and formal patient consent. Thirty adult subjects with confirmed OSA underwent DISE and cryotherapy in two sessions with two weeks interval using a flexible cryocanalization probe (78 cm in length/2.4 mm in diameter, ERBE, Medizintechnik GmbH, Tübingen, Germany) with cryomachine (ERBECRYO CA, ERBE, Tübingen, Germany). Polysomnogram (PSG) was done pre-intervention and repeated 12-weeks post-intervention. Primary outcomes were reduction in baseline DISE score and apnea hypopnea index (AHI), and improvements in excessive daily sleepiness (EDS) and other OSA related symptoms. Patients follow up was done at two-weeks and, and 12-weeks post-intervention.

Results

Twenty men and 10 women with OSA were included in the study. There mean (SD) age and BMI were 42.57(9.52) years and 32.28 (3.19), respectively. Preoperative Mallampati, tonsillar size and VOTE mean scores were 2.4 (0.49), 1.33 (0.47) and 2.7 (1.02) respectively. Preoperative mean AHI and desaturation index were 31.10 (19.15) and 29.01(20.40), respectively. A two-week post cryotherapy evaluation showed reduction in the mean of VOTE score to 1.6 (0.93) and significant improvements in all sleep related clinical symptoms. Twelve-week post cryotherapy assessment revealed a significant reduction in the mean AHI, and desaturation index to 10.07 (7.65), and 10.3(8.33) respectively. The median (range) of percentage reduction in baseline AHI was 71.36% (42.05-86.38). Above 50% reduction in baseline AHI was achieved in 90% of patients with a mean of 70.63%, while only 10% showed 20-50% reduction with a mean of 45.78%. Significant independent predictors for percentage reduction were age and preoperative total VOTE score. No immediate or remote side effects were reported.

Conclusion

Cryotherapy is a safe and promising intervention for treatment of OSA patients.

Support (if any)

No
0616 Effects of Oropharyngeal Rehabilitation After Transoral Robotic Surgery in Patients with Obstructive Sleep Apnea
Authors: Lai Yi-Ju , Li Chung-Yi , Tsai Kun-Ling , Lin Cheng-Yu , Hung Ching-Hsia
Published: April 2024

Introduction

To demonstrate the effects of postoperative oropharyngeal rehabilitation on inflammatory mediators and antioxidant capacity in adult obstructive sleep apnea patients.

Methods

Obstructive sleep apnea patients were recruited and divided into conservative treatment group (n = 17), surgery group (n = 23), or surgery combined with oropharyngeal rehabilitation group (n = 19) by their willingness. Polysomnography data and the concentration of inflammatory mediators and antioxidant capacity were determined at baseline, after 6 weeks and 18 weeks of treatment.

Results

The data of fifty-nine patients was analyzed. Post-treatment percent change of apnea–hypopnea index in rapid eye movement sleep was positively correlated with that of interleukin-6 (0.641, 95%CI 0.598 to 0.685; P<.001). Compared with the patients in control group, those in surgery combined with oropharyngeal rehabilitation group had significantly reduced post-treatment percent change of interleukin-6 (-77.273, 95%CI -144.580 to -9.966; P=.216). In addition, the concentration of interleukin-6 (-3.423, 95%CI -6.638 to -0.207; P=.037) and matrix metallopeptidase-9 (-20.517, 95%CI -40.584 to -0.450; P=.045) exhibited significantly decreased in the surgery combined with oropharyngeal rehabilitation group. The level of total antioxidant capacity exhibited significantly improved in the surgery combined with oropharyngeal rehabilitation group as compared to the surgery–only group (0.034, 95%CI 0.005 to 0.063; P=.020).

Conclusion

The presented results demonstrate postoperative oropharyngeal rehabilitation could decreased the serum level of inflammatory mediators and increased antioxidant capacity. Results from this study could potentially be targeted by combination of different treatments.

