Calcium, Magnesium, Potassium, and Sodium Oxybates Oral Solution: A Lower-Sodium Alternative for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy

Figures & data

Table 1 Key Findings from Historical Studies of Sodium Oxybate in Narcolepsy and a Recent Study of Lower-Sodium Oxybate in Idiopathic Hypersomnia^{8–12,21,33,34}

Study	Trial Design and Dosing	Efficacy Outcomes	Key Efficacy Results
The US Xyrem^® Multicenter Study Group, 2002^Citation8	Design: Multicenter, double-blind, placebo-controlled in participants with narcolepsy with cataplexy (N=136) Dosing: 3, 6, or 9 g/night	Primary: Change from baseline in weekly cataplexy attacks Secondary: Change from baseline in EDS (ESS), inadvertent daytime naps/sleep attacks, nighttime awakenings, and clinician impression of change in disease severity (CGI-c)	SXB dose-dependently reduced cataplexy attacks, ESS scores, and the frequency of inadvertent naps and nighttime awakenings, and improved CGI-c ratings, with the largest changes at 9 g/night
The US Xyrem^® Multicenter Study Group, 2003^Citation9	Design: 12-Month, multicenter, open-label extension trial in participants with narcolepsy with cataplexy (N=118) Dosing: 3–9 g/night	Primary: Change from baseline (of prior 4-week trial) in weekly cataplexy attacks Secondary: Change from baseline in EDS (ESS), inadvertent daytime naps/sleep attacks, nighttime awakenings, and clinician impression of change in disease severity (CGI-c)	SXB reduced weekly cataplexy attacks and ESS scores from baseline Improvements (relative to baseline) were reported for ≈80% of patients on the CGI-c
The US Xyrem^® Multicenter Study Group, 2004^Citation10	Design: Long-term open-label extension study with a 2-week, double-blind, randomized withdrawal phase in patients with narcolepsy with cataplexy (N=55) Dosing: Individually optimized (3–9 g/night)	Primary: Change in incidence of cataplexy in patients randomized to placebo compared with continued SXB treatment	Mean weekly number of cataplexy attacks was stable in participants randomized to continued SXB (n=26), but increased significantly in participants randomized to placebo (n=29) during the 2-week double-blind withdrawal period
The Xyrem^® International Study Group, 2005^Citation11	Design: 8-Week, multicenter, double-blind, placebo-controlled trial in participants with narcolepsy with cataplexy (N=228) Dosing: 4.5, 6, and 9 g/night	Primary: Change in EDS from baseline to endpoint (ESS) Secondary: Change in EDS (MWT) and inadvertent naps from baseline and clinician impression of change in disease severity (CGI-c)	Mean ESS scores and weekly inadvertent naps decreased with SXB treatment at 6 or 9 g/night; sleep latency on the MWT decreased with SXB treatment at 9 g/night 50%, 51.7%, and 63.8% of participants were reported as much/very much improved on the CGI-c at the 4.5-g, 6-g, and 9-g doses, respectively, compared with 22% for placebo
Black, 2006^Citation12	Design: Multicenter, double-blind, placebo-controlled trial in participants with narcolepsy (N=278) Treatment groups: placebo (n=55), SXB alone (n=50), modafinil alone (n=63), or SXB plus modafinil (n=54) Dosing: SXB at 6 g/night (4 weeks) then 9 g/night (4 weeks) during the double-blind period; as monotherapy or in conjunction with modafinil (at established stable dose, 200–600 mg/day)	Primary: Sleep latency on the MWT relative to placebo Secondary: EDS (ESS), clinician impression of change in disease severity (CGI-c), and subjective reports of inadvertent naps and changes in sleep quality	Mean MWT and ESS scores improved and weekly inadvertent naps decreased with SXB treatment alone or in conjunction with modafinil 48.0% and 46.3% of participants in the SXB and SXB/modafinil group were reported as much/very much improved, respectively, compared with 21.8% in the placebo group SXB was superior to modafinil monotherapy on the ESS, CGI-c, and weekly number of inadvertent naps
Plazzi, 2018^Citation33	Design: Double-blind, placebo-controlled, randomized withdrawal multisite study and open-label investigation in pediatric patients with narcolepsy with cataplexy (N=106) Dosing: Individually optimized (median, 7 g/night)	Primary: Change in weekly number of cataplexy attacks from the last 2 weeks of the stable-dose period to the 2 weeks of the double-blind treatment period Key Secondary: Change in clinician impression of change in cataplexy severity (CGI-c) at the end of the double-blind treatment period and change in EDS (ESS-CHAD) from the end of the stable-dose period to the end of double-blind treatment period Other Secondary: Change in CGI-c for narcolepsy overall and SF-10 Health Survey for Children	Weekly cataplexy attacks increased, median ESS-CHAD scores were greater, and CGI-c ratings for cataplexy severity worsened in participants randomized to placebo (n=32) compared with those who continued taking SXB treatment (n=31) CGI-c ratings for narcolepsy overall worsened in participants randomized to placebo (59% much/very much worse) compared with continued SXB (10% much/very much worse) Meaningful differences were not observed on the SF-10
Bogan, 2021^Citation21	Design: Double-blind, placebo-controlled, randomized withdrawal study in adult patients with narcolepsy with cataplexy (N=201) Dosing: Individually optimized (median, 7.5 g/night)	Primary: Change in weekly number of cataplexy attacks from during the 2-week stable-dose period to during the 2-week double-blind treatment period Key Secondary: Change in ESS score from the end of the stable-dose period to the end of the double-blind treatment period	Median number of weekly cataplexy attacks and median ESS score increased significantly in the participants randomized to placebo (n=65) compared with those who continued taking LXB treatment (n=69)
Dauvilliers, 2022^Citation34	Design: Double-blind, placebo-controlled, randomized withdrawal study in adult patients with idiopathic hypersomnia (N=154) Dosing: Individually optimized (median, 4.5 g/night for once nightly, 7.5 g/night for twice nightly)	Primary: Change in EDS (ESS) from the end of the 2-week stable-dose period to the end of the 2-week double-blind treatment period Key Secondary: Change in PGI-c at the end of the double-blind treatment period and change in Idiopathic Hypersomnia Severity Scale (IHSS) total score from the end of the stable-dose period to the end of the double-blind treatment period	ESS scores, PGI-c ratings, and IHSS total scores worsened in participants randomized to placebo (n=59) compared with those who continued taking LXB treatment (n=56) PGI-c ratings worsened in participants randomized to placebo (88% minimally/much/very much worse) compared with continued LXB (21% minimally/much/very much worse)

