Lower-sodium oxybate treatment is associated with clinically meaningful improvement in excessive daytime sleepiness and overall idiopathic hypersomnia symptoms, according to study findings published in the Lancet Neurology.
Idiopathic hypersomnia, a central hypersomnolence disorder, is associated with excessive daytime sleepiness, prolonged nighttime sleep, and pronounced sleep inertia. In August 2021, the U.S. Food and Drug Administration approved lower-sodium oxybate, the first drug to treat idiopathic hypersomnia in adults. Prior, lower-sodium oxybate was approved in the U.S. to treat cataplexy or excessive daytime sleepiness in patients aged 7 years and older with narcolepsy.
The objective of the current study sought to assess the therapeutic benefit of lower-sodium oxybate in adults with idiopathic hypersomnia.
The international, phase 3, double-blind, placebo-controlled, randomized withdrawal study was conducted at 50 specialist sleep centers and included patients aged 18 to 75 years with a primary diagnosis of idiopathic hypersomnia.
The study included a screening period of at least 30 days, an open-label titration and optimization period (OLT; 10-14 weeks), a stable-dose period (SDP; 2 weeks), a double-blind, randomized withdrawal period (DBRWP; 2 weeks), an open-label safety extension period (24 weeks), and a safety follow-up (2 weeks). Participants who met randomization criteria were then randomly assigned 1:1 to either lower-sodium oxybate or placebo for 2 weeks. The maximum single dose was 6 g, and the maximum total nightly dose was 9 g.
The change in Epworth Sleepiness Scale (ESS) score from the end of the SDP to the end of the DBRWP was the primary efficacy endpoint.
A total of 154 patients (mean age, 40.3 [13.7] years; 68% female; 84% White) were enrolled from November 27, 2018, to March 6, 2020, and received at least 1 dose of treatment during the OLT. After the open-label periods, 115 participants were randomly assigned to placebo (n=59) or lower-sodium oxybate (n=56) and were included as the modified intention-to-treat population.
The median total dose of lower-sodium oxybate during the SDP was 4.5 (interquartile range, 3.0-5.0) g/night (once nightly) and 7.5 (6.5-8.1) g/night (twice nightly). The mean ESS scores in the overall modified intention-to-treat population were 15.7 (SD 3.8) at baseline and 6.1 (SD 4.0) at the end of the SDP.
The least squares mean difference between groups at the end of the DBRWP regarding change in ESS score was −6.5 (95% CI, −8.0 to −5.0; P <.0001). In addition, the difference in change in Idiopathic Hypersomnia Severity Scale score was significant (estimated median difference in change −12.0; 95% CI, −15.0 to −8.0; P <.0001).
Treatment-emergent adverse events occurred in 123 (80%) of 154 participants, including 73 (83%) of 88 participants who were receiving medication at study entry for idiopathic hypersomnia symptoms and 50 (76%) of 66 participants who were treatment naive at study entry. TEAEs reported by >10% of participants in all study periods, excluding placebo data, were nausea (34 [22%] of 154), headache (27 [18%]), dizziness (19 [12%]), anxiety (17 [11%]), and vomiting (17 [11%]).
Among several study limitations, 31 participants discontinued before the SDP, which may affect the generalizability of the findings. Also, the participants may have become accustomed to the effects of open-label treatment, which could potentially lead to inadvertent unmasking at randomized withdrawal. In addition, the study included participants with and without long sleep time.
“An approved, effective medication for idiopathic hypersomnia will benefit patients by enabling increased participation in academic, social, and work domains, and will support clinician recognition of the necessity to accurately diagnose and effectively manage idiopathic hypersomnia,” the researchers stated. “These findings indicate that lower-sodium oxybate might be useful for the management of idiopathic hypersomnia as a first-line therapy and in combination with an alerting agent.”
Disclosure: This research was supported by Jazz Pharmaceuticals. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study. Lancet Neurol. Published online January 1, 2022. doi: 10.1016/S1474-4422(21)00368-9