Individualized Treatment Patterns for Patients with Narcolepsy Treated with Oxybate: A Clinical Practice Perspective.

Purpose: Real-world data regarding divided nightly dosing of oxybate and individualized prescribing in patients with narcolepsy are limited. Study objectives were to understand oxybate prescribing practices, including optimizing dose regimens and adjusting dosing per occasional changes in patients' routines, and physician recommendations for representative patient scenarios. Patients and Methods: A cross-sectional, web- and audio-based survey of physicians treating ≥2 patients with narcolepsy, prescribed nightly oxybate (sodium oxybate) dosing for ≥6 months, was conducted. Physicians were surveyed on patients' usual oxybate dosing regimens, frequency of and reasons for oxybate dosing-related discussions, and preferred methods for and perceptions of adjusting oxybate dosing. Physicians provided dosing-related guidance for 4 representative scenarios. Results: Participating physicians (N=25) were neurologists (52%), psychiatrists (44%), and neuropsychiatrists (4%). Individualized oxybate prescribing practices were reflected by the variability of physicians' reporting of the percentage of their patients being prescribed once-nightly, twice-nightly, and thrice-nightly dosing regimens. Most physicians (68%) reported discussing adjusting individualized treatment to accommodate occasional changes to patients' routines; the most common reasons were consuming contraindicated beverages (alcohol; 65%) and travel (59%). Adjusting total nightly dose (68%) and dose timing (68%) were preferred adjustment methods. Most physicians (88%) felt the ability to individualize oxybate dosing was important and had a positive impact on ability to provide care. For each representative scenario, physicians provided several dose-adjustment recommendations, and physician responses encouraged patient participation in treatment decision-making. Conclusion: Physicians provided guidance supportive of oxybate dose adjustments to accommodate occasional changes in patients' routines, and perceived individualized dosing as important in providing care.

Development of a lower-sodium oxybate formulation for the treatment of patients with narcolepsy and idiopathic hypersomnia.

INTRODUCTION: Sodium oxybate (SXB) is a standard of care for cataplexy, excessive daytime sleepiness, and disrupted nighttime sleep in narcolepsy. At recommended dosages in adults (6-9 g/night), SXB increases daily dietary intake of sodium by 1100-1640 mg. Because excess sodium intake is associated with increased blood pressure and cardiovascular risk, an oxybate formulation containing 92% less sodium than SXB (lower-sodium oxybate; LXB) was developed to provide an alternative oxybate treatment option. In 2020, LXB was approved for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and in 2021, for treatment of idiopathic hypersomnia in adults. AREAS COVERED: Development of LXB from initial concept to regulatory approval is described, including formulation development and preclinical and clinical studies. Pharmacokinetic parameters and bioequivalence evaluations from phase 1 clinical trials are detailed. Efficacy and safety results from phase 3 clinical trials of LXB in patients with narcolepsy or idiopathic hypersomnia are presented and discussed. EXPERT OPINION: Reducing sodium from high sodium‒containing medications is an important step to offset cardiovascular risks associated with high sodium consumption. The development of LXB exemplifies the importance of a collaborative approach to drug development, with patient needs paramount. PLAIN LANGUAGE SUMMARY: Sodium oxybate (Xyrem®) is a medication for people with narcolepsy aged 7 years and older. Xyrem treats symptoms of excessive daytime sleepiness (EDS) or cataplexy (attacks of muscle weakness caused by emotion) in narcolepsy. At the recommended dosages in adults, Xyrem adds a large amount of sodium to daily dietary intake. Too much sodium in the diet is associated with increased blood pressure and risks of damage to the heart and blood vessels. Researchers used calcium, magnesium, and potassium ions in addition to a small amount of sodium to make a new oxybate medication, called Xywav®, that has 92% less sodium than Xyrem. Xywav and Xyrem were similar in laboratory and animal studies. In people, the body absorbs and processes Xywav slightly differently than Xyrem, but Xywav treatment has been shown to work the same to reduce symptoms of cataplexy and EDS in people with narcolepsy and is approved by the US Food and Drug Administration. Another neurological disorder with EDS is called idiopathic hypersomnia. Based on a clinical study, Xywav also reduced EDS and other symptoms in people with idiopathic hypersomnia. Side effects with Xywav are similar to those seen in previous studies with Xyrem.

