Analysis of Low-sodium Oxybate Proposes Minimal Clinically Important Difference in Visual Analog Scale for Sleep Inertia

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An analysis of a phase 3 trial of low sodium oxybate in patients with idiopathic hypersomnia identified a minimal clinically important difference in the visual analog scale for sleep inertia.

Richard Bogan, MD, FCCP, FAASM, medical director of SleepMed of South Carolina and associate clinical professor at the University of South Carolina School of Medicine

Richard Bogan, MD, FCCP, FAASM

Credit: Cardiometabolic Health Congress

In an analysis of data from a phase 3 trial (NCT03533114) assessing low sodium oxybate (LXB; Xywav; Jazz Pharmaceuticals) for idiopathic hypersomnia (IH), investigators identified 10–12 mm as a minimal clinically important difference for the visual analog scale for sleep inertia (VAS-SI). These findings were presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, by lead author Richard Bogan, MD, FCCP, FAASM, medical director of SleepMed of South Carolina and associate clinical professor at the University of South Carolina School of Medicine, and colleagues.1

Among 109 participants (mean age, 40.8 [SD, 14.1]; women, 70%; White, 82%), the median changes in VAS-SI for Patient Global Impression of Change (PGIc) levels were 52.4 (quartile 1, 31.6; quartile 3, 59.6) for very much worse; 18.8 (quartile 1, 2.4; quartile 3, 34.3) for much worse; 2.5 (quartile 1, –3.2; quartile 3, 14.0) for minimally worse. In addition, the changes in VAS-SI for PGIc levels were 0.4 (quartile 1, –3.0; quartile 3, 6.7) for no change; –12.3 (quartile 1, –17.4; quartile 3, 2.2) for minimally improved; –15.6 (quartile 1, –35.7; quartile 3, –5.1) for much improved; and –28.7 (quartile 1, –51.6; quartile 3, –17.6) for very much improved (Kruskal-Wallis test statistic, 110.2; P <.001). In a linear mixed model, the mean difference in VAS-SI scores between consecutive PGIc levels was 10.9 (SE, 0.8).

Top Clinical Takeaways

  • Low sodium oxybate treatment for idiopathic hypersomnia may improve sleep inertia, as indicated by changes in VAS-SI scores.
  • The study suggests a minimal clinically important difference for VAS-SI between 10 and 12 mm using an anchor-based approach.
  • The analysis utilized a combination of Kruskal-Wallis test and linear mixed model to assess the impact of LXB treatment on sleep inertia and patient perception of change.

In the trial, participants began open-label LXB treatment (10­–14 weeks), followed by a 2-week stable-dose period (SDP). Investigators randomized the participants to placebo or continued LXB for 2-week, double-blind, randomized-withdrawal period (DBRWP). Participants then rated their difficulty of awakening using the VAS-SI, on a 100-mm line anchored at 0 (very easy) and 100 (very difficult), at baseline, end of SDP, and at the end of DBRWP. Additionally, the patients rated their change in condition on the PGIc, a 7-point Likert-type scale (very much improved to very much worse), at the end of SDP and DBRWP. The minimal clinically important difference was predicted based on change in VAS-SI and PGIc scores evaluated via Kruskal-Wallis test and a linear mixed model with repeated measures.

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At the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, a post-hoc analysis of the phase 3 trial revealed patients with higher sleep inertia generally had greater baseline disease burden; however, treatment with LXB remained efficacious regardless of inertia status.2 Led by Yves Dauvilliers, MD, PhD, director, Sleep and Wake Disorders Center, Gui de Chauliac Hospital, VAS-SI terciles comprised score segments of less than 44 (group A; n = 34), 44 to 70 (group B; n = 33), and greater than 70 (group C; n = 32). At baseline, those with the highest VAS-SI scores demonstrated numerically higher mean Epworth Sleepiness Scale (ESS; group A: 16.0 [SD, 3.1], B: 15.6 [SD, 2.6]; C: 17.1 [SD, 2.4]) and Idiopathic Hypersomnia Severity Scale (IHSS; A: 26.7 [SD, 7.7]; B: 34.5 [SD, 5.9]; C: 36.3 [SD, 5.5]) scores.

Low sodium oxybate was originally approved for the treatment of cataplexy or excessive daytime sleepiness in patients 7 year or older with narcolepsy in July 2020, and later received an expanded indication to treat IH in August 2021, becoming the first FDA-approved therapy for IH. Also known as JZP-258, the phase 3 trial served as the basis for its approval.

At the conclusion of the SDP, all groups, regardless of VAS-SI tercile, showed improvements in ESS (A = ­­–9.9 [SD, 5.1]; B = –9.8 [SD, 3.5]; C = –10.0 [SD, 5.1]) and IHSS (A = –14.1 [SD, 9.9]; B = –19.0 [SD, 9.0]; C = –18.1 [SD, 9.9]). Nearly all (99%) participants demonstrated improvement in the Patient Global Impression of Change (GCI) scale. At the SDP, investigators recorded decreases of 9.3 (SD, 11.9), 31.5 (SD, 14.8), and 42.8 (SD, 22.9), respectively, in VAS-SI scores for groups A, B, and C. Spearman correlation coefficients for VAS-SI and IHSS items assessing sleep inertia were moderate (≥3.0) to strong (≥0.6).

In addition to numerically higher ESS and IHSS, participants with the highest baseline sleep inertia were more frequently rated severely ill on GCI (A = 17.6%; B = 12.1%; C = 34.4%). Notably, baseline total sleep time trended higher with increasing VAS-IH scores.

In the original study, those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (P <.0001), PGIC (P <.0001), and IHSS (P <.0001). The most common adverse reactions, occurring in at least 5% of adults were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.3

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REFERENCES
1. Bogan R, Fuller D, Whalen M, et al. Minimal Clinically Important Difference for the Visual Analog Scale for Sleep Inertia Using Data from a Phase 3 Trial of Low-sodium Oxybate for Idiopathic Hypersomnia. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
2. Dauvilliers Y, Chen A, Whalen M, Macfadden W, Thorpy M. Efficacy of lower-sodium oxybate by baseline sleep inertia in a phase 3 clinical study in patients with idiopathic hypersomnia. Presented at: 2023 SLEEP Annual Meeting; June 3-7; Indianapolis, Indiana. Abstract 0592
3. Jazz Pharmaceuticals Completes Submission of Supplemental New Drug Application for Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Idiopathic Hypersomnia. News release. February 16, 2021. Accessed April 14, 2024. prnewswire.com/news-releases/jazz-pharmaceuticals-completes-submission-of-supplemental-new-drug-application-for-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-for-idiopathic-hypersomnia-301228862.html
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