# Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture

Thomas Roth, Yves Dauvilliers, Richard K Bogan, Giuseppe Plazzi, Jed Black

► To cite this version:

Thomas Roth, Yves Dauvilliers, Richard K Bogan, Giuseppe Plazzi, Jed Black. Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture. Sleep Medicine, 2024, 114, pp.255-265. 10.1016/j.sleep.2023.12.015. hal-04784723

HAL Id: hal-04784723

https://hal.science/hal-04784723v1

Submitted on 15 Nov 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
# Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture

Thomas Roth<sup>a, *,</sup> Yves Dauvilliers<sup>b, c</sup>, Richard K. Bogan<sup>d, e</sup>, Giuseppe Plazzi<sup>f, g</sup>, Jed Black<sup>h, i</sup>

<figure><img src="image_2.png" /></figure>

## ARTICLE INFO

### Keywords:

Sodium oxybate

Narcolepsy

Sleep quality

Disrupted nighttime sleep

Polysomnography

## ABSTRACT

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantages and disadvantages of each agent.

## 1. Introduction

Narcolepsy is a rare central hypersomnolence disorder that affects approximately 0.04 % of individuals in the United States [1]. Narcolepsy occurs as 1 of 2 types. Narcolepsy type 1 (NT1) is characterized by the presence of cataplexy and/or orexin deficiency (cerebrospinal fluid [CSF] orexin or hypocretin-1 ≤110 pg/mL), whereas narcolepsy type 2 (NT2) is characterized by the absence of cataplexy and CSF orexin levels >110 pg/mL. Narcolepsy is characterized by a pentad of symptoms: excessive daytime sleepiness (EDS), cataplexy, sleep-related hallucinations (hypnagogic and hypnopompic), sleep paralysis, and disrupted nighttime sleep (DNS) [2]. All patients with narcolepsy experience EDS,

and presentation of other symptoms can vary depending on the type of narcolepsy. Behind EDS and cataplexy (NT1 only), DNS has been reported to be the third most common symptom, with approximately 30 %–95 % of patients with narcolepsy experiencing DNS [3,4].

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep) [5]. Diminished sleep quality and impaired daytime functioning may partially result from these increased awakenings/arousals and fluctuations between stages of deeper and lighter sleep [5].

Sleep duration, quality, and regularity are associated with metabolic and cardiovascular (CV) disease [6], and, since 2022, sleep has been

Abbreviations: CSF, cerebrospinal fluid; CV, cardiovascular; DNS, disrupted nighttime sleep; EDS, excessive daytime sleepiness; GHB, gamma-hydroxybutyrate; LS, least squares; LSMD, least squares mean difference; LXB, low-sodium oxybate; ON-SXB, once-nightly sodium oxybate; SXB, sodium oxybate.

* Corresponding author. Sleep Disorders and Research Center, Henry Ford Hospital, 799 W. Grand Boulevard, Detroit, Michigan 48202, USA.

E-mail address: troth1@hfhs.org (T. Roth).

<footnote><sup>a</sup> Henry Ford Hospital, Detroit, MI, USA</footnote>

<footnote><sup>b</sup> Sleep and Wake Disorders Centre, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France</footnote>

<footnote><sup>c</sup> University of Montpellier, INSERM Institute Neuroscience Montpellier (INM), Montpellier, France</footnote>

<footnote><sup>d</sup> Medical University of South Carolina, Charleston, SC, USA</footnote>

<footnote><sup>e</sup> Bogan Sleep Consultants, LLC, Columbia, SC, USA</footnote>

<footnote><sup>f</sup> Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy</footnote>

<footnote><sup>g</sup> IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy</footnote>

<footnote><sup>h</sup> Stanford University Center for Sleep Sciences and Medicine, Palo Alto, CA, USA</footnote>

<footnote><sup>i</sup> Jazz Pharmaceuticals, Palo Alto, CA, USA</footnote>
incorporated into the American Heart Association's Life's Essential 8 heart health measures [7]. This highlights the importance of improving DNS in patients with narcolepsy who are already at an increased risk of developing metabolic, hypertension, and CV diseases [8-10].

Sodium oxybate (SXB, Xyrem®), dosed twice nightly, has been used since the early 2000s to improve sleep, and subsequently excessive daytime sleepiness (EDS), in patients with narcolepsy. In 2002 and 2005, SXB was approved by the US Food and Drug Administration (FDA) for the treatment of cataplexy and EDS, respectively, in adults with narcolepsy, with an extension in 2018 to pediatric patients aged 7 years and older [11]. In 2005, SXB was approved by the European Medicines Agency (EMA) for the treatment of narcolepsy with cataplexy in adults, with an extension in 2020 to adolescents and children aged 7 years and older [12]. Recently, new formulations have been developed to address the sodium content and twice-nightly dosing regimen of SXB. In 2020, Xywav® (low-sodium oxybate; LXB), which contains 92 % less sodium than SXB and is dosed twice nightly, was approved by the FDA for the treatment of cataplexy and EDS in patients 7 years and older with narcolepsy [13,14]. In 2023, Lumryz™ (once-nightly sodium oxybate; ON-SXB), which is dosed once nightly but has the same sodium content as SXB, was approved by the FDA for the treatment of cataplexy or EDS in adults with narcolepsy [15].

To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and DNS in patients with narcolepsy. Importantly, no data are currently available on the effects of LXB on sleep. LXB contains the same active moiety as SXB, thus it is probable that the effects of LXB on sleep are similar to SXB. As such, this review focuses on SXB and ON-SXB.

## 2. Normal sleep architecture

In healthy individuals, sleep stages, aromals, and awakenings occur in predictable patterns across the night, cycling between non-rapid eye movement (NREM), including N1, N2, and N3 ("deep" or "slow wave" sleep [SWS]), and rapid eye movement (REM) sleep [16]. Sleep stages typically transition through N1, occurring after sleep onset, followed by N2, N3, and then REM in repetitive cycles each lasting approximately 90 min across the sleep episode [16]. Polysomnography (PSG) is a mainstay in the objective measurement of sleep function and in the diagnosis and evaluation of sleep disorders [17]. PSG is used to assess multiple sleep parameters across the sleep cycle including: total sleep time (TST), wake after sleep onset (WASO), arousal/awakening, N1 sleep, N2 sleep, SWS, REM sleep, delta power, sleep efficiency, and sleep latency [5,18,19].

PSG studies demonstrate that brief disruptions in sleep are normal even in healthy individuals, within a range of approximately 29-130 aromals and 4 to 40 awakenings per night (generally increasing in frequency with age) [20,21]. As expected, increased awakenings and aromals are accompanied by a reduction in TST, SWS, and sleep efficiency [18,20]. However, definitions of aromals and awakenings have changed over time, and may not be consistent between studies. According to the American Sleep Disorders Association (ASDA) [22] and, more recently, American Academy of Sleep Medicine (AASM) [23] criteria for PSG scoring, aromals are defined as an abrupt shift in electroencephalogram (EEG) frequency lasting ≥3 s, which may include theta, alpha, and/or frequencies >16 Hz, but not spindles, occurring after ≥10 continuous seconds of any sleep stage. Awakening was described as EEG containing alpha activity and/or a low-voltage, mixed-frequency activity in the early ASDA scoring [24], with AASM criteria now defining an awakening as alpha activity over the occipital region and/or other findings consistent with wake (eye blinks, REM associated with normal or high chin muscle tone, or reading eye movements) lasting ≥15 s [23].

In healthy people, TST decreases linearly at a rate of 10 min per decade of age, declining from a mean of 410.6 min at age 18-34 years to 346.0 min at age 65-79 years of age [18,25]. Linear reductions in SWS and sleep efficiency of 2 % and 3 % per decade of age, respectively, are observed across this age range [18,25]. These reductions are paralleled by increases in N1, aromals/awakenings, and WASO, with significantly fewer aromals/awakenings in those aged 18-20 years (arousal index/awakenings: 10.6/21.5) relative to the 30- to 40-year age group (16.8/29.8), and fewer than in the 50- to 60-year age group (21.9/43.3) [20]. In contrast, WASO increases at a rate of approximately 10 min per decade from 30 years of age [18]. It has been reported that healthy adults experience approximately 251.8 stage shifts per night, but to our knowledge no study has assessed whether stage shifts change in frequency as people age [26].

Sleep cycles through the same stages in children as in adults, but this again varies by age. For healthy children aged 3-12 years, TST is approximately 449.3 min and comprises approximately 3.5 % N1, 44 % N2, 32 % SWS, and 21 % REM sleep [27]. Adolescent sleep macrostructure also includes approximately 36.9 min of WASO, with 10.5 aromals, 0.8 awakenings, and 12.5 stage shifts per hour [27]. When accounting for differences in development according to Tanner stage, the percentage of TST spent in SWS and N2 are significantly correlated; SWS decreases from approximately 26 %-16 % of TST, while N2 significantly increases from approximately 48 %-60 % of TST [28]. These differences are important to consider when assessing changes to sleep architecture in pediatric patients with narcolepsy.

## 3. Sleep architecture and DNS in narcolepsy

In comparison with healthy individuals, patients with narcolepsy experience differences in sleep architecture, including decreased TST, increased WASO, increased N1 sleep (absolute duration and percentage of TST), decreased N2 sleep (duration and percentage of TST), decreased N3 sleep (duration and percentage of TST), and lower sleep efficiency (TST relative to total time in bed) [21,26,29-34]. In patients with narcolepsy, PSG data are characterized by a dysregulated sleep-wake state process, which manifests as rapid entry into REM after sleep onset (sleep onset REM period [SOREMP]), mixing/dissociation of sleep/wake stages, frequent spontaneous awakenings, and increased sleep stage transitions (ie, sleep state instability) [5].

