Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia

Abstract

Study objectives: To evaluate 6-month efficacy and safety of low-sodium oxybate in people with idiopathic hypersomnia during an open-label extension period (OLE) of a phase 3 clinical trial.

Methods: Efficacy measures included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change (PGIc), Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Treatment-emergent adverse events were collected throughout the OLE.

Results: The OLE population included 106 participants. Most were female (71%) and White (83%), and the mean (SD) age was 41.0 (13.8) years. ESS scores decreased (improved) during the OLE (mean [SD], study baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7]), and IHSS total scores trended toward a decrease (study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]. Median (minimum, maximum) paired differences from OLE week 2 to OLE end were ESS, -1.0 (-20, 7; nominal P = .012); IHSS, -1.0 (-31, 19; nominal P = .086). The proportion of participants reporting PGIc ratings of "very much improved" increased from 36.7% at OLE week 2 to 53.8% at the OLE end. The FOSQ-10 and WPAI:SHP scores remained stable during OLE. The incidence of newly reported treatment-emergent adverse events decreased over the duration of the OLE.

Conclusions: Efficacy and safety of low-sodium oxybate were maintained or improved during the 6-month OLE, supporting long-term treatment with low-sodium oxybate in adults with idiopathic hypersomnia.

Clinical trial registration: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) With an Open-label Safety Extension; URL: https://clinicaltrials.gov/study/NCT03533114; Identifier: NCT03533114 and Registry: EU Clinical Trials; Name: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension; URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001311-79/results; Identifier: 2018-001311-79.

Citation: Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023;19(10):1811-1822.

Keywords: quality of life; sleep inertia; sleepiness; work productivity.

Figure 1. Timeline of the entire study.

DBRWP = double-blind randomized withdrawal period, LXB = low-sodium oxybate, OLE = open-label extension, OLT = open-label titration and optimization period, SDP = stable-dose period, SXB = high-sodium oxybate. Modified from 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, randomized withdrawal study. Lancet Neurol. 2022;21(1):53-65. doi:10.1016/S1474-4422(21)00368-9, with permission from Elsevier.

Figure 2. ESS (A) and IHSS (B) scores throughout the study.

Higher scores indicate greater levels of sleepiness (ESS) or idiopathic hypersomnia symptom severity (IHSS). The blue-shaded portions represent the 2-week SDP, and the pink-shaded portions represent the 2-week DBRWP. ^amITT population excludes participants taking high-sodium oxybate at study entry. Time points prior to OLE include the total mITT population. DB = double-blind, DBRWP = double-blind randomized withdrawal period, ESS = Epworth Sleepiness Scale, IHSS = Idiopathic Hypersomnia Severity Scale, LXB = low-sodium oxybate, mITT = modified intent-to-treat, OLE = open-label extension period, OLT = open-label titration and optimization period, SDP = stable-dose period, W = week.

Figure 3. IHSS component scores throughout the study: day/performance (A), night/inertia (B), and napping (C).

Higher scores indicate greater idiopathic hypersomnia symptom severity. The blue-shaded portions represent the 2-week SDP, and the pink-shaded portions represent the 2-week DBRWP. Night/Inertia component includes items 1, 2, 3, 4, and 8. Day/Performance component includes items 5, 9, 10, 11, 12, 13, and 14. Napping component includes items 6 and 7. ^amITT population excludes participants taking high-sodium oxybate at study entry. Time points prior to the OLE include the total mITT population. DB = double-blind, IHSS = Idiopathic Hypersomnia Severity Scale, LXB = low-sodium oxybate, mITT = modified intent-to-treat, OLE = open-label extension period, OLT = open-label titration and optimization period, SDP = stable-dose period, W = week.

Figure 4. Increase in proportion of participants with the least impairment on each individual IHSS item from DBRWP to OLE W2 and end of OLE (placebo group).

Higher IHSS total scores indicate more severe or frequent idiopathic hypersomnia symptoms. Due to no adjustments for multiplicity, P values are nominal. Placebo group = mITT population, excluding participants taking high-sodium oxybate at study entry; percentages are based on 44 participants in the placebo group with IHSS scores available at the end of DBRWP, OLE W2, and OLE end. ^aDifference between the proportions at the end of the DBRWP and OLE W2. CI = confidence interval, DBRWP = double-blind randomized withdrawal period, IHSS = Idiopathic Hypersomnia Severity Scale, mITT = modified intent-to-treat, OLE = open-label extension period, W = week.

Figure 5. Change in PGIc ratings from baseline to OLT W1 and end of the SDP and during the OLE.

Categories with zero responses are not shown. ^amITT population excludes participants taking high-sodium oxybate at study entry. Time points prior to the OLE include the total mITT population. mITT = modified intent-to-treat, OLE = open-label extension period, OLT = open-label titration and optimization period, PGIc = Patient Global Impression of Change, SDP = stable-dose period, W = week.

Figure 6. FOSQ-10 (A), WPAI:SHP absenteeism (B), presenteeism (C), overall work productivity (D), and activity (E) scores throughout the study.

The blue-shaded portions represent the 10–14-week OLT and the 2-week SDP. The pink-shaded portions represent the 2-week DBRWP. ^aFOSQ-10 score is the mean of the non-missing 5 subscales multiplied by 5. Score range is 5–20 points, with higher scores indicating better functional status. WPAI:SHP score range is 0–100, with higher scores indicating greater impairment. ^bItems relating to work productivity were completed only by participants who were employed; the item relating to activity impairment was completed by all participants. ^cAbsenteeism was defined as percentage of work time missed because of idiopathic hypersomnia. ^dPresenteeism was defined as percentage of impairment while working because of idiopathic hypersomnia. ^eAbsenteeism plus presenteeism because of idiopathic hypersomnia. ^fRefers to overall daily activity, other than working. ^gmITT population excludes participants taking high-sodium oxybate at study entry. Time points prior to the OLE include the total mITT population. BL = baseline, DBRWP = double-blind randomized withdrawal period, FOSQ-10 = Functional Outcomes of Sleep Questionnaire, short version, LXB = low-sodium oxybate, mITT = modified intent-to-treat, OLE = open-label extension period, OLT = open-label titration and optimization period, SDP = stable-dose period, W = week, WPAI:SHP = Work Productivity and Activity Impairment Questionnaire: Specific Health Problem.