Validation of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) questionnaire in pediatric patients with narcolepsy with cataplexy aged 7-16 years.

OBJECTIVE/BACKGROUND: The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) measures daytime sleepiness, but had not previously been validated in children <12 years of age. PATIENTS/METHODS: Data from a sodium oxybate (SXB) study in pediatric participants with narcolepsy with cataplexy (ClinicalTrials.gov, NCT02221869) were used in this validation study. SXB-naive participants completed an open-label titration period prior to entering a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. RESULTS: The analysis population (N = 100) had a mean (SD) age of 11.9 (2.39) years. Internal consistency as assessed by Cronbach's alpha was 0.750 (95% CI, 0.681-0.819). The intraclass correlation coefficient for the test-retest reliability assessment (n = 64 with stable or no stimulant use at study entry) was 0.755 (95% CI, 0.626-0.844). Responsiveness to change, measured as the mean within-person change in 1-week ESS-CHAD score over time in SXB-naive participants (n = 59) from baseline (before taking SXB) to end of the stable-dose period (taking the titrated amount of SXB), was -6.31 (95% CI: -7.61, -5.00; nominal P < 0.0001). For convergent construct validity, the mean (SD) scores for female (n = 40) and male (n = 60) participants were 13.98 (4.440) and 14.65 (4.050), respectively (nominal P = 0.4430). For divergent construct validity, the mean (SD) scores were 16.31 (2.978) in the group who were taking neither SXB nor stimulants at study entry (n = 32) and 13.47 (4.400) in the group taking SXB with or without stimulants at study entry (n = 68; nominal P = 0.0003). CONCLUSIONS: This evidence supports the validity of the 1-week ESS-CHAD in a pediatric population with narcolepsy.

Validation of the Pediatric Narcolepsy Screening Questionnaire (PNSQ): A cross-sectional, observational study.

OBJECTIVE/BACKGROUND: This study evaluated psychometric properties of the Pediatric Narcolepsy Screening Questionnaire (PNSQ), developed in response to the difficulty of identifying pediatric narcolepsy. PATIENTS/METHODS: The initial PNSQ was updated following debriefing interviews with parents of children with suspected/diagnosed narcolepsy. Subsequently, newly recruited caregivers were categorized into groups: clinician-confirmed narcolepsy, other sleep problems (OSP), and no sleep problems (controls). Caregivers completed the 11-item PNSQ assessing narcolepsy symptomatology. PNSQ psychometric properties were evaluated; mean PNSQ Total Score (TS) was compared inter-group using analysis of variance. RESULTS: The analysis population (N = 158) included patients with narcolepsy (n = 49), OSP (n = 55), and controls (n = 54); mean ± SD age was 13.8 ± 2.8, 10.2 ± 4.3, and 10.0 ± 3.8 years, respectively. Inter-item Pearson correlations (range, 0.22-0.75) indicated good construct validity. Principal component analysis confirmed unidimensionality. Item discriminative power was high for narcolepsy vs control (range, 0.693-0.936) and lower for narcolepsy vs OSP (range, 0.584-0.729). The latent trait was well covered (separation index = 0.868). Item 7 (vivid dreams/nightmares), having low discriminative power and specificity, was removed. Cronbach's alpha (final PNSQ) indicated high internal consistency reliability (raw alpha = 0.88). Mean ± SD PNSQ TS (range, 0-50) in the narcolepsy, OSP, and control groups were 34.98 ± 7.98, 25.20 ± 9.43, and 9.54 ± 9.38, respectively (nominal P < 0.0001). Classification by PNSQ TS was defined: PNSQ+ (likely narcolepsy, TS ≥ 29), PNSQ 0 (likely OSP, TS 19-28), and PNSQ- (narcolepsy unlikely, TS ≤ 18); patients with narcolepsy were classified as PNSQ+ (79.6%), PNSQ 0 (18.4%), and PNSQ- (2.0%). CONCLUSIONS: The PNSQ demonstrated good psychometric properties and excellent performance discriminating narcolepsy, OSP, and control groups.

The Xyrem® (Sodium Oxybate) Risk Evaluation and Mitigation Strategy (REMS) Program in the USA: Results From 2016 to 2017.