An important aspect of DNS, nocturnal awakenings/aromals are more frequent in narcolepsy. In 1 study, untreated adults with narcolepsy experienced approximately 80 aromals and 35 awakenings (<3 min each) in a single night, compared with 30 aromals and 4 awakenings for healthy individuals [21]. When compared with sleepy controls, nocturnal awakenings (undefined) were significantly increased in people with NT1 (33.5 vs 20.3 awakenings) [32]. Patients with narcolepsy reported approximately 2.5- to 3.5-fold more nightly awakenings versus controls in early studies [35-37]. Finally, patient-reports of reduced sleep quality and nocturnal sleep disturbance corroborate the increased objectively measured awakenings and aromals, with as many as 81 % of patients with narcolepsy reporting frequent, brief awakenings in 1 study [35,38].

In pediatric patients, DNS (as evidenced by a wake/N1 index of ≥5.5/h) and/or the presence of nocturnal SOREMP (nSOREMP) are indicative of a diagnosis of NT1 [39]. In these patients (mean age 12 years), TST remained stable (8.7 h for both), while mean sleep onset latency (9.4 vs 33.8 min; *P* < 0.0005), mean WASO (57.2 vs 40.8 min; *P* < 0.0005), and proportion of patients experiencing nSOREMP (71.3 % vs 2.6 %; *P* < 0.0005) were significantly altered relative to similarly aged control subjects with normal PSG parameters [39].

Although the pathophysiology underlying DNS is not fully understood, an association between orexin deficiency (CSF orexin levels ≤110 pg/mL) and increased awakenings, increased sleep fragmentation, and
decreased sleep latency has been observed in a mixed population of both adult and pediatric patients referred for suspected central sleep disorders [40]. However, self-reported DNS (assessed using item 15 of the Narcolepsy Severity Scale) was not associated with CSF orexin levels in a recent study of 145 untreated patients with narcolepsy from the same group [41], indicating that other factors likely contribute to this symptom.

# 4. Effect of oxybates on DNS

## 4.1. Early GHB clinical studies

Preceding the assessments of the impact of SXB on DNS in larger trials that were carried out for the treatment's approval, several small-scale clinical studies were published in the 1980s and 1990s on the use of gamma-hydroxybutyrate (GHB) in adult patients with narcolepsy [42-46]. These studies were mostly uncontrolled, observational studies;

only 2 were double-blind, placebo-controlled or crossover studies [42-46]. Summarized in Table 1, overall these studies found that GHB decreased the number of awakenings/arousals and increased SWS, consistent with the findings of later studies.

## 4.2. Sodium oxybate: larger scale clinical studies in adult patients

Subsequent to the early clinical studies of GHB, 5 clinical trials assessed the impact of oxybate treatments on DNS in patients with narcolepsy. These include 2 double-blind, placebo-controlled trials of SXB in adults (study 1 [48,49] and study 2 [50,51]), 1 placebo-controlled, double-blind trial of ON-SXB in adults (study 3) [19, 52], 1 open-label pilot study of SXB in adults (study 4) [53], and 1 double-blind, placebo-controlled study of SXB in pediatric patients (study 5) [54]. While there is overlap in the variables each study assessed, important differences in study design and approaches to analysis must be acknowledged.

<table><caption>**Table 1**
Effects on sleep architecture from early clinical studies of GHB in adult narcolepsy.</caption><thead><tr><th rowspan="2">Reference</th><th rowspan="2">Number of Patients; Sleep Evaluation Measures; Study Design</th><th rowspan="2">GHB Dose; Duration</th><th colspan="2">Main Findings</th></tr><tr><th>Sleep Architecture</th><th>Adverse Events</th></tr></thead><tbody><tr><td>Scrima et al., 1990 [42]; Scrima et al., 1989 [47]</td><td>N = 20<br>PSG and MSLT; double-blind, placebo, crossover study</td><td>50 mg/kg/night; 29 days</td><td><ul><li>PSG vs placebo:<br>o N1: ↓<br>o N3: ↑<br>o Delta: ↑<br>o Sleep latency: ↑<br>o Stage shifts: ↓<br>o Awakenings: ↓</li><li>MSLT vs placebo:<br>o Wakefulness: ↑<br>o REM naps: ↓</li></ul></td><td><ul><li>Upset stomach</li><li>Upset stomach with vomiting</li><li>Sluggishness</li><li>Stiffness on morning awakening</li><li>Urinary urgency</li><li>General weakness and fatigue</li><li>Dizziness</li></ul></td></tr><tr><td>Lammers et al., 1993 [43]</td><td>N = 23<br>PSG and MSLT; double-blind, placebo-controlled, crossover study</td><td>60 mg/kg/night; 4 weeks</td><td><ul><li>PSG vs placebo:<br>o Awakenings: ↓<br>o % of wakefulness in REM sleep: ↓<br>o % of SWS: ↑</li><li>MSLT vs placebo (n = 7):<br>o No significant change in mean sleep latency</li></ul></td><td><ul><li>Protracted sleep paralysis with hypnagogic hallucinations (n = 1)</li><li>Weight loss (n = 1)</li></ul></td></tr><tr><td>Scharf et al., 1985 [44]</td><td>N = 30<br>PSG and MSLT; open-label, observational study</td><td>5-7 g/night; up to 30 weeks</td><td><ul><li>PSG vs baseline:<br>o TST: ↑<br>o Total wake time: ↓<br>o Awakenings: ↓<br>o % SWS: ↑<br>o REM latency: ↓</li><li>MSLT vs baseline:<br>REM latency: ↑</li></ul></td><td><ul><li>Protracted sleep paralysis (n = 3)</li><li>Enuresis (n = 1)</li><li>Increased transient sexual drive (n = 1)</li><li>Difficulty staying asleep after second nightly GHB dose</li></ul></td></tr><tr><td>Broughton et al., 1980 [45]</td><td>N = 14<br>PSG; open-label, observational study</td><td>3.75-6.25 g/night; 7-10 days</td><td><ul><li>PSG (nocturnal) vs baseline:<br>o N1: ↓<br>o SWS: ↑<br>o Sleep efficiency: ↑<br>o REM latency and density: ↓<br>o REM efficiency: ↑<br>o Stage shifts from REM: ↓<br>o Sleep fragmentation: ↓</li><li>PSG (daytime) vs baseline:<br>o TST: ↓<br>o SWS duration: ↓<br>o REM duration: ↓<br>o Number of daytime sleep periods (46-60 min and >61 min): ↓</li></ul></td><td><ul><li>N/A</li></ul></td></tr><tr><td>Bédard et al., 1989 [46]</td><td>N = 12 (includes 6 with PLMS)<br>PSG; open-label, observational study</td><td>2.25 g/night; 1 month</td><td><ul><li>PSG vs baseline:<br>o Number of SOREMPs: ↑<br>o REM latency: ↓<br>o REM efficiency: ↑<br>o In first third of night only:<br>  - % WASO: ↓<br>  - % N1: ↓<br>  - % REM: ↑<br>  - REM efficiency: ↑</li></ul></td><td><ul><li>N/A</li></ul></td></tr></tbody></table>