Support (if any)

This work was supported by National Cheng Kung University Hospital (grant numbers NCKUH 10802018, NCKUH-10902002, and NCKUH-11002046).
0621 Glucagon-Like Peptide 1 Receptor Agonist and Positive Airway Pressure Use in Patients with OSA and Obesity
Authors: Malik Anita , Cameron Ann , Woodford Caleb , Alpert Naomi , McConnell Will , Sterling Kimberly , Cistulli Peter , Malhotra Atul , Pépin Jean-Louis , Cole Kate
Published: April 2024

Introduction

Obstructive sleep apnea (OSA) and obesity are strongly associated and highly prevalent in the United States (US). Routine treatment for OSA often includes positive airway pressure (PAP) therapy combined with weight management strategies, more recently including use of glucagon-like peptide 1 (GLP-1) receptor agonists. This real-world analysis assessed the impact of recent GLP-1 use on PAP therapy use over 1 year in non-diabetic patients with PAP-treated OSA and obesity.

Methods

Administrative claims data from January 2014-May 2023 linked to objective PAP usage data were analyzed. Commercially- or Medicaid insured non-diabetic adults (18-64 years) with OSA and obesity, ≥1 year of claims data before and after PAP setup (index date), and ≥1 year of PAP therapy data post index were included. Patients who filled a GLP-1 prescription within 90 days prior to index were considered recent GLP-1 users. Other GLP-1 users were excluded. PAP therapy adherence was categorized as adherent, intermediately adherent, or non-adherent based on objective usage over 1 year. PAP discontinuation was defined as >30 consecutive days with no use. Inverse probability of treatment weighting was used to balance groups on baseline covariates to compare PAP use over 1 year for OSA patients with and without a recent GLP-1 fill prior to index.

Results

A total of 267,794 patients with OSA were included (mean age 47.7 years; 44.1% female), of which 1,137 (0.43%) were recent GLP-1 users at index. Recent GLP-1 users were more commonly female (66.6% vs 44.0%), commercially insured (82.2% vs 77.7%), and with class III obesity (67.5% vs 46.8%) than those without a recent GLP-1 prescription fill. Average hours/day of PAP use at 1 year did not differ significantly between groups (3.80 vs 3.96). There was no significant difference in PAP adherence rates (adherent: 42.1% vs 45.1%; intermediately adherent: 29.5 vs 28.4%; non-adherent: 28.5 vs 26.5%) or PAP discontinuation (43.9% vs 41.7%) for those with and without recent GLP-1 use prior to index.

Conclusion

PAP use was similar among non-diabetic patients with OSA and obesity who did and did not have recent GLP-1 use prior to PAP.

Support (if any)

ResMed
0622 Remote Patient Monitoring to Manage OSA Using a Variety of Therapeutic Approaches in an Active Sleep Practice
Authors: Simmons Jerald , Sadeghian Sam , Lavender Maggie , Hua Olivia , Jarreau Jordan , Mira Catherine , Lopez Stormy
Published: April 2024

Introduction

Remote Patient Monitoring (RPM) using the REST-Tracker system incorporates FDA cleared SleepImage OSA analysis from a ring oximeter worn nightly providing output metrics corresponding to the AASMs 1A/1B Hypopnea rules (sAHI3%/sAHI4% respectively). The REST-Tracker system assists in improving clinical decisions, reducing treatment failures and lowering the burden of repeated (in-lab/home) OSA sleep testing. Other systems currently in use for OSA management rely on PAP derived indexes, loosely labeled as an AHI equivalent, and are falsely considered by many as equivalent to FDA cleared HSAT derived metrics. Such systems only provide data while using PAP devices and have no utility with other treatment approaches such as Inspire or OAT. Our OSA patients are treated via a variety of therapeutic approaches and we provide here a summarization of our current experience using this new REST-Tracker approach and an additional PAP-subanalysis to assess the sensitivity of the PAP derived AHI metric (pAHI) metric which is used by other RPM systems.

Methods

OSA patients undergoing treatments ranging from PAP, OAT, Inspire, surgery, or in-combination were monitored nightly with the REST-Tracker ring RPM platform. The sAHI3%/sAHI4% output metrics were managed by staff using REST-Tracker and therapy adjusted in accordance with patients' circumstances, optimizing treatment. PAP-subanalysis: A subset of 10 PAP patients data was extracted to compare the pAHI metric to the corresponding sAHIs(3%&4%).