Abbreviations: CGI-c, Clinical Global Impression of Change; EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; ESS-CHAD, Epworth Sleepiness Scale for Children and Adolescents; IHSS, Idiopathic Hypersomnia Severity Scale; LXB, lower-sodium oxybate; MWT, maintenance of wakefulness test; PGI-c, Patient Global Impression of Change; SXB, sodium oxybate.

Figure 1 Neurobiological effects of oxybate. Data from ^4,50–59

Abbreviations: GABA, gamma-aminobutyric acid; GHB, gamma-hydroxybutyrate; mRNA, messenger ribonucleic acid; SXB, sodium oxybate.

Figure 2 LXB improved symptoms of cataplexy during a pivotal phase 3 trial in patients with narcolepsy. During open-label treatment with LXB in the OLOTTP and SDP of a phase 3 trial of LXB for patients with narcolepsy with cataplexy, the median number of cataplexy attacks (solid symbols) decreased and the median number of cataplexy-free days (open symbols) increased in participants who were naive to anticataplectic treatment during the OLOTTP. Treatment at study entry (SXB only, SXB + other anticataplectics, other anticataplectics only, and anticataplectic naive) is shown in each panel.

Abbreviations: LXB, lower-sodium oxybate; OLOTTP, open-label optimization and titration period; SDP, stable-dose period; SXB, sodium oxybate.

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