GHB, gamma-hydroxybutyrate; MSLT, Multiple Sleep Latency Test; PLMS, periodic limb movements during sleep; PSG, polysomnography; REM, rapid eye movement; SOREMP, sleep onset rapid eye movement period; SWS, slow-wave sleep; TST, total sleep time; WASO, wake after sleep onset. All reported main findings were significant (P < 0.05) unless otherwise specified.
<table><caption>**Table 2**
Oxybate effects on sleep architecture in adult participants.</caption><thead><tr><th>Data Measure</th><th>Study 1 [48]<br>Median Change From<br>Baseline to 8 Weeks</th><th>Study 2 [50]<br>Median Change From Baseline to<br>4 Weeks (6 g) or 8 Weeks (9 g)</th><th>Study 3 [19]<br>LSMD vs Placebo at Week 3 (6 g), Week 8<br>(7.5 g), or Week 13 (9 g)</th><th>Study 4 [53]<br>Mean at 4 Weeks (4.5 g), 6 Weeks (6 g),<br>8 Weeks (7.5 g), or 10 Weeks (9 g)</th></tr></thead><tbody><tr><td>Total sleep time, min</td><td><strong>Increased</strong><ul><li>Placebo: 0.3</li><li>SXB 4.5 g: 0</li><li>SXB 6 g: 13.0</li><li>SXB 9 g: 18.0<sup>†</sup></li></ul></td><td><strong>No change</strong><ul><li>Placebo: -5.5</li><li>SXB 6 g: -5</li><li>Placebo: -0.5</li><li>SXB 9 g: -4.5</li></ul></td><td><strong>Not assessed</strong><ul><li>Baseline: 383.4</li><li>SXB 4.5 g: 364.8*</li><li>SXB 6 g: 363.0</li><li>SXB 7.5 g: 374.1</li><li>SXB 9 g: 380.8</li></ul></td><td><strong>No change (4.5 g decreased)</strong><ul><li>Baseline: 383.4</li><li>SXB 4.5 g: 364.8*</li><li>SXB 6 g: 363.0</li><li>SXB 7.5 g: 374.1</li><li>SXB 9 g: 380.8</li></ul></td></tr><tr><td>Wake after sleep onset, min</td><td><strong>Decreased</strong><ul><li>Placebo: 2.0</li><li>SXB 4.5 g: -5.8</li><li>SXB 6 g: -3.8</li><li>SXB 9 g: -22.0<sup>†</sup></li></ul></td><td><strong>Not assessed</strong><ul><li>Baseline: 2.0</li><li>SXB 4.5 g: -5.8</li><li>SXB 6 g: -3.8</li><li>SXB 9 g: -22.0<sup>†</sup></li></ul></td><td><strong>Not assessed</strong><ul><li>Baseline: 2.0</li><li>SXB 4.5 g: -5.8</li><li>SXB 6 g: -3.8</li><li>SXB 9 g: -22.0<sup>†</sup></li></ul></td><td><strong>Not assessed</strong><ul><li>Baseline: 2.0</li><li>SXB 4.5 g: -5.8</li><li>SXB 6 g: -3.8</li><li>SXB 9 g: -22.0<sup>†</sup></li></ul></td></tr><tr><td>Awakenings/arousals, n</td><td><strong>Awakenings decreased</strong><ul><li>Placebo: -0.5</li><li>SXB 4.5 g: -5.0</li><li>SXB 6 g: -8.0<sup>††</sup></li><li>SXB 9 g: -12.0<sup>††</sup></li></ul></td><td><strong>Awakenings decreased</strong><ul><li>Placebo: -0.5</li><li>SXB 6 g: -1</li><li>Placebo: -0.5</li><li>SXB 9 g: -6<sup>††</sup></li></ul></td><td><strong>Arousals decreased</strong><ul><li>ON-SXB 6 g: -11.3<sup>†</sup></li><li>ON-SXB 7.5 g: -19.4<sup>†††</sup></li><li>ON-SXB 9 g: -23.7<sup>†††</sup></li></ul></td><td><strong>Awakenings decreased</strong><ul><li>Baseline: 50.2</li><li>SXB 4.5 g: 50.0</li><li>SXB 6 g: 45.1</li><li>SXB 7.5 g: 37.3<sup>***</sup></li><li>SXB 9 g: 37.8<sup>**</sup></li></ul></td></tr><tr><td>N1 sleep time, min</td><td><strong>Decreased</strong><ul><li>Placebo: -2.3</li><li>SXB 4.5 g: -9.5</li><li>SXB 6 g: -13.5<sup>††</sup></li><li>SXB 9 g: -22.5<sup>††</sup></li></ul></td><td><strong>Decreased</strong><ul><li>Placebo: 3.25</li><li>SXB 6 g: -9.5</li><li>Placebo: 1.5</li><li>SXB 9 g: -16<sup>†††</sup></li></ul></td><td><strong>Decreased</strong><ul><li>ON-SXB 6 g: -5.9<sup>†</sup></li><li>ON-SXB 7.5 g: -11.0<sup>††</sup></li><li>ON-SXB 9 g: -13.4<sup>†††</sup></li></ul></td><td><strong>No change</strong><ul><li>Baseline: 74.8</li><li>SXB 4.5 g: 72.3</li><li>SXB 6 g: 68.1</li><li>SXB 7.5 g: 69.4</li><li>SXB 9 g: 62.6</li></ul></td></tr><tr><td>N2 sleep time, min</td><td><strong>No change</strong><ul><li>Placebo: 3.5</li><li>SXB 4.5 g: 9.5</li><li>SXB 6 g: 13.0</li><li>SXB 9 g: 31.5</li></ul></td><td><strong>No change</strong><ul><li>Placebo: -5.25</li><li>SXB 6 g: 0.5</li><li>Placebo: -8.25</li><li>SXB 9 g: 3.5</li></ul></td><td><strong>No change</strong><ul><li>ON-SXB 6 g: -6.6</li><li>ON-SXB 7.5 g: 3.6</li><li>ON-SXB 9 g: -13.5</li></ul></td><td><strong>No change</strong><ul><li>Baseline: 217.8</li><li>SXB 4.5 g: 216.9</li><li>SXB 6 g: 216.9</li><li>SXB 7.5 g: 224.1</li><li>SXB 9 g: 238.0</li></ul></td></tr><tr><td>Slow-wave sleep time, min</td><td><strong>Increased</strong><ul><li>Placebo: 0</li><li>SXB 4.5 g: 3.0<sup>†</sup></li><li>SXB 6 g: 21.0<sup>††</sup></li><li>SXB 9 g: 52.5<sup>†††</sup></li></ul></td><td><strong>Increased</strong><ul><li>Placebo: 0</li><li>SXB 6 g: 11<sup>†</sup></li><li>Placebo: 0</li><li>SXB 9 g: 43.5<sup>†††</sup></li></ul></td><td><strong>Increased</strong><ul><li>ON-SXB 6 g: 22.1<sup>†††</sup></li><li>ON-SXB 7.5 g: 26.8<sup>††</sup></li><li>ON-SXB 9 g: 38.4<sup>†††</sup></li></ul></td><td><strong>Increased</strong><ul><li>Baseline: 3.0 (1st half), 0.6<br>(2nd half)</li><li>SXB 4.5 g: 3.5 (1st half), 0.7<br>(2nd half)</li><li>SXB 6 g: 5.5 (1st half), 4.5<br>(2nd half)</li><li>SXB 7.5 g: 9.8 (1st half), 4.5<sup>*</sup><br>(2nd half)</li><li>SXB 9 g: 14.2 (1st half), 12.6<sup>*</sup><br>(2nd half)</li></ul></td></tr><tr><td>Rapid eye movement sleep time, min</td><td><strong>Decreased</strong><ul><li>Placebo: -1.0</li><li>SXB 4.5 g: -6.0</li><li>SXB 6 g: -7.0</li><li>SXB 9 g: -22.0<sup>†</sup></li></ul></td><td><strong>Decreased</strong><ul><li>Placebo: 6.25</li><li>SXB 6 g: -14.5<sup>††</sup></li><li>Placebo: 10</li><li>SXB 9 g: -38.5<sup>†††</sup></li></ul></td><td><strong>Decreased</strong><ul><li>ON-SXB 6 g: -16.7<sup>†††</sup></li><li>ON-SXB 7.5 g: -27.2<sup>††</sup></li><li>ON-SXB 9 g: -24.5<sup>†††</sup></li></ul></td><td><strong>Decreased</strong><ul><li>Baseline: 31.2 (1st half), 56.0<br>(2nd half)</li><li>SXB 4.5 g: 29.7 (1st half), 43.5<sup>*</sup><br>(2nd half)</li><li>SXB 6 g: 26.3 (1st half), 42.7<sup>***</sup><br>(2nd half)</li><li>SXB 7.5 g: 31.3 (1st half), 34.9<sup>***</sup><br>(2nd half)</li><li>SXB 9 g: 22.9 (1st half), 30.5<sup>***</sup><br>(2nd half)</li></ul></td></tr><tr><td>Delta power<sup>a</sup>, μV<sup>2</sup>/Hz</td><td><strong>Increased</strong><ul><li>Placebo: -1103.0</li><li>SXB 4.5 g: 7166.2<sup>††</sup></li><li>SXB 6 g: 14,736.3<sup>†††</sup></li><li>SXB 9 g: 28,796.7<sup>†††</sup></li></ul></td><td><strong>Increased</strong><ul><li>Placebo: -2326</li><li>SXB 6 g: 10,474</li><li>Placebo: -3221</li><li>SXB 9 g: 18,443<sup>†††</sup></li></ul></td><td><strong>Increased (in NREM only)</strong><ul><li>ON-SXB 6 g: 245.8<sup>††</sup></li><li>ON-SXB 7.5 g: 310.0<sup>†</sup></li><li>ON-SXB 9 g: 573.6<sup>†††</sup></li></ul></td><td><strong>Increased</strong><ul><li>Baseline: 69,709</li><li>SXB 4.5 g: 74,480</li><li>SXB 6 g: 82,308<sup>*</sup></li><li>SXB 7.5 g: 91,917<sup>***</sup></li><li>SXB 9 g: 102,338<sup>***</sup></li></ul></td></tr></tbody></table>

LSMD, least squares mean difference; min, minutes; NREM, non-rapid eye movement; ON-SXB, once-nightly sodium oxybate; SXB, sodium oxybate.

†P < 0.05 vs placebo. ††P < 0.01 vs placebo. †††P < 0.001 vs placebo. *P < 0.05 vs baseline. **P < 0.01 vs baseline. ***P < 0.005 vs baseline.