Results

95 patients monitored, ranging 6-28 months, across all treatment groups (39-PAP, 14-Inspire, 7-OAT, 9-combo-PAP-OAT, 16-combo-Inspire-PAP and 10-Combo-MMA-Inspire/other), with an average Diagnostic 1A AHI=30.4(+/-21.0)/1B AHI=15.65(+/-17.8) improved with most recent 30-day data demonstrating average sAHI3%=11.5(+/- 8.0) sAHI4%=6.3(+/-5.6). For the PAP-subanalysis, duration ranged/per patient from 120-284 nights, Median values of pAHI=2.6, sAHI3%=10.4 & sAHI4%=3.4

Conclusion

The REST-Tracker provides longitudinal nightly assessment giving clinicians objective measures to assist treatment decisions and is superior to single-night testing and agnostic to treatment approaches, unlike other PAP-dependant RPM systems. A more elaborate detailed presentation with clinical examples will be presented at the conference, demonstrating this futuristic approach in sleep health disease management.

Support (if any)
0624 A Mass Spectrometry Method Evaluating Orexin Metabolites Suggest Abnormalities in Hypersomnias of Central Origin
Authors: Horie Kanta , Steger Christopher , Koppisetti Rama Krishna , Mignot Emmanuel , Lucey Brendan
Published: April 2024

Introduction

Narcolepsy type 1 (NT1) is caused by orexin (hypocretin) deficiency with 85-95% loss of orexinergic neurons reported in the hypothalamus. Patients with NT1 have cerebrospinal fluid (CSF) orexin-A immunoreactivity deficiency ≤110 pg/ml, as detected using a polyclonal anti-orexin-A radioimmunoassay (RIA). Although some narcolepsy type 2 patients (NT2) have been reported to have a partial loss of orexinergic neurons, the large majority of patients with NT2 have normal levels of CSF orexin-A. Previous work has shown that the RIA measures < 10% of the intact orexin-A peptide, suggesting that the RIA for CSF orexin-A primarily measures unauthentic orexin-A-related metabolites. In this study, we developed a novel mass spectrometry assay to measure intact prepro-orexin, orexin-A, and orexin-B, and their metabolites, in CSF collected from patients with NT1, NT2, idiopathic hypersomnia (IH), and controls.

Methods

Using a novel sequential immunoprecipitation/mass spectrometry method, all orexin species (intact-long and short-metabolite forms) were comprehensively measured in CSF collected from patients diagnosed with NT1 (N=15), NT2 (N=15), IH (N=15), and controls (N=15). Orexin peptides were analyzed by a nanoAcquity ultra-performance liquid chromatography system coupled to an Orbitrap Tribid Eclipse mass spectrometer.

Results

NT1 showed pan-orexin deficiency with lower predicted levels of prepro-orexin, orexin-A, and orexin-B species compared to NT2, IH, and controls (all p< 0.05 after Tukey correction for multiple comparisons). Short-form metabolites of orexin-B differentiated both NT2 and IH from NT1 and from controls (all p< 0.05 after Tukey correction for multiple comparisons). Further, the ratio of the shortest form of orexin-B/longer orexin-B species was decreased in NT2 compared to IH and controls (all p< 0.05 after Tukey correction for multiple comparisons).

Conclusion

A novel mass spectrometry assay comprehensively measuring different forms of CSF orexin differentiated among the hypersomnias of central origin and may have diagnostic utility. As expected, all forms of orexin were lower in CSF collected from NT1 patients compared to other groups. We also found that short metabolites of orexin-B are reduced in participants with NT2 and IH. Abnormal orexin transmission may also be involved in the pathophysiology of NT2 and IH, with differential impact on orexin peptide species.

Support (if any)

R21 AG074151 and Eisai
0626 Impact of Washout Timing of Psychotropic Medications on the MSLT
Authors: Farris Alex , Araujo Matheus Lima Diniz , Saribalas Michael , Foldvary-Schaefer Nancy
Published: April 2024

Introduction

While highly reproducible in narcolepsy type 1, MSLT results are more variable in other CNS hypersomnolence disorders. Use of psychotropic medications is a known contributor to MSLT validity given the high comorbidity of psychiatric illness in patients with hypersomnolence disorders. We leveraged a large MSLT database to study the impact of timing of washout of psychotropic medications with known REM-suppressing effects on MSLT results.

