Efficacy and Safety of Sodium Oxybate in Adults With Idiopathic Hypersomnia: A Randomized Controlled Trial.

Abstract

BACKGROUND AND OBJECTIVES Idiopathic hypersomnia (IH) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. Low-sodium oxybate is the sole Food and Drug Administration-approved treatment for IH. Objective measures of nighttime sleep and daytime sleepiness are lacking with oxybates in IH. We aimed to evaluate efficacy and safety of sodium oxybate (SXB) in IH. METHODS This phase 3, double-blind, parallel-group, placebo-controlled trial was conducted at the National Reference Center for Hypersomnia in Montpellier-France. Eligible participants aged 18-60 years with IH with an Epworth Sleepiness Scale (ESS) score ≥14 were randomly assigned to receive SXB or placebo (1:1). After a 2-week screening without any drugs and without exposure to oxybate, patients started a 6-week individual twice-nightly up-titration scheme from 4.5 g to a maximum of 9 g. Treatment was administered at stable dose for 2 weeks, followed by a 2-week taper period. The primary endpoint was the between-group difference in ESS scores at week 8, identified by a covariance analysis, including baseline ESS scores. The same methodology was applied for secondary endpoints including Idiopathic Hypersomnia Severity Scale (IHSS) score and sleep latency on the Maintenance of Wakefulness Test (MWT). Safety was examined as a secondary endpoint. RESULTS Among the 48 patients screened, 45 were randomized (36 women, 29.0 ± 7.5 years, 22 assigned to SXB, 23 to placebo) and 40 (19 receiving SXB, 21 placebo) completed the study. In the intention-to-treat analysis, the mean ESS score was significantly reduced in the SXB group compared with placebo, after adjusting for the baseline score (least squared [LS] mean difference: -6.86, 95% CI [-9.73 to -4.00]), p < 0.0001). Significant differences between SXB and placebo groups at week 8 were observed for the IHSS score (LS mean difference: -11.61; 95% CI [-16.63 to -6.59], p < 0.0001) and MWT latency (14.75; 95% CI [9.98-19.52], p < 0.0001). Treatment-emergent adverse events (nausea, headache, and dizziness) were reported in 81.8% patients with SXB and 26.1% with placebo. DISCUSSION SXB resulted in a clinically meaningful improvement in adults with IH, reducing excessive sleepiness on ESS, improving wakefulness on MWT, and decreasing IH severity on IHSS after 8 weeks. The safety profile was consistent with previous reports on SXB. TRIAL REGISTRATION INFORMATION ClinicalTrials.gov NCT03597555, EudraCT number 2017-004122-15. CLASSIFICATION OF EVIDENCE This article provides Class I evidence that sodium oxybate at a dose of 4.5-9 g per night compared with placebo reduces excessive sleepiness, improves wakefulness, and decreases disease severity with expected side effects in patients with idiopathic hypersomnia.