<footnote>a Assessment methodology of delta power varied across studies (eg, assessed during entire sleep episode or during NREM only), complicating comparison of absolute values.</footnote>
<table><caption>**Table 3**
Oxybate effects on DNS and sleep quality in adult participantsª.</caption><thead><tr><th>Data Measure</th><th>Study 1 [49]<br>LS Mean Change From Baseline to Week 8 (per Hour)<sup>b</sup></th><th>Study 2 [51]<br>LS Mean Change From Baseline (Total)</th><th>Study 3 [19]<br>LS Mean Change From Baseline (Total)</th><th>Study 4 [53]<br>Participants, %</th></tr></thead><tbody><tr><td>Shifts from N2/N3/REM to N1/wake</td><td>Decreased<br>• Placebo: -0.8<br>• SXB 4.5 g: -1.7<br>• SXB 6 g: -2.7<sup>†</sup><br>• SXB 9 g: -4.4<sup>††</sup></td><td>Decreased<br>• Placebo: -0.6<br>• SXB 9 g: -16.5<sup>††</sup></td><td>Not assessed</td><td>Not assessed</td></tr><tr><td>Shifts from N2/N3 to N1/wake</td><td>Decreased<br>• Placebo: -0.3<br>• SXB 4.5 g: -0.9<br>• SXB 6 g: -1.7<sup>†</sup><br>• SXB 9 g: -3.1<sup>††</sup></td><td>Not assessed</td><td>Not assessed</td><td>Not assessed</td></tr><tr><td>Shifts from REM to N1/wake</td><td>Decreased<br>• Placebo: -1.9<br>• SXB 4.5 g: -3.8<br>• SXB 6 g: -5.0<br>• SXB 9 g: -7.6<sup>†</sup></td><td>Decreased<br>• Placebo: -0.6<br>• SXB 9 g: -6.0<sup>††</sup></td><td>Not assessed</td><td>Not assessed</td></tr><tr><td>Shifts from N1/N2/N3/REM to N1/wake<sup>c</sup></td><td>Not assessed</td><td>Not assessed</td><td>Decreased<br>• ON-SXB 6 g: -11.0<sup>††</sup><br>• ON-SXB 7.5 g: -17.7<sup>††</sup><br>• ON-SXB 9 g: -22.6<sup>††</sup></td><td>Not assessed</td></tr><tr><td>Participant-reported sleep quality</td><td>Improved (4-point Likert scale)<sup>d</sup><br>• Placebo: -0.10<br>• SXB 4.5 g: -0.41<sup>†</sup><br>• SXB 6 g: -0.31<sup>†</sup><br>• SXB 9 g: -0.46<sup>††</sup></td><td>Improved (Question 6 of the PSQI)<br>• Placebo: -0.07<br>• SXB 9 g: -0.52<sup>††</sup></td><td>Improved (Visual analog scale from 0-100)<sup>e</sup><br>• ON-SXB 6 g: 7.0<sup>††</sup><br>• ON-SXB 7.5 g: 9.9<sup>††</sup><br>• ON-SXB 9 g: 10.4<sup>††</sup></td><td>Improved (Self-reported degree of change)<br>• Baseline: 0 % (much), 14 % (somewhat)<br>• SXB 4.5 g: 19 % (much), 57 % (somewhat)<br>• SXB 6 g: 24 % (much), 67 % (somewhat)<br>• SXB 7.5 g: 24 % (much), 62 % (somewhat)<br>• SXB 9 g: 24 % (much), 57 % (somewhat)</td></tr></tbody></table>

DNS, disrupted nighttime sleep; LS, least squares; ON-SXB, once-nightly sodium oxybate; PSQI, Pittsburgh Sleep Quality Index; REM, rapid eye movement; SXB, sodium oxybate.

†P < 0.05 vs placebo. ††P < 0.01 vs placebo. †††P < 0.001 vs placebo.

ª Differences in trial design and statistical analysis complicate cross-trial comparisons. No head-to-head trials have been conducted.

ᵇ Per hour values at 9 g translate to reductions of approximately 30.8 (N2/3/REM to N1/wake), 21.7 (N2/3 to N1/wake), and 53.2 (REM sleep to N1/wake) total shifts per night, assuming a total sleep time of 7 h hours but not accounting for time spent in individual sleep stages.

ᶜ Assessed as total number of transitions from sleep to wake or N1 from N1, N2, N3, and REM.

ᵈ Assessed with 4-point Likert-type scale (0, excellent; 1, good; 2, fair; 3, poor).

ᵉ Baseline scores were 53.8 and 55.9 in ON-SXB and placebo groups, respectively.

Firstly, each study design is unique. In particular, study 1 uses a parallel group design, while studies 2, 3, and 4 use ascending dose designs; dosing in the pediatrics study (study 5) is individually optimized for each participant. Further differentiating the pediatric trial, patients could be taking SXB at study entry or be SXB-naive, and PSG was performed at screening and end of stable dosing, not during the double-blind, randomized, withdrawal portion (so no comparisons to placebo are possible). Further, different estimates are used to report the data between trials (studies 1 and 2: median and least squares [LS] mean change from baseline; study 3, least squares mean difference [LSMD] vs placebo; study 4, median or mean value at each timepoint; study 5, median change from baseline). Finally, some variables are assessed differently between trials. For example, delta power is assessed based on NREM and REM sleep in studies 1, 2, and 4, but on NREM sleep only in trial 3; stage shifts are assessed per hour in study 1, but across the whole night in studies 2 and 3. Each of these factors precludes cross-trial comparisons. No head-to-head trials have been conducted.

### 4.2.1. Study 1 [48,49,55]

#### 4.2.1.1. Design.
Study 1 was an 8-week, double-blind, placebo-controlled, parallel group, multicenter trial that evaluated the efficacy of SXB in the treatment of EDS in 228 adult patients (aged ≥16 years; analyses were performed on the intent-to-treat population) with narcolepsy with cataplexy, including post hoc analysis of the effects of SXB on sleep architecture [48,49,55]. Patients were randomized to 8 weeks of treatment (4 weeks of dose titration followed by 4 weeks of stable dose) with placebo, SXB 4.5 g nightly, SXB 6 g nightly, or SXB 9 g nightly. PSG and Maintenance of Wakefulness Test (MWT) were performed at the end of the lead-in period (prior to withdrawal of cataplexy medications), at the end of the baseline period (after withdrawal of cataplexy medications and subsequent washout period), after the 4-week titration period, and at the conclusion of the trial (following 8 weeks of treatment). During the in-lab PSG nights, the total duration of PSG recording was set at 8 h, and the 8-h night was split into 2 consecutive 4-h periods. SXB was dosed at the beginning of each 4-h period [48,49]. Participant-reported sleep quality was assessed using a 4-point Likert-type scale (0 = excellent, 1 = good, 2 = fair, 3 = poor).
**4.2.1.2. Sleep architecture.** Overall, SXB treatment improved sleep architecture (Table 2). Sleep latency did not significantly differ among treatment groups following the first or second SXB doses [48]. TST increased from baseline with SXB treatment in a dose-dependent manner, whereas WASO decreased. Duration of N1 and SWS significantly decreased and increased, respectively, in a dose-dependent manner relative to baseline and compared with placebo. In addition, delta power significantly increased with SXB relative to baseline and compared with placebo, particularly during the second half of the night. Duration of N2 and REM were not consistently affected by SXB treatment [48].

**4.2.1.3. DNS.** Overall, SXB treatment improved measures of DNS (Table 3). Number of nocturnal awakenings decreased in a dose-dependent manner during both the first (median change from baseline: placebo, -1.5; SXB 4.5 g, -2.0; SXB 6 g, -3.0; SXB 9 g, -3.0) and second half of the night (median change from baseline: placebo, -0; SXB 4.5 g, -3.0; SXB 6 g, -5.0; SXB 9 g, -9.0) [48]. In addition, number of sleep stage shifts per hour significantly decreased in a dose-dependent manner [49]. There were significant reductions from baseline in the number of shifts per hour from N2/3/REM to N1/wake (LSM, -4.4), from N2/3 to N1/wake (LSM, -3.1), and from REM sleep to N1/wake (LSM, -7.6) following 8 weeks of SXB treatment (9 g/night). Patient-reported nocturnal sleep quality significantly improved with SXB relative to baseline (P < 0.001) and compared with placebo (P < 0.05). Quality of nocturnal sleep correlated with total number of shifts from N2/N3/REM to N1/wake [49].

**4.2.1.4. Safety.** The most common adverse events (AEs; incidence ≥5%) were nausea, headache, dizziness, nasopharyngitis, and enuresis; sleepwalking occurred in 3% of participants [48]. Of these, only nausea (18.3%) and dizziness (16.7%) occurred more frequently in patients treated with SXB compared with placebo. Serious AEs were reported by 6 patients (placebo, n = 3; SXB, n = 3): pneumonitis (n = 1; SXB 6 g), a fractured ankle following an accidental fall during the night (n = 1; SXB 9 g), and abnormal alanine aminotransferase and aspartate aminotransferase levels at the end of the study (n = 1; SXB 4.5 g). A total of 21 patients discontinued the study due to an AE, with most (n = 15) discontinuations occurring in patients receiving SXB 9 g [48].

### **4.2.2. Study 2 [50,51,56]**

**4.2.2.1. Design.** Study 2 was an 8-week, double-blind, placebo-controlled, parallel group, multicenter trial that evaluated the efficacy of SXB in the treatment of EDS in 222 adult patients (aged ≥18 years; analyses were performed on the intent-to-treat population) with narcolepsy (the presence of cataplexy was not included as an enrollment criterion) who were currently on stable doses of modafinil (200-600 mg/day for ≥1 month), including post hoc analyses of the effects of SXB on sleep architecture [50,51,56]. Patients were randomized to 8 weeks of treatment with placebo SXB and placebo modafinil (placebo group), SXB and placebo modafinil (SXB group), modafinil and placebo SXB (modafinil group), or SXB and modafinil (SXB/modafinil group). SXB was administered in 2 equally divided doses at bedtime and 2.5-4 h later, at 6 g nightly for the first 4 weeks, then 9 g nightly for the final 4 weeks. Patients in the modafinil and SXB/modafinil groups remained on their usual doses of modafinil [49,50]. PSG and MWT were conducted prior to and at the end of the baseline period, as well as after 4 and 8 weeks of treatment. Participant-reported sleep quality used 1 item of the Pittsburgh Sleep Quality Index (PSQI; question 6: "During the past month, how would you rate your sleep quality overall?"). Effects were assessed for the entire night (ie, not by half of night/after each SXB dose).

**4.2.2.2. Sleep architecture.** Overall, SXB alone and in combination with

modafinil improved sleep architecture (Table 2). There were no significant changes in TST in any treatment group compared with placebo [50]. Changes in WASO were not reported. Duration of N1 and REM sleep significantly decreased with both SXB and SXB/modafinil treatment compared with placebo, whereas SWS significantly increased. In addition, delta power significantly increased from baseline with both SXB and SXB/modafinil treatment compared with placebo. Duration of N2 was not consistently affected by SXB or modafinil treatment [50].