Methods

This was a retrospective analysis of MSLTs performed 2012-2023 at Cleveland Clinic. Medication groups studied included selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). Date of last dose prior to MSLT was collected and categorized as ≤14 days or >14 days prior to MSLT. Multivariable adjusted regression analyses (linear and logistic) adjusting for age, sex, and BMI were conducted to evaluate the influence of a late washout (ie ≤14 days prior to MSLT) on recording ≥2 sleep onset REM periods (SOREMPs) and on recording a mean sleep latency (MSL) < 8 minutes.

Results

180 unique MSLTs were analyzed. Of these, 80 patients had recorded use of SSRIs, SNRIs, and/or TCAs leading up to the MSLT, and 63 of these 80 patients used such a medication ≤14 days before the MSLT. Seven of 80 patients (8.8%) had ≥2 SOREMPs, and 27 (33.8%) had MSL < 8 minutes. Logistic regression analysis showed a negative correlation between a late washout and obtaining ≥2 SOREMPs (OR 0.05, p< 0.01), but no significant correlation with obtaining MSL < 8 minutes (p=0.07). Linear regression analysis similarly showed a negative correlation between a late washout and obtaining ≥2 SOREMPs (coefficient -0.77, p>0.001) but no significant correlation with obtaining MSL < 8 minutes.

Conclusion

These findings underscore the importance of appropriately timed REM suppressant washout prior to MSLT to optimize test validity. Further analyses will examine the effects of other CNS-active medication classes in a larger cohort of patients.

Support (if any)

NIH grant R21HL170206
0627 Influenza HA Antibody Titers in Recent Onset Type-1 Narcolepsy
Authors: Yan Han , Lin Ling , Zhang Jing , Mignot Emmanuel
Published: April 2024

Introduction

Epidemiological studies have shown associations between pandemic H1N1 2009 Influenza-A infection and vaccination (only using Pandemrix®) and the onset of narcolepsy, an autoimmune disease associated with HLA-DQB1*0602. We tested whether recent onset type 1 narcolepsy patients have increased influenza antibody titers comparing with matched HLA-DQB1*0602 positive controls.

Methods

Sera of 82 recent onset type-1 narcolepsy patients (12 [1-25] months) and 84 healthy controls matched by sex, age, and year and season of sample collection were used. Sera were tested for Influenza-A and B HA antibodies using hemagglutinin inhibition (HAI) assays against the dominant strains known to circulate at time of collection. HAI assays against H1N1pdm09 were also tested independently in samples collected after 2009. Antibody titers were log2 transformed into geometric mean, with zero being < 1/10 dilution, 1 as 1/10, 2 as 1/20 etc., so that every dilution represents an increment of 1 unit. Further analysis using multiple variable linear regression and logistic regression were done to analyze association between confounding factors and disease status and HA antibody titers.

Results

H1N1pdm09 HA titers were increased in 25/63 (39.7%) subjects collected after 2009. Increasing HA titers (doubling rate) of H1N1pdm09 [OR=1.2962(1.0513, 1.5984), p=0.015], all H1N1 [OR=1.13(1.03-1.24), p=0.023] and B/Victoria [1.37 (1.16-1.61), p=0.001] were associated with narcolepsy, whereas no association was found with H3N2 and B/Yamagata. Logistic regression shows after controlling sex, age and season of sample collection, narcolepsy is associated with H1N1pdm09 [4.68(1.5281, 14.3392), p=0.007] and B/Victoria strains [5.5306 (2.6039, 11.8224), p=0.001].

Conclusion

Both H1N1 and B/Victoria, but not other strains, may trigger narcolepsy onset. This result is in line with a recent epidemiological study in Europe that reported a strong increase in narcolepsy onset in 2010 (following 2009 H1N1 pandemic) and a secondary peak in 2013 following a season with a dominant B/Victoria infection.

