Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study

• Published in: Lancet neurology 2022-01, Vol.21 (1), p.53-65
• Main Authors: Dauvilliers, Yves, Arnulf, Isabelle, Foldvary-Schaefer, Nancy, Morse, Anne Marie, Šonka, Karel, Thorpy, Michael J, Mignot, Emmanuel, Chandler, Patricia, Parvataneni, Rupa, Black, Jed, Sterkel, Amanda, Chen, Dan, Skobieranda, Franck, Bogan, Richard K
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adverse events; Aged; Clinical trials; Disorders of Excessive Somnolence - chemically induced; Disorders of Excessive Somnolence - drug therapy; Double-Blind Method; Double-blind studies; Drug dosages; Drug withdrawal; FDA approval; Humans; Idiopathic Hypersomnia - drug therapy; Middle Aged; Narcolepsy; Nausea; Placebos; Potassium; Regulatory approval; Safety; Sleep; Sleep and wakefulness; Sleep deprivation; Sleep disorders; Sodium; Sodium Oxybate - adverse effects; Titration; Treatment Outcome; Vomiting; Young Adult
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(21)00368-9

Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia. This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18–75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10–14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants’ baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5–9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete. Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 p