**4.2.2.3. DNS.** Overall, SXB alone and in combination with modafinil improved measures of DNS (Table 3). Number of nocturnal awakenings significantly decreased with both SXB and SXB/modafinil treatment compared with placebo [50]. In addition, number of sleep stage shifts significantly decreased with SXB and SXB/modafinil [51]. Patient-reported nocturnal sleep quality using item 6 of PSQI significantly improved with SXB and SXB/modafinil relative to baseline (P < 0.001 for both) and compared with placebo (P < 0.05 for both) [51].

**4.2.2.4. Safety.** Incidence of AEs was greater in patients treated with SXB in combination with modafinil (78.9%) than in those treated with SXB alone (60.0%), modafinil alone (54.0%), or placebo (69.6%) [50]. The most common AEs were headache, nausea, dizziness, nasopharyngitis, vomiting, and somnolence. Of these, only nausea (11.7%), vomiting (6.1%), and dizziness (9.1%) occurred more frequently in patients treated with SXB and/or modafinil compared with placebo. Nausea and vomiting occurred with the highest frequency in patients treated with SXB, while dizziness occurred most frequently in patients treated with SXB in combination with modafinil. Serious AEs were reported by 3 patients: abdominal pain (modafinil), palpitations (placebo), and a psychotic disorder due to a general medical condition (narcissistic personality disorder; SXB/modafinil). A total of 13 patients discontinued the study due to an AE (SXB/modafinil, n = 6; SXB, n = 4; modafinil, n = 2; placebo, n = 1) [50].

### **4.2.3. Study 3 [19,52]**

**4.2.3.1. Design.** The REST-ON trial was a 17-week, double-blind, placebo-controlled, randomized, multicenter study that evaluated the efficacy of ON-SXB in the treatment of EDS in 190 adult patients (≥16 years of age; modified intent-to-treat) diagnosed with NT1 or NT2, including both objective and subjective assessments of sleep architecture and DNS [19,57]. Following a 3-week screening period, patients were administered 13 weeks of treatment with ON-SXB in sequentially ascending doses or placebo: 4.5 g (1 week), 6 g (2 weeks), 7.5 g (5 weeks), and 9 g (5 weeks). PSG was performed at baseline, week 3, week 8, and week 13. Participant-reported sleep quality was reported using a visual analog scale from 0 to 100. Effects were assessed for the entire night (ie, not by half of night).

**4.2.3.2. Sleep architecture.** Overall, ON-SXB treatment improved sleep architecture (Table 2). Duration of N1 significantly decreased from baseline compared with placebo, while SWS significantly increased. REM sleep duration also significantly decreased. In addition, delta power during NREM significantly increased with ON-SXB relative to baseline and compared with placebo. Duration of N2 was not consistently affected by ON-SXB.

**4.2.3.3. DNS.** Overall, ON-SXB treatment improved measures of DNS (Table 3). Number of nocturnal arousals significantly decreased in a dose-dependent manner. In addition, number of sleep stage shifts also significantly decreased in a dose-dependent manner. Participant-reported nocturnal sleep quality significantly improved from baseline and relative to placebo with all ON-SXB doses (P < 0.001). A post hoc analysis of participants split by narcolepsy type also found a significant decrease in sleep stage shifts and improvement in sleep quality in both
<table><caption>**Table 4**
Oxybate effects on sleep architecture in pediatric participants.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td><strong>Data Measure</strong></td><td><strong>Study 5 [54]</strong></td></tr><tr><td>Total sleep time, min</td><td><strong>Median Change From Baseline (Individual Doses)</strong></td></tr><tr><td>Wake after sleep onset, min</td><td><strong>Not assessed</strong></td></tr><tr><td>Awakenings/arousals, n</td><td><strong>Not assessed</strong></td></tr><tr><td>N1 sleep time, %</td><td><strong>Arousals decreased</strong></td></tr><tr><td>N2 sleep time, %</td><td><strong>Decreased</strong></td></tr><tr><td>Slow-wave sleep time, %</td><td><strong>SXB-naive: -4.6 %<br>Taking SXB at study entry: -0.6 %</strong></td></tr><tr><td>Rapid eye movement sleep time, %</td><td><strong>No change</strong></td></tr><tr><td>Delta power, μV<sup>2</sup>/Hz</td><td><strong>Values not reported</strong></td></tr><tr><td>min, minutes; SXB, sodium oxybate.</td><td><strong>Increased</strong></td></tr><tr><td>NT1 and NT2 (LSMD vs placebo, P < 0.05, for all doses for both subgroups) [52].</td><td><strong>SXB-naive: 12.6 %<br>Taking SXB at study entry: -1.0 %</strong></td></tr><tr><td>4.2.3.4. Safety. The most common AEs were nausea, headache, vomiting, dizziness, and enuresis [57]. Serious AEs were reported by 7 participants (3.3 %) overall (placebo, n = 2 [1.9 %]; ON-SXB, n = 5 [4.7 %]). Among those treated with ON-SXB, these serious AEs were diabetes mellitus inadequate control (n = 1, 4.5 g), paresthesia (n = 1, 6 g), perirectal abscess (n = 1, 7.5 g), and suicidal ideation (n = 1, 9 g); 1 participant in this group experienced hypertension in the posttreatment follow up. A total of 17 (15.9 %) participants in the ON-SXB group and 2 (1.9 %) in the placebo group discontinued due to adverse drug reactions.</td><td><strong>Decreased</strong></td></tr><tr><td>4.2.4. Study 4 [53]</td><td><strong>SXB-naive: -6.0 %<br>Taking SXB at study entry: not reported</strong></td></tr><tr><td>4.2.4.1. Design. A 14-week, open-label, pilot study was conducted to determine whether SXB modifies sleep architecture in a dose-dependent fashion that is related to improvements in narcolepsy symptoms in adults (≥18 years old) diagnosed with narcolepsy [53]. Twice-nightly SXB was initiated at 4.5 g/night for 4 weeks. The dose was then increased to 6 g/night for 2 weeks, then to 7.5 g/night for 2 weeks, and, finally, to 9 g/night for 2 weeks. PSG was conducted before the washout period (Visit 1) of antidepressant and sedative hypnotic medications; patients were permitted to stay on their stable doses of pre-trial stimulants), at the end of the washout period (baseline, Visit 2a), on the first night of treatment (Visit 2b), after 4 weeks of treatment (Visit 3), and at the end of each dosing period (Visits 4, 5, and 6). PSG sleep parameters were assessed by half of night. The MWT was conducted at Visit 1, Visit 2a, Visit 3, and Visit 6. Participant-reported sleep quality was assessed as a percentage of participants indicating their nighttime sleep quality was “much improved,” “somewhat improved,” “unchanged,” “somewhat worse,” or “much worse.” A total of 25 patients (enrolled; 7 males and 18 females) participated in this trial. Caution should be applied when interpreting the reported levels of significance as this pilot study was not statistically powered.</td><td><strong>Not assessed</strong></td></tr><tr><td>4.2.4.2. Sleep architecture. Overall, SXB treatment improved sleep architecture (Table 2). TST did not significantly change from baseline, except at a dose of 4.5 g. Duration of REM sleep significantly decreased, whereas SWS significantly increased; these increases were consistently greater in the second half of the night. In addition, delta power significantly increased from baseline in a dose-related manner. Duration of N1 and N2 was not affected by SXB.</td><td>4.2.4.3. DNS. Overall, SXB treatment improved measures of DNS (Table 3). Number of nocturnal awakenings significantly decreased compared with baseline, with 7.5 g and 9 g. SXB also improved patient-reported nocturnal sleep quality with 19 %–24 % of participants reporting their nighttime sleep quality as “much improved” and 57 %–67 % of participants reporting their nighttime sleep quality as “somewhat improved” with SXB (4.5, 6.0, 7.5, or 9 g) compared with their symptom severity prior to enrolling in the trial.</td></tr><tr><td>4.2.4.4. Safety. The most commonly reported AEs were nausea (n = 5, 20 %); back pain, anorexia, vomiting, and edema (n = 3, 12 % each); and sleep disorder (not further defined in the text) and somnolence (n = 2, 8 % each). Two patients discontinued the study because of AEs, namely a respiratory disorder at the 4.5 g dose of SXB and respiratory depression at the 7.5 g dose, respectively; none of the AEs were assessed as serious. There were no significant changes in clinical laboratory parameters or vital signs. Of the 25 patients who enrolled in the trial, 18 patients reported ≥1 AE, and 13 patients reported AEs considered to be related to the study drug.</td><td>4.2.4.5. Safety. The most commonly reported AEs were nausea (n = 5, 20 %); back pain, anorexia, vomiting, and edema (n = 3, 12 % each); and sleep disorder (not further defined in the text) and somnolence (n = 2, 8 % each). Two patients discontinued the study because of AEs, namely a respiratory disorder at the 4.5 g dose of SXB and respiratory depression at the 7.5 g dose, respectively; none of the AEs were assessed as serious. There were no significant changes in clinical laboratory parameters or vital signs. Of the 25 patients who enrolled in the trial, 18 patients reported ≥1 AE, and 13 patients reported AEs considered to be related to the study drug.</td></tr><tr><td>4.3. Sodium oxybate: key clinical study in pediatric patients</td><td>4.3.1. Study 5 [54,58–60]</td></tr><tr><td>4.3.1.1. Design. This study was a double-blind, placebo-controlled, randomized, withdrawal study that evaluated the efficacy of SXB for the treatment of cataplexy and EDS in 106 pediatric patients (aged 7–16 years old; enrolled) with narcolepsy with cataplexy who were on stable doses of SXB or SXB-naive at study entry [58,59]. Patients who were SXB-naive were titrated to an optimal stable dose over 3–10 weeks; patients taking SXB at study entry had no titration period. Patients then completed 2 (SXB-naive) or 3 (on SXB at study entry) weeks of stable-dose SXB treatment, followed by a 2-week, double-blind, placebo-controlled, randomized, withdrawal period, during which patients were randomized to continue SXB or switch to placebo [58]. PSG was performed during screening, stable-dose, and safety periods, but not</td><td>4.3.1.2. Design. This study was a double-blind, placebo-controlled, randomized, withdrawal study that evaluated the efficacy of SXB for the treatment of cataplexy and EDS in 106 pediatric patients (aged 7–16 years old; enrolled) with narcolepsy with cataplexy who were on stable doses of SXB or SXB-naive at study entry [58,59]. Patients who were SXB-naive were titrated to an optimal stable dose over 3–10 weeks; patients taking SXB at study entry had no titration period. Patients then completed 2 (SXB-naive) or 3 (on SXB at study entry) weeks of stable-dose SXB treatment, followed by a 2-week, double-blind, placebo-controlled, randomized, withdrawal period, during which patients were randomized to continue SXB or switch to placebo [58]. PSG was performed during screening, stable-dose, and safety periods, but not</td></tr></tbody></table>
<table><caption>**Table 5**
Additional studies and meta-analyses of the impact of oxybate on sleep architecture and DNS.</caption><thead><tr><th>Reference</th><th>Study Design (N)</th><th>SXB Dose and Duration</th><th>Sleep Assessments</th><th>Main Findings for Effects on Sleep Architecture and Adverse Events</th></tr></thead><tbody><tr><td>Alshaikh et al., 2011 [62]</td><td>Long-term (2-year), observational, case study (N = 4)</td><td><ul><li>SXB dose and duration varied by patient (ranged from 5 to 9 g nightly for 18-31 months)</li></ul></td><td><ul><li>PSG + MSLT at SXB initiation and after 3, 9, and 14 months of SXB treatment</li></ul></td><td><ul><li>Compared with baseline, SXB was associated with ↓ N1, ↑ SWS, ↑ REM, ↓ arousal index, and ↑ sleep latency</li><li>AEs: weight loss, nausea, vomiting, snoring, enuresis, convulsions, nightmares and body jerks during sleep, dizziness, and lower limb paresthesia</li></ul></td></tr><tr><td>Donjacour et al., 2011 [64]; Donjacour et al., 2011 [63]; Donjacour et al., 2012 [65]</td><td>In-laboratory, matched-controlled study (N = 16)</td><td><ul><li>SXB 6 g nightly for 5 nights</li></ul></td><td><ul><li>PSG at baseline and on last (5th) night</li></ul></td><td><ul><li>Compared with baseline, SXB was associated with ↓ N1, ↓ N2, ↓ REM, ↑ SWS, and ↓ number of awakenings</li><li>AEs: mild drowsiness</li></ul></td></tr><tr><td>Poryazova et al., 2011 [66]</td><td>Long-term (≈2-year), single-center study (N = 18)</td><td><ul><li>SXB dose and duration varied by patient (mean [SD] 6.4 [1.2] g for 26 [13] months)</li></ul></td><td><ul><li>PSG + MSLT + MWT + actigraphy before and after treatment</li></ul></td><td><ul><li>Compared with baseline, SXB was associated with ↓ N1, ↓ N2, ↓ REM, ↑ SWS, and ↓ arousal index</li><li>AEs: nighttime confusion, nausea, enuresis, diffuse muscle pain, headache, flatulence, disturbance in attention, and forgetfulness</li></ul></td></tr><tr><td>Tantrakul et al., 2011 [67]</td><td>Retrospective study (N = 10)</td><td><ul><li>SXB dose and duration varied by patient (mean [SD] 6.8 [2.0] g for 8.1 [4.1] weeks)</li></ul></td><td><ul><li>PSG at baseline and follow-up</li></ul></td><td><ul><li>Compared with baseline, SXB was associated with ↓ REM, ↑ SWS, ↓ arousal index, ↑ A1 CAP subtype, and ↓ A2 and A3 CAP subtypes</li><li>AEs were not reported</li></ul></td></tr><tr><td>van der Heide et al., 2016 [68]</td><td>Real-world, ambulatory study (N = 25)</td><td><ul><li>SXB dose varied by patient (mean [SD], 5.8 [2.2] g nightly)</li></ul></td><td><ul><li>PSG at SXB initiation and after 3 months of SXB treatment</li></ul></td><td><ul><li>Compared with baseline, SXB was associated with ↑ SWS</li><li>AEs were not reported</li></ul></td></tr><tr><td>Peraita-Adrados et al., 2023 [69]</td><td>Longitudinal (3-year), observational study (N = 23)</td><td><ul><li>SXB dose varied by patient (ranged from 4.5 to 9 g nightly)</li></ul></td><td><ul><li>PSG after 6 months, 1 year later, and after 3 years of SXB treatment</li></ul></td><td><ul><li>Across the duration of the study (no baseline assessment), SXB was associated with ↑ N1, ↑ N2, and ↑ sleep fragmentation (independent of second SXB dose)</li><li>AEs: dizziness, enuresis, unpleasant feeling of coldness after first dose, and unintentional weight loss</li></ul></td></tr><tr><td>Xu et al., 2019 [70]</td><td>Systematic review and meta-analysis (15 RCTs involving 2104 patients)</td><td><ul><li>SXB dose and duration varied by patient (ranged from 3 to 9 g for 4-8 weeks)</li></ul></td><td><ul><li>PSG data</li></ul></td><td><ul><li>Compared with placebo, GHB was associated with ↓ N1, ↑ SWS, ↓ REM, ↓ number of sleep stage shifts, ↓ number of nocturnal awakenings, and ↑ quality of nocturnal sleep</li><li>AEs: dizziness, nausea, vomiting, and enuresis</li></ul></td></tr></tbody></table>