Support (if any)

This work was supported by 5R01AI144798-03/HHS|NIH|National Institute of Allergy and Infectious Diseases (NIAID).
0632 Design Elements for a Switch Study from High- to Low-Sodium Oxybate Evaluating Blood Pressure in Narcolepsy (XYLO)
Authors: White William , Macfadden Wayne , Baranak Christine , Nichols Deborah , Akerman Sarah , Somers Virend
Published: April 2024

Introduction

High sodium intake can increase blood pressure (BP) and future cardiovascular risk. Individuals with narcolepsy have an elevated cardiovascular comorbidity burden before considering medication-specific risks. Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration (FDA) to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy and idiopathic hypersomnia in adults. LXB has the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but contains 92% less sodium. The objective of XYLO is to measure ambulatory and in-clinic systolic BP (SBP) changes after switching to LXB from a high-sodium oxybate in participants with narcolepsy (NCT05869773).

Methods

This 6-week, open-label, multicenter, switch study is enrolling participants 18–70 years of age with narcolepsy (type 1 or 2) taking 6–9 g/night of high-sodium oxybate for ≥6 weeks. Hybrid enrollment supports both on-site and decentralized (monitored at the participant’s home by mobile health professionals) participation, and may broaden the pool of eligible participants. After ≥2 weeks on stable high-sodium oxybate dose/regimens (screening period), participants switch to the same dose/regimen of LXB for 6 weeks (intervention period). The primary endpoint is the change in 24-hour SBP from baseline (the most recent screening measurement prior to switching) to the end-of-treatment visit (approximately 6 weeks after switching) measured via 24-hour ambulatory BP monitoring (ABPM). Secondary endpoints evaluate change from baseline to end-of-treatment visit in-clinic SBP, as well as daytime average SBP and nighttime average SBP measured via 24-hour ABPM.

Results

Recruitment began in June 2023. This study uses a group sequential design with an adaptive sample size target of 57–77 participants completing the 6-week intervention period. This design provides 90% power to detect a mean difference of 3.5 mmHg (a clinically relevant change) in 24-hour SBP (assuming a standard deviation of the differences in 24-hour SBP of 8 mmHg).

Conclusion

XYLO will enable the assessment of 24-hour BP changes following transition from a high-sodium oxybate to LXB. Planned hybrid enrollment with a decentralized option may increase study access leading to a more diverse clinical trial population.

Support (if any)

Jazz Pharmaceuticals
0638 Stability of Once-Nightly Sodium Oxybate in Alternative Liquid Reconstitution Vehicles
Authors: Lavender Maggie , Wermter Ellen , Morse Anne , Horsnell Matthew , Vaughn Jason , Ascencion Frederik , Gudeman Jennifer
Published: April 2024

Introduction

LUMRYZ™ is a once-nightly formulation of sodium oxybate (ON-SXB) containing both immediate and pH-dependent controlled-release granules designed to be reconstituted in water and administered orally. This study was conducted to determine the dissolution profile of ON-SXB at prescribed doses after reconstitution in alternative liquids.

Methods

Dissolution and pH testing was conducted with ON-SXB 4.5-g and 9-g single-dose packs reconstituted in Milli-Q® water (control), Crystal Light© Raspberry Lemonade (CL), MiO© Fruit Punch Concentrate (Mio), and alkaline water (AW). CL and Mio were prepared with tap water. Dissolution (percent of label claim) was measured at 15 minutes and 1, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours after 5-minute (AW only) and 30-minute (CL, Mio, and AW) rest periods. The pH of each reconstitution solution was measured prior to and then 5 and 30 minutes after addition of ON-SXB.