BACKGROUND: Sodium oxybate, which is approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy, is available in the USA only through the restricted-distribution Xyrem® Risk Evaluation and Mitigation Strategy Program (Xyrem REMS Program, XRP). The XRP requires prescriber enrollment and certification, patient enrollment, and prescriber attestation of patient counseling. Sodium oxybate is dispensed only by the certified pharmacy. After pharmacist/patient counseling, sodium oxybate is shipped only to enrolled patients, with documentation of safe use. Documentation of enrollments, prescriptions, counseling, shipments, and adverse events in a central database, and risk management reporting of any suspicion of abuse, misuse, or diversion, ensure provider notification and facilitate monitoring. OBJECTIVE: This analysis reports data from the XRP regarding assessment of the risks of serious adverse outcomes that may result from inappropriate prescribing, abuse, misuse, and diversion. METHODS: Data collected from December 2016 to December 2017 were analyzed. RESULTS: Prescriptions were from enrolled prescribers (n = 4524); 17,037 patients received one or more shipment of sodium oxybate. No patients were shipped sodium oxybate under more than one name/identifier or after being disenrolled; no individual patient had overlapping active prescriptions. Sodium oxybate was dispensed in 146,426 shipments containing 375,173 bottles; of those, 13 shipments (0.009%) and 26 bottles (0.007%) were lost in delivery and not recovered. Notifications regarding potential abuse (n = 31), misuse (n = 343), or diversion (n = 22) were discussed with prescribers. Most patients and prescribers were aware of the main safety risks of sodium oxybate. CONCLUSIONS: The XRP maintains controlled access to sodium oxybate; additional prescriber education on safety risks may be warranted.

Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy.

STUDY OBJECTIVES: To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy. METHODS: These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, participants entering on modafinil (n = 231) received placebo (n = 56), SXB (n = 55), modafinil (n = 63), or SXB and modafinil (n = 57). SXB was initiated at 6 g for weeks 1-4 and increased to 9 g for weeks 5-8. TEAEs reported more frequently in SXB-treated participants than placebo and in ≥5% of any SXB treatment group during week 1 were examined as TEAEs of interest. RESULTS: Dizziness and nausea met criteria as TEAEs of interest in both studies; headache also met criteria as a TEAE of interest in SXB-15. Incidence of new or worsened TEAEs was highest at week 1 (SXB-15: dizziness, 7.5%; headache, 7.5%; nausea, 5.9%; SXB-22: dizziness, 5.4%; nausea, 7.1%) and decreased over time in both studies. The longest median duration was reported for dizziness: 9.0 and 17.5 days in SXB-15 and SXB-22, respectively. Dizziness caused discontinuation in 2.2% and 3.6% of participants in SXB-15 and SXB-22, respectively; nausea caused discontinuation in 2.7% and 1.8%. CONCLUSIONS: Common early-onset TEAEs associated with SXB treatment were generally of short duration and their incidence decreased over time. These TEAEs accounted for few discontinuations overall. CLINICAL TRIALS REGISTRATION: Registry: ClinicalTrials.gov; Names: Safety and Efficacy of Xyrem Oral Solution (Sodium Oxybate) Compared With Placebo in Narcoleptic Patients; Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy; URLs: https://clinicaltrials.gov/ct2/show/NCT00049803 and https://clinicaltrials.gov/ct2/show/NCT00066170; Identifiers: NCT00049803 and NCT00066170.

Burden of disease in pediatric narcolepsy: a claims-based analysis of health care utilization, costs, and comorbidities.

BACKGROUND: This study analyzed a privately insured pediatric population with and without narcolepsy to determine the impact of pediatric narcolepsy on comorbidities, health care utilization, and cost. Additional analyses compared narcolepsy type 1 and type 2. METHODS: This retrospective cross-sectional study identified US patients with narcolepsy <18 years of age with ≥2 claims with a diagnosis code of narcolepsy using Truven MarketScan® data 2011 to 2015. Patients were matched to controls without narcolepsy. Comorbid conditions, health care utilization, and costs were measured by calendar year. P values are nominal, and no adjustments for multiplicity or multiple comparisons were made. RESULTS: A total of 1427 pediatric patients with narcolepsy were identified and matched with 4281 controls from 2011 to 2015. Patients with narcolepsy had more comorbid conditions (mean 5.8 vs 2.4, nominal P < 0.001). Respiratory diseases and mood disorders were more common in patients with narcolepsy than controls (57% vs 32% and 56% vs 14%, respectively; both nominal P < 0.001). Compared to controls, patients with narcolepsy underwent more diagnostic tests (electroencephalogram, EEG [0.13 vs 0.0053]) and brain computed tomography, CT/magnetic resonance imaging, MRI (0.26 vs 0.022; both nominal P < 0.001). Mean annual inpatient days (0.71 vs 0.15), emergency department visits (0.51 vs 0.15), and outpatient office visits (8.6 vs 2.3) were higher for patients with narcolepsy than controls (all nominal P < 0.001). Annual mean health care costs were higher for patients with narcolepsy versus controls ($15,797 vs $2449, nominal P < 0.001). CONCLUSION: Pediatric patients with narcolepsy had greater comorbidity, higher health care utilization, and higher costs than patients without narcolepsy.