AE, adverse event; CAP, cyclic alternating pattern; DNS, disrupted nighttime sleep; GHB, gamma-hydroxybutyrate; MSLT, Multiple Sleep Latency Test; MWT, Maintenance of Wakefulness Test; PSG, polysomnography; RCT, randomized controlled trial; REM, rapid eye movement; SD, standard deviation; SWS, slow wave sleep; SXB, sodium oxybate.

during the double-blind, randomized, withdrawal period [60]. Patients then entered an open-label safety period for up to 47 weeks [59]. Effects were assessed for the entire night (ie, not by half of night/after each SXB dose).

### 4.3.1.2. Sleep architecture.
Overall, treatment with SXB improved parameters of sleep architecture in patients who were SXB-naive at study entry (Table 4) [60]. Changes in TST, WASO, and delta power were not reported. Arousals and duration of N1 and REM sleep significantly decreased in SXB-naive patients, whereas SWS significantly increased. Duration of N2 was similar throughout the study. All comparisons were to baseline as there was no placebo group in this study. Patients who were on SXB at study entry did not show changes from baseline in these parameters.

### 4.3.1.3. Safety.
Incidence of AEs was greater in patients who were SXB-naive (83 %) at study entry than in those taking SXB at study entry (63 %). The most common AEs were enuresis (19.2 %), nausea (19.2 %), vomiting (18.3 %), headache (17.3 %), decreased weight (11.5 %), and decreased appetite (8.7 %), all more frequent in SXB-naive patients. Sleepwalking was reported in 6 % of patients [13]. Two serious AEs occurred (suicidal ideation and acute psychosis) in patients who were SXB-naive during the open-label titration period and resolved after SXB was discontinued. One patient with suicidal ideation withdrew from the study and the other resumed SXB at a lower dose without recurrent psychosis.

### 4.4. Sodium oxybate: additional publications

Additional "real-world" and laboratory studies, as well as a meta-analysis, have evaluated the effects of twice-nightly oxybate (SXB or GHB) on sleep architecture in patients with narcolepsy, summarized in Table 5 [61-70]. The findings of these studies are primarily consistent with the findings observed in the key clinical trials, with the exception of a recent observational study of 23 patients with NT1 taking SXB over 3 years in Spain [69]. In that study, sleep fragmentation with stage shifts was noted in the final 3rd of the night from 6 months onward; the 10 participants remaining at the 3-year follow-up showed increased N1%, with no significant change in SWS or REM. Further, number of awakenings per hour of sleep decreased progressively over time, but did not reach statistical significance. However, interpretation of these data is difficult because no baseline values (prior to initiating SXB) were collected, and the mean dose was <6 g at each timepoint with no change in ESS scores indicating patients may not have been titrated to efficacy.

### 4.5. Additional information regarding oxybate treatment in pediatric narcolepsy

In addition to PSG, actigraphy, which is wearable technology that provides indirect assessment of sleep through quantifying movement, is a useful tool to monitor efficacy of oxybate on DNS, particularly in pediatric patients since it can be used at home [71,72]. A 1-year longitudinal study evaluating the effect of SXB on sleep in 24 pediatric patients with NT1 using at-home actigraphy found that SXB treatment was associated with decreased estimated WASO and awakenings and
increased estimated TST [71]. Also of note is the efficacy of oxybate on REM sleep without atonia (RWA) in pediatric patients with NT1 [73]. A study of 19 pediatric patients with NT1 found that measures of RWA improved compared to baseline after stable treatment with SXB [73].

