Application of AASM Clinical Significance Thresholds to Once-Nightly Sodium Oxybate for Improvement in Narcolepsy Symptoms

This study was funded by Avadel Pharmaceuticals. Introduction: Efficacy of extended-release sodium oxybate (once-nightly sodium oxybate [ON-SXB]; LUMRYZ™) for treatment of narcolepsy in adults was demonstrated in the phase 3 REST-ON trial (NCT02720744); ON-SXB was well tolerated (most common adverse drug reactions: dizziness, nausea, vomiting, headache, enuresis). REST-ON results, published after the cutoff for inclusion in the 2021 AASM clinical practice guidelines, were analyzed according to AASM-established clinical significance thresholds (CSTs) for posttreatment change vs placebo or pre/posttreatment difference. Methods: Individuals (≥16 years) with narcolepsy type 1/2 were randomly assigned to double-blind ON-SXB (week 1, 4.5 g; weeks 2–3, 6 g; weeks 3–8, 7.5 g; weeks 5–13, 9 g) or matching placebo. CSTs were least-squares mean (LSM) changes from baseline vs placebo at weeks 3, 8, and 13: Maintenance of Wakefulness test (MWT), ≥2-minute increase; Epworth Sleepiness Scale (ESS), ≥2-point decrease; and ≥25% decrease in number of cataplexy attacks (NCA). CST for Clinical Global Impression-Improvement (CGI-I) was ≥33% reporting improvement. Results: 190 participants were in the modified intent-to-treat population. Differences in LSM change from baseline for ON-SXB 6, 7.5, and 9 g vs placebo met the CST for MWT (range, 5.0–6.2 min), ESS (range, −2.1 to −3.9), and NCA (range, 26.0%– 36.1% reduction). Percentage of participants with improvement on CGI-I for ON-SXB 6 g (80.5%), 7.5 g (88.0%), and 9 g (92.8%) met the AASM CST. Conclusions: Clinically significant improvement in excessive daytime sleepiness, cataplexy, and overall condition per AASM-established criteria was achieved with once-at-bedtime ON-SXB doses of 6, 7.5, and 9 g.