Results

After 15 minutes, ON-SXB 4.5 g was 50% dissolved in control, 51% in CL and Mio, and 49% in AW after both rest periods; at 8 hours, 98% was dissolved in control, 101% in CL and Mio, and 99% in AW after both rest periods. At 15 minutes, ON-SXB 9 g was 50% dissolved in control and CL, and 51% in Mio and AW after both rest periods; at 8 hours, 98% was dissolved in control, 101% in CL and Mio, 97% in AW after the 5-minute rest period, and 98% in AW after the 30-minute rest period. Before addition of ON-SXB, the pH of control, CL, Mio, and AW was 7.03, 3.02, 2.95, and 9.53, respectively. For ON-SXB 4.5 g in control, CL, Mio, and AW, the pH was 5.6, 5.3, 5.4, and 5.6 at 5 minutes and 5.6, 5.2, 5.3, and 5.5 at 30 minutes, respectively. For ON-SXB 9 g in control, CL, Mio, and AW, the pH was 5.7, 5.5, 5.6, and 5.7 at 5 minutes and 5.7, 5.6, 5.6, and 5.7 at 30 minutes, respectively.

Conclusion

These results show consistent and acceptable dissolution of ON-SXB in various liquids, which may be preferred by some patients as alternatives to water.

Support (if any)

Avadel Pharmaceuticals
0643 Patient Preferences of Sodium Oxybate Treatment for Narcolepsy: RESTORE End-of-Study Survey Data
Authors: Ajayi Akinyemi , Mignot Emmanuel , Roy Asim , Corser Bruce , Stern Thomas , Hudson J Douglas , Santamaria Adrian , Abaluck Brian , Gudeman Jennifer
Published: April 2024

Introduction

Until recently, the only available oxybate therapy options were immediate-release (IR) formulations requiring patients to awaken 2.5 to 4 hours after their first dose to take a second dose. Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is an extended-release formulation of sodium oxybate that eliminates the need for a middle-of-the-night dose. RESTORE (NCT04451668) was an open-label/switch study that evaluated the safety and tolerability of ON-SXB and surveyed patient preferences for ON-SXB or IR oxybate therapies.

Methods

Participants were ≥16 years of age with narcolepsy type 1 or 2 who either completed the phase 3 REST-ON trial and were on stable doses of IR oxybate for ≥1 month or oxybate naive. Participants completed end-of-study (EOS) questionnaires to capture their experience with ON-SXB.

Results

As of November 2023, EOS questionnaire data were available for 89 participants, including 21 participants who completed REST-ON or were oxybate naive and 68 participants who switched from IR oxybate to ON-SXB. In total, 71% (63/89) of responders rated their narcolepsy “much better” or “somewhat better” after initiating ON-SXB. After starting ON-SXB, 75% (67/89) were very satisfied with ON-SXB compared to other treatments they had taken, and 89% (79/89) would recommend ON-SXB to a family member or friend with narcolepsy. Approximately 69% (61/89) of participants found it easier to go through the day without falling asleep, 91% (81/89) were better able to sleep through the night, 64% (57/89) were able to get more done at work or school, and 64% (57/89) were better able to socialize with friends or family. Additionally, 43% (38/89) of responders were able to perform or better perform certain daily activities. Of the participants who switched from IR oxybate to ON-SXB, 91% (62/68) were better able to follow the recommended dosing schedule of ON-SXB.

Conclusion

These EOS RESTORE data show a high level of satisfaction with ON-SXB, improved symptom control, and a preference for ON-SXB over other treatment options. A majority switching from IR oxybate treatment reported improvement in dosing as directed.

Support (if any)

Avadel Pharmaceuticals
0646 Efficacy Outcomes Among Male and Female Participant Subgroups: A Post Hoc Analysis from REST-ON
Authors: Thorpy Michael , Ajayi Akinyemi , Corser Bruce , Kushida Clete , Ohayon Maurice , Bogan Richard , Gudeman Jennifer
Published: April 2024

Introduction

Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is an effective and safe treatment for excessive daytime sleepiness (EDS) and cataplexy in adults with narcolepsy. This post hoc analysis assessed efficacy in female and male participant subgroups from the phase 3 REST-ON trial.

Methods

REST-ON (NCT02720744) participants (≥16 years) with narcolepsy type 1 (NT1) or NT2 were randomized (1:1) to receive ON-SXB at 4.5 g (week 1), 6 g (weeks 2–3), 7.5 g (weeks 4–8), and 9 g (weeks 9–13) or placebo. Data shown are least squares mean changes from baseline (SE) in mean sleep latency on the Maintenance of Wakefulness Test (MWT) and weekly number of cataplexy episodes (NCA; NT1 only) calculated at week 13 (9 g) in the modified intent-to-treat (mITT) population (ie, randomized participants with ≥1 efficacy measurement post 6-g dose).