# 5. Treatment considerations

## 5.1. Management of adverse events and comorbidities

Oxybate treatment can result in adverse events, which can be further complicated by comorbid conditions commonly associated with narcolepsy. Due to its respiratory depressant effects, patients prescribed an oxybate should be monitored for the development or worsening of existing sleep-disordered breathing. This is particularly important in the event of comorbid obesity, which increases the risk of these events [11, 74]. SXB administration has been associated with increased central apneas and clinically relevant desaturation events in adults with obstructive sleep apnea (OSA) and children with narcolepsy [11,74]. The safety of ON-SXB has not been established in people with apnea/hypopnea indexes >15 or in pediatric patients (in whom OSA is rare) [15,75]. Importantly, the key clinical trials summarized here excluded patients with any sleep disorder other than narcolepsy or other disease that could compromise the study objectives.

Episodes of sleepwalking have been reported in adults taking SXB (6 % of 781 participants in controlled and long-term, open-label trials; 5 instances involving potential or significant injury), ON-SXB (3 % of 107 participants in a controlled trial), and LXB (2 % of 201 participants in the phase 3 trial) [14]. Sleepwalking has also been reported in children taking SXB (6 % of 104 participants in a controlled trial and in post-marketing reports). Sleepwalking episodes should be evaluated by a healthcare provider to consider possible interventions [11]. Children prescribed SXB, and their caregivers, should also be informed of the risk of enuresis, which was reported by 19.2 % of patients in the pediatric clinical trial of SXB [60]. In adults, reported rates of enuresis ranged from 3 % to 7 % in clinical trials of SXB and from 2 % to 9 % in a clinical trial of ON-SXB and increased dose-dependently [11,15]. Enuresis occurred in 3.5 % of participants in the phase 3 trial of LXB for narcolepsy and was not reported during the 12-month open-label extension [14,76]. To date, no studies have been conducted to evaluate the effects of ON-SXB or LXB in children.

Patients prescribed SXB, LXB, or ON-SXB should be monitored for the emergence of depressive symptoms or suicidality, particularly individuals with a history of depression or past suicide attempt [11,13, 15]. Among 781 adults taking SXB in clinical trials, depression was reported by 7 %, and there were 2 suicides and 2 attempted suicides. Two of 104 pediatric patients taking SXB in a clinical trial also reported depression, and 1 had suicidal ideation. Depression was reported by 1 % of 107 adults taking 6 g ON-SXB, rising to 1.1 % at 7.5 g titration and 1.3 % at 9 g; 1 participant also reported suicidal ideation at 9 g.

# 6. Limitations and future directions

To date, no head-to-head comparisons of oxybate therapies have been performed, limiting comparisons between each oxybate formulation. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, inclusion criteria (eg, NT1 only vs NT1 or NT2), outcomes assessed (eg, awakenings vs arousals), and statistical analyses. Future head-to-head trials are needed to elucidate whether any oxybate product is superior for improving sleep, sleep architecture, DNS, and daytime symptoms in patients with narcolepsy.

# 7. Conclusions

In conclusion, patients with narcolepsy have DNS characterized by altered sleep architecture, mixing of sleep/wake stages, frequent

spontaneous arousals and awakenings, and increased transitions between sleep stages. Oxybates improve DNS in patients with narcolepsy by increasing time in SWS, decreasing time in REM sleep, decreasing arousals and awakenings, and decreasing shifts between sleep stages. These improvements are seen when oxybate is dosed once- or twice-nightly. When assessed by half of night, SXB showed a greater impact on DNS in the second half of the night. Future studies that directly compare the efficacy and safety of available oxybate products are needed to better understand the advantages and disadvantages of each agent over the other and as a function of the underlying sleep disorder (eg, NT1 or NT2 or idiopathic hypersomnia).

# Role of funding source

Although Jazz Pharmaceuticals reviewed the content of this manuscript, the ultimate interpretation and the decision to submit it for publication was made by the authors independently.

# Data sharing statement

All relevant data are provided within the manuscript and supporting files.

# CRediT authorship contribution statement

**Thomas Roth:** Conceptualization, Writing – original draft, Writing – review & editing. **Yves Dauvilliers:** Conceptualization, Writing – original draft, Writing – review & editing. **Richard K. Bogan:** Conceptualization, Writing – original draft, Writing – review & editing. **Giuseppe Plazzi:** Conceptualization, Writing – original draft, Writing – review & editing. **Jed Black:** Conceptualization, Writing – original draft, Writing – review & editing.

# Declaration of competing interest

**T Roth** has served as a consultant for Abbott, Acadia, Acogolix, Acorda, Actelion, Addrenex, Alchemer, Alza, Ancel, Arena, AstraZeneca, Aventis, AVER, Bayer, BMS, BTG, Cephalon, Cypress, Dove, Eisai, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz Pharmaceuticals, Johnson and Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Otsuka, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Yanda, VivoMetrics, Wyeth, Yamanouchi, and XenoPort. He has been a speakers bureau member for Purdue and Sepracor. He has received research support from Apnex, Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sanofi, Schering Plough, Sepracor, Somaxon, Syrex, Takeda, Transcept, Wyeth, and XenoPort.

**Y Dauvilliers** is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Harmony Biosciences, Idorsia, Orexia, Takeda, Paladin, and Bioprojet.

**RK Bogan** is a shareholder of Watermark Medical and Healthy Humming, LLC; serves on the board of directors for Watermark; is a medical consultant to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, and Oventus; has conducted industry-funded research for Avadel, Axsome, Bresotec, Bayer, Idorsia, Suven, Jazz, Balance, NLS, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Livanova, Roche, Sanofi, Sommetrics, and Noctrix; and is on speakers bureaus for Jazz, Eisai, and Harmony.

**G Plazzi** is a former consultant to Jazz Pharmaceuticals and has participated in advisory boards for UCB Pharma, Bioprojet, Idorsia, Jazz Pharmaceuticals, and Takeda.

**J Black** is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals, plc.
Acknowledgments

Funding: This work was supported by Jazz Pharmaceuticals. Under the direction of the authors, Hannah Ritchie, PhD, and Sean Anderson, PhD, of Peloton Advantage, LLC, an OPEN Health company, provided medical writing and editorial support for this manuscript, which was funded by Jazz Pharmaceuticals.

References

[1] Acquavella J, Mehra R, Bron M, Suomi JMH, Hess GP. Prevalence of narcolepsy, other sleep disorders, and diagnostic tests from 2013–2016: insured patients actively seeking care. J Clin Sleep Med 2020;16(8):1255–63.

[2] American Academy of Sleep Medicine. International classification of sleep disorders. In: Text revision (ICSD-3-TR). third ed. Darien, IL: American Academy of Sleep Medicine; 2023.

[3] Dauvilliers Y, Barateau L, Lopez R, et al. Narcolepsy Severity Scale: a reliable tool assessing symptom severity and consequences. Sleep 2020;43(6):zsaa009.

[4] Roth T, Dauvilliers Y, Mignot E, et al. Disrupted nighttime sleep in narcolepsy. J Clin Sleep Med 2013;9(9):955–65.

[5] Maski K, Mignot E, Plazzi G, Dauvilliers Y. Disrupted nighttime sleep and sleep instability in narcolepsy. J Clin Sleep Med 2022;18(1):289–304.

[6] Makarem N, Castro-Diehl C, St-Onge MP, et al. Redefining cardiovascular health to include sleep: prospective associations with cardiovascular disease in the MESA sleep study. J Am Heart Assoc 2022;11(21):e025252.

[7] Lloyd-Jones DM, Allen NB, Anderson CAM, et al. Life's Essential 8: updating and enhancing the American Heart Association's construct of cardiovascular health: a presidential advisory from the American Heart Association. Circulation 2022;146(5):e18–43.

[8] Ben-Joseph RH, Saad R, Black J, et al. Cardiovascular Burden of Narcolepsy Disease (CV-BOND): a real-world evidence study [published online ahead of print June 12, 2023]. Sleep 2023:zsad161.

[9] Bosco A, Lopez R, Barateau L, et al. Effect of psychostimulants on blood pressure profile and endothelial function in narcolepsy. Neurology 2018;90(6):e479–91.

[10] Mohammadi S, Moosaie F, Saghazadeh A, Mahmoudi M, Rezaei N. Metabolic profile in patients with narcolepsy: a systematic review and meta-analysis. Sleep Med 2021;81:268–84.

[11] Xyrem® (sodium oxybate) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2023.

[12] Xyrem [summary of product characteristics]. Brussels, Belgium: UCB Pharma; 2022.

[13] Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution, CIII [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2023.

[14] Bogan RK, Thorpy MJ, Dauvilliers Y, et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep 2021;44(3):zsaa206.

[15] Lumryz™ (sodium oxybate. For extended-release oral solution, CIII [prescribing information]. Chesterfield, MO: Avadel CNS Pharmaceuticals; 2023.

[16] Carskadon MA, Dement WC. Normal human sleep: an overview. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. fifth ed. St. Louis, MO: Elsevier Saunders; 2011. p. 16–26.

[17] Markun LC, Sampat A. Clinician-focused overview and developments in polysomnography. Curr Sleep Med Rep 2020;6(4):309–21.

[18] Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep 2004;27(7): 1255–73.

[19] Roth T, Dauvilliers Y, Thorpy MJ, et al. Effect of FT218, a once-nightly sodium oxybate formulation, on disrupted nighttime sleep in patients with narcolepsy: results from the randomized phase III REST-ON trial. CNS Drugs 2022;36(4): 377–87.

[20] Bonnet MH, Arand DL. EEG arousal norms by age. J Clin Sleep Med 2007;3(3): 271–4.

[21] Jimenez-Correa U, Haro R, Obdulia Gonzalez R, Velazquez-Moctezuma J. Correlations between subjective and objective features of nocturnal sleep and excessive diurnal sleepiness in patients with narcolepsy. Arq Neuropsiquiatr 2009; 67(4):995–1000.