Nocturnal blood pressure dipping and beta-adrenergic receptor sensitivity.

BACKGROUND: Blunted nocturnal blood pressure (BP) dipping has been observed in patients with various cardiovascular pathophysiology. However, the mechanisms underlying relationships between blunted dipping and pathophysiologic end points remain unclear. This study examined relationships between beta-adrenergic receptor sensitivity and nocturnal BP dipping. METHODS: Ambulatory BP monitoring took place in each patient's home. On a separate occasion, beta-adrenergic receptor sensitivity was determined by response to isoproterenol infusion. RESULTS: Participants with less sensitive beta-adrenergic receptors had less nocturnal BP dipping across BP measures (all P < .001). CONCLUSIONS: These findings suggest that beta-adrenergic receptor sensitivity may contribute to relationships between blunted nocturnal BP dipping and various cardiovascular end points.

A randomized, controlled trial of 1 week of continuous positive airway pressure treatment on quality of life.

BACKGROUND: This study examines the effect of continuous positive airway pressure (CPAP) treatment on quality of life (QOL)in patients with obstructive sleep apnea. METHODS: Thirty-nine patients with sleep apnea were studied. Health-related quality of life was measured (HRQL) with the use of the Medical Outcomes Survey (MOS) instrument, before and after patients were randomized to receive either 1 week of CPAP or placebo-CPAP (CPAP administered at ineffective pressure). RESULTS: CPAP was not found to have a specific effect on QOL as compared with placebo-CPAP. However, several aspects of HRQL improved in both groups over time in this study. Time effects were found in the following subscales of the MOS: satisfaction with physical functioning; effects of pain; pain severity; cognitive functioning; mental health index I; psychological well-being I; depression/behavioral-emotional control; anxiety I; psychological distress I; positive affect II; mental health index II; psychological distress II; anxiety II; psychological well-being II; mental health index III; role limitations due to emotional problems; and physical/physiologic functioning. CONCLUSIONS: CPAP treatment does appear to improve several aspects of HRQL. However, this improvement may reflect a nonspecific response (ie, placebo) because comparable improvements were observed in both the active treatment group and the placebo treatment group. Additional study with placebo-CPAP designs is warranted.

Are there ethnic differences in sleep architecture?

The possibility of ethnic differences in sleep architecture was initially examined in conjunction with studies of sleep apnea (study 1). This possibility was then examined in another cohort of patients to determine whether the results might generalize (study 2). Polysomnography was obtained in both cohorts as part of larger protocols investigating sympathetic nervous system activity, blood pressure, and sleep. Sleep monitoring took place in an inpatient clinical research center of a university hospital. Study 1 focused on sleep apnea physiology and involved volunteers with sleep apnea who were otherwise healthy. Study 2 focused on differences in stress reactivity between American Black and White subjects and involved hypertensive and normotensive volunteers who were otherwise healthy. Analyses include 61 participants from study 1 and 35 participants from study 2. Ethnicity in both cohorts was determined by self-report. Participants in both studies were monitored during sleep with traditional polysomnography including electroencephalography (EEG), electromyography (EMG), electrooculography (EOG), and oximetry. In Study 1, Blacks had longer TST (P < 0.01), more REM sleep (P < 0.05), and less WASO (P < 0.05) than Whites. After controlling for RDI, Blacks had longer TST and spent a smaller percentage of time in deep sleep (P < 0.05). In study 2, Blacks had longer TST and REM sleep, lower percent deep sleep, and lower percent deep sleep controlling for RDI (P < 0.05). In two separate studies, Blacks had longer TST, more minutes of REM, and lower percentage deep sleep. These findings suggest possible ethnic differences in sleep architecture.