Results

The mITT population included more female (ON-SXB, n=60; placebo, n=65) than male (ON-SXB, n=37; placebo, n=28) participants. Baseline mean sleep latency (SD) on the MWT (min) was 5.24 (3.41) and 4.59 (2.65) for female and male participants in the ON-SXB arm, respectively. At week 13, improvements on the MWT with ON-SXB were greater for female than for male participants (11.62 [1.39], 9.52 [1.26]). Baseline mean weekly NCA (SD) was 19.63 (9.0) and 17.48 (8.03) for female and male participants, respectively, in the ON-SXB arm. Improvements in weekly NCA with ON-SXB were similar for female and male participants at week 13 (–11.80 [1.23], –11.31 [1.62]).

Conclusion

These post-hoc subgroup data demonstrate improvement with ON-SXB in EDS and in cataplexy for people with narcolepsy regardless of gender.

Support (if any)

Avadel Pharmaceuticals
0647 Efficacy of Low-Sodium Oxybate in Narcolepsy Patients with and Without Cardiovascular or Cardiometabolic Disorders
Authors: Corser Bruce , Candler Shawn , Macfadden Wayne , Fuller Douglas , Measey Thomas , Bogan Richard
Published: April 2024

Introduction

Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy, and idiopathic hypersomnia in adults. LXB contains the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but with 92% less sodium. Previous studies have reported increased cardiovascular (CV) and cardiometabolic (CM) comorbidities in people with narcolepsy. This post-hoc analysis of a phase 3 trial assessed LXB efficacy and safety in participants with narcolepsy with and without CV/CM comorbidities.

Methods

Participants 18–70 years of age with narcolepsy with cataplexy optimized/titrated their LXB dose (up to 12 weeks) before entering a 2-week stable-dose period (SDP) (NCT03030599). Following SDP, participants withdrew to placebo or continued LXB during a 2-week double-blind randomized-withdrawal period (DBRWP). Epworth Sleepiness Scale (ESS) scores, cataplexy (average N/week), Patient Global Impression of Change (PGIc) scores, and treatment-emergent adverse events (TEAEs) were assessed in participants with and without CV/CM comorbidities, per medical history.

Results

Of 201 participants, 69 reported CV/CM comorbidities at baseline (most commonly hypertension and obesity). Participants with and without CV/CM comorbidities, respectively, had mean (SD) BMI of 31.6 (6.4) and 27.2 (5.3); mean age was 43.4 (12.0) and 33.9 (11.0) years; 66.7% and 57.6% were female. Participants randomized to placebo in the DBRWP in both subgroups showed worsening (increases) in ESS scores compared with those randomized to LXB (least squares mean differences, LXB vs placebo [95% CI], with CV/CM comorbidities: −2.6 [−4.5, −0.70], P=0.0077; without CV/CM comorbidities: −2.7 [−4.2, −1.2], P=0.0004; subgroup interaction, P=0.95). Participants without CV/CM comorbidities randomized to placebo had increased cataplexy attacks compared with those taking LXB (median, placebo, 3.0; LXB, 0.0; P< 0.0001); those with CV/CM comorbidities had similar efficacy (placebo, 1.9; LXB, 0.0; P=0.0745). PGIc scores showed worsening in participants randomized to placebo vs LXB in both subgroups (P< 0.0001 for both). Serious TEAEs were reported by 3% of participants with CV/CM comorbidities and 2% of those without.

Conclusion

In this post-hoc analysis, the efficacy and safety of LXB were similar in participants with narcolepsy with and without CV/CM comorbidities.