[22] Bonnet M, Carley D, Carskadon M, et al. EEG arousals: scoring rules and examples. A preliminary report from the sleep disorders atlas task force of the American sleep disorders association. Sleep 1992;15(2):173–84.

[23] Berry RB, Quan SF, Abreu AR, et al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Darien, IL: American Academy of Sleep Medicine; 2020. Version 2.6.

[24] Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: US Government Printing Office; 1968.

[25] Boulos MI, Jairam T, Kendzerska T, Im J, Mekhael A, Murray BJ. Normal polysomnography parameters in healthy adults: a systematic review and meta-analysis. Lancet Respir Med 2019;7(6):533–43.

[26] Mukai J, Uchida S, Miyazaki S, Nishihara K, Honda Y. Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal subjects. J Sleep Res 2003;12 (1):63–71.

[27] Bruni O, Kohler M, Novelli L, et al. The role of NREM sleep instability in child cognitive performance. Sleep 2012;35(5):649–56.

[28] Tapia IE, Karamessinis L, Bandla P, et al. Polysomnographic values in children undergoing puberty: pediatric vs. adult respiratory rules in adolescents. Sleep 2008;31(12):1737–44.

[29] Khatami R, Landolt HP, Achermann P, et al. Insufficient non-REM sleep intensity in narcolepsy-cataplexy. Sleep 2007;30(8):980–9.

[30] Khatami R, Landolt HP, Achermann P, et al. Challenging sleep homeostasis in narcolepsy-cataplexy: implications for non-REM and REM sleep regulation. Sleep 2008;31(6):859–67.

[31] Harsh J, Peszka J, Hartwig G, Mitler M. Night-time sleep and daytime sleepiness in narcolepsy. J Sleep Res 2000;9(3):309–16.

[32] Pizza F, Vandi S, Iliot M, et al. Nocturnal sleep dynamics identify narcolepsy type 1. Sleep 2015;38(8):1277–84.

[33] Vandi S, Rodolfi S, Pizza F, et al. Cardiovascular autonomic dysfunction, altered sleep architecture, and muscle overactivity during nocturnal sleep in pediatric patients with narcolepsy type 1. Sleep 2019;42(12):zs169.

[34] Walacik-Ufnal E, Piotrowska AJ, Wolynczyk-Gmaj D, et al. Narcolepsy type 1 and hypersomnia associated with a psychiatric disorder show different slow wave activity dynamics. Acta Neurobiol Exp 2017;77(2):147–56.

[35] Rosenthal LD, Merlotti L, Young DK, et al. Subjective and polysomnographic characteristics of patients diagnosed with narcolepsy. Gen Hosp Psychiatr 1990;12 (3):191–7.

[36] Bruck D, Parkes JD. A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary. J Neurol Neurosurg Psychiatry 1996;60(5):576–8.

[37] Parkes JD, Chen SY, Clift SJ, Dahlitz MJ, Dunn G. The clinical diagnosis of the narcoleptic syndrome. J Sleep Res 1998;7(1):41–52.

[38] Frauscher B, Gschliesser V, Brandauer E, et al. Motor disturbances during non-REM and REM sleep in narcolepsy-cataplexy: a video-polysomnographic analysis. J Sleep Res 2011;20(4):514–21.

[39] Maski K, Pizza F, Liu S, et al. Defining disrupted nighttime sleep and assessing its diagnostic utility for pediatric narcolepsy type 1. Sleep 2020;43(10):zsaa066.

[40] Barateau L, Lopez R, Chenini S, et al. Association of CSF orexin-A levels and nocturnal sleep stability in patients with hypersomnolence. Neurology 2020;95 (21):e2900–11.

[41] Barateau L, Lopez R, Chenini S, et al. Linking clinical complaints and objective measures of disrupted nighttime sleep in narcolepsy type 1. Sleep 2022;45(6): zsac054.

[42] Scrima L, Hartman PG, Johnson Jr FH, Thomas EE, Hiller FC. The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep 1990;13(6):479–90.

[43] Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G, Troost J. Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 1993;16(3):216–20.

[44] Scharf MB, Brown D, Woods M, Brown L, Hirschowitz J. The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy. J Clin Psychiatry 1985;46(6):222–5.

[45] Broughton R, Mamelak M. Effects of nocturnal gamma-hydroxybutyrate on sleep/waking patterns in narcolepsy-cataplexy. Can J Neurol Sci 1980;7(1):23–31.

[46] Bédard MA, Montplaisir J, Godbout R, Lapierre O. Nocturnal gamma-hydroxybutyrate. Effect on periodic leg movements and sleep organization of narcoleptic patients. Clin Neuropharmacol 1989;12(1):29–36.

[47] Scrima L, Hartman PG, Johnson Jr FH, Hiller FC. Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures. Biol Psychiatr 1989;26(4):331–43.

[48] Black J, Pardi D, Hornfeldt CS, Inhaber N. The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med 2010;6(6):596–602.

[49] Roth T, Dauvilliers Y, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res 2017;26(4):407–14.

[50] Black J, Pardi D, Hornfeldt CS, Inhaber N. The nightly administration of sodium oxybate results in significant reduction in the nocturnal sleep disruption of patients with narcolepsy. Sleep Med 2009;10(8):829–35.

[51] Dauvilliers Y, Roth T, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy. Sleep Med 2017;40:53–7.

[52] Dauvilliers Y, Roth T, Bogan R, et al. Efficacy of once-nightly sodium oxybate (FT218) in narcolepsy type 1 and type 2: post hoc analysis from the phase 3 REST-ON trial. Sleep 2023:zsad152 [published online ahead of print May 29, 2023].

[53] Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27(7):1327–34.

[54] Mignot E, Bogan RK, Black J, et al. Effects of sodium oxybate treatment on sleep architecture in paediatric patients with narcolepsy [abstract]. Sleep Med 2019;64 (suppl 1):S256.

[55] Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 2005;1(4):391–7.

[56] Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29(7):939–46.

[57] Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. Sleep 2022;45(6):zsab200.
[58] Plazzi G, Ruoff C, Lecendreux M, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health 2018; 2(7):483-94.

[59] Lecendreux M, Plazzi G, Dauvilliers Y, et al. Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients. J Clin Sleep Med 2022;18(9):2217-27.

[60] Mignot E, Bogan RK, Black J, et al. Effects of sodium oxybate treatment on sleep architecture in paediatric patients with narcolepsy [oral presentation]. Vancouver, Canada: Biennial World Sleep Congress; 2019.

[61] Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev 2012;16 (5):431-43.

[62] Alshaikh MK, Gacuan D, George S, Sharif M, Bahammam AS. Long-term follow-up of patients with narcolepsy-cataplexy treated with sodium oxybate (Xyrem). Clin Neuropharmacol 2011;34(1):1-4.

[63] Donjacour CE, Aziz NA, Frölich M, et al. Sodium oxybate increases prolactin secretion in narcolepsy patients and healthy controls. Eur J Endocrinol 2011;164 (3):363-70.

[64] Donjacour CE, Aziz NA, Roelfsema F, et al. Effect of sodium oxybate on growth hormone secretion in narcolepsy patients and healthy controls. Am J Physiol Endocrinol Metab 2011;300(6):E1069-75.

[65] Donjacour CE, Kalsbeek A, Overeem S, et al. Altered circadian rhythm of melatonin concentrations in hypocretin-deficient men. Chronobiol Int 2012;29(3):356-62.

[66] Poryazova R, Tartarotti S, Khatami R, et al. Sodium oxybate in narcolepsy with cataplexy: Zurich sleep center experience. Eur Neurol 2011;65(3):175-82.

[67] Tantrakul V, Guilleminault C. Effect of gammahydroxybutyrate on cyclic alternating pattern (CAP) in patients with narcolepsy with cataplexy [abstract 0604]. Sleep 2011;34(abstract suppl):A208.

[68] van der Heide A, Werth E, Donjacour CE, et al. Core body and skin temperature in type 1 narcolepsy in daily life; effects of sodium oxybate and prediction of sleep attacks. Sleep 2016;39(11):1941-9.

[69] Peraita-Adrados R, Bellón JM, Lillo-Triguero L, López-Esteban P, Medrano-Martínez P. Long-term follow-up on the effects of sodium oxybate on daytime sleepiness and sleep architecture in patients with narcolepsy type 1. Rev Neurol 2023;76(2):35-40.

[70] Xu XM, Wei YD, Liu Y, Li ZX. Gamma-hydroxybutyrate (GHB) for narcolepsy in adults: an updated systematic review and meta-analysis. Sleep Med 2019;64: 62-70.

[71] Filardi M, Pizza F, Antelmi E, Ferri R, Natale V, Plazzi G. In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: an actigraphic study. Sleep 2018;41(6):zxy050.

[72] Liguori C, Mombelli S, Fernandes M, et al. The evolving role of quantitative actigraphy in clinical sleep medicine. Sleep Med Rev 2023;68:101762.

[73] Antelmi E, Filardi M, Pizza F, et al. REM sleep behavior disorder in children with type 1 narcolepsy treated with sodium oxybate. Neurology 2021;96(2):e250-4.

[74] Feldman NT. Clinical perspective: monitoring sodium oxybate-treated narcolepsy patients for the development of sleep-disordered breathing. Sleep Breath 2010;14 (1):77-9.

[75] Filardi M, Demir N, Pizza F, et al. Prevalence and neurophysiological correlates of sleep disordered breathing in pediatric type 1 narcolepsy. Sleep Med 2020;65: 8-12.

[76] Bogan RK, Foldvary-Schaefer N, Skowronski R, Chen A, Thorpy MJ. Long-term safety and tolerability during a clinical trial and open-label extension of lower-sodium oxybate in participants with narcolepsy with cataplexy. CNS Drugs 2023; 37(4):323-35.