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

BACKGROUND

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.

METHODS

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.

FINDINGS

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 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study.

INTERPRETATION

Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults.

FUNDING

Jazz Pharmaceuticals.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests YD is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Idorsia, Takeda, Theranexus, and Bioprojet. IA has participated in an advisory board for Idorsia. NF-S has received research grants or contracts from Jazz Pharmaceuticals, Suven, and Takeda; served on an advisory committee for Jazz Pharmaceuticals; received support for attending meetings or travel from Jazz Pharmaceuticals; and participated in clinical trials supported by Jazz Pharmaceuticals, Suven, and Takeda. AMM has received research funding from the National Institutes of Health, Geisinger Health Plan, and the Klarman Foundation; has been a site investigator for Avadel Pharmaceuticals and Jazz Pharmaceuticals; has served on an advisory board/speakers bureau for Jazz Pharmaceuticals; has received payment or honoraria from Harmony Biosciences; and has served on an AASM public advocacy committee. KŠ has served on the speakers’ bureau for Sanofi, Angelini, and Stada and as a consultant for AOP Orphan; participated in advisory boards for UCB and in clinical trials for Jazz Pharmaceuticals, Flamel-Avadel, and Luitpold Pharmaceuticals; and received funding from the Ministry of Health, Czech Republic, and the Michael J Fox Foundation. MJT has received research or grant support and consultancy fees from Jazz Pharmaceuticals, Harmony Biosciences, Balance Therapeutics, Axsome Therapeutics, and Avadel Pharmaceuticals; and has participated in data safety monitoring or advisory boards for Axsome, Balance Therapeutics, Eisai Pharmaceuticals, Flamel–Avadel, Harmony Biosciences, LLC, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, Takeda Pharmaceutical, and XW Pharma. EM has received research support from Apple, Jazz Pharmaceuticals, Merck, Takeda, and Huami; is a consultant for Dreem, Alerion, Orexia, and Inexia; and is on the speakers’ bureau for Vox Media. PC, AS, and FS are full-time employees of Jazz Pharmaceuticals who, in the course of this employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals. RP and DC are former full-time employees of Jazz Pharmaceuticals who, in the course of this employment, received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals. JB is a part-time employee of Jazz Pharmaceuticals and shareholder of Jazz Pharmaceuticals. RKB has served on the speakers’ bureau and participated in advisory boards for Jazz Pharmaceuticals; has received consulting fees from Jazz Pharmaceuticals and Harmony Biosciences; and has received payment or honoraria from Eisai.