Support (if any)

Jazz Pharmaceuticals
0649 Samelisant Improves the Symptoms of Excessive Daytime Sleepiness in Narcolepsy: Results from a Phase-2 Study
Authors: Nirogi Ramakrishna , Ravula Jyothsna , Jayarajan Pradeep , Goyal Vinod Kumar , Benade Vijay , Jetta Satish , Shinde Anil , Dogiparti Dhanunjay , Subramanian Ramkumar , Kalaikadhiban Ilayaraja , Jasti Venkat
Published: April 2024

Introduction

Narcolepsy is a lifelong sleep disorder characterized by a classic tetrad of excessive daytime sleepiness (EDS) with irresistible sleep attacks, cataplexy, hypnagogic hallucination, and sleep paralysis. The currently available treatments suffer from major limitations like side effects, modest efficacy or they must be prescribed in combination. Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor inverse agonist. In orexin knockout mice, samelisant produced wake-promoting and anticataplectic effects suggesting its potential therapeutic utility in the treatment of narcolepsy. Safety and tolerability studies in animals and healthy human volunteers suggest a favorable risk/benefit profile for samelisant.

Methods

Samelisant had been evaluated as monotherapy in a Phase-2 proof of concept study in the USA and Canada for the treatment of EDS in patients with narcolepsy (ClinicalTrials.gov Identifier: NCT04072380). Patients diagnosed with narcolepsy as per ICSD-3 criteria, aged between 18 to 65 years with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean Maintenance of Wakefulness Test (MWT) time of < 12 min were recruited in the study. A total of 190 patients were randomized into 3 treatment arms (placebo, samelisant 2 mg and samelisant 4 mg) in 1:1:1 ratio and received either placebo or samelisant, once daily for 2 weeks. The primary efficacy endpoint was change in ESS score from baseline to Day 14. Secondary endpoints were changes from baseline to week 2 in Clinical Global Impression - Severity (CGI-S) and MWT scores. The medical monitor and the data safety monitoring committee monitored safety throughout the study.

Results

The baseline characteristics and demographics were consistent with the general narcolepsy population and equally distributed between treatment groups. The study met the pre-specified primary efficacy endpoint. In comparison against placebo, samelisant as monotherapy demonstrated statistically significant (p< 0.024) and clinically meaningful reduction (-2.1 point) in EDS measured by ESS. Samelisant was generally safe and well tolerated.

Conclusion

Samelisant holds promise as a monotherapy treatment of EDS in narcolepsy.

Support (if any)
0651 Pharmacokinetics of Morning and Nighttime Doses of KP1077, an Investigational Treatment for Idiopathic Hypersomnia
Authors: Braeckman Rene , Smith Adam , Lubert Adam , Vrishabhendra Leela
Published: April 2024

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 (d-MPH). SDX is converted to d-MPH in the lower intestinal tract, with a delay and kinetics leading to a unique pharmacokinetic (PK) profile and an extended duration product. The objectives of the study were to assess the PK and safety after single morning and nighttime doses in healthy volunteers.

Methods

Heathy adult subjects received single oral doses of 240 mg SDX, either in the morning or at night, just before bedtime, in a randomized fashion with a washout of 6 days between treatments. Multiple blood PK samples and safety parameters were collected after each administration.

Results

A total of 15 subjects (9 males/6 females) were randomized with 14 completing both treatments. Both treatments were well-tolerated with adverse events typical for d-MPH. After the morning dose, d-MPH exposure was characterized by little or no d-MPH exposure for the first 4 hours followed by a gradual rise up to ~7 hour post-dose (Tmax), followed by a gradual decline. The rise in d-MPH concentrations after the nighttime dose was even more gradual than after the morning dose, with substantial levels reached around 10 hours postdose and a statistically significantly longer Tmax of 15 hours. Mean d-MPH peak concentrations were lower after the evening dose (22.0 ng/mL) compared to the morning dose (26.8 ng/mL) while total exposures (AUCinf) were similar (594 and 557 h*ng/mL, respectively).

Conclusion

Peak exposure of SDX-derived d-MPH and the bulk of the total d-MPH exposure after a nighttime dose of SDX occurs during the next morning compared to a morning dose where most exposure occurs the same day. This difference is likely due to a longer intestinal transit time and lower intestinal activity during the nighttime sleeping hours. This delay supports nighttime dosing of SDX in patients with IH who suffer from EDS and Sleep Inertia (difficulty waking up in the morning).

Support (if any)

Zevra Therapeutics