Once-nightly sodium oxybate (FT218) demonstrated improvement of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy

Abstract

Study objectives: To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial.

Methods: Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments.

Results: In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105). For the three coprimary endpoints and Epworth Sleepiness Scale, all three doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement versus placebo (all p < 0.001). For ON-SXB 9 g versus placebo, increase in mean sleep latency was 10.8 versus 4.7 min (Least squares mean difference, LSMD [95% CI], 6.13 [3.52 to 8.75]), 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76 to 11.23]), change in mean weekly number of cataplexy attacks was -11.5 versus -4.9 (LSMD [95% CI], -6.65 [-9.32 to -3.98]), and change in Epworth Sleepiness Scale was -6.5 and -2.7 (LSMD [95% CI], -6.52 [-5.47 to -2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis.

Conclusions: ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.

Clinical trial registration: ClinicalTrials.gov: NCT02720744, https://clinicaltrials.gov/ct2/show/NCT02720744.

Keywords: NT1/NT2; modified release; narcolepsy; once-nightly; safety; sodium oxybate.

Figure 1.

Study design.REST-ON is a 13-week, phase 3, double-blind, multicenter trial with a 1:1 randomization to ON-SXB vs. placebo. Participants receiving ON-SXB underwent a forced titration from 4.5 g (week 1) to 6 g (weeks 2–3) to 7.5 g (weeks 4–8), and finally 9 g (weeks 9–13). Randomization was stratified according to narcolepsy type (NT1/NT2). There was a 3-week baseline screening period before randomization. MWT, number of cataplexy attacks, ESS, and PSG were assessed at baseline and at weeks 3, 8, and 13 of treatment. Number of cataplexy attacks, hypnagogic hallucinations, and sleep paralysis events were recorded in the daily sleep and symptom diaries, which were reviewed at weeks 3, 8, and 13. CGI-S (for sleepiness) was recorded at baseline; CGI-I was recorded at weeks 3, 8, and 13. Adverse events were documented at weeks 3, 8, and 13, but could be reported at any time during the trial. CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression of Severity; ESS, Epworth Sleepiness Scale; MWT, Maintenance of Wakefulness Test; NT1, narcolepsy type 1; NT2, narcolepsy type 2; ON-SXB, once-nightly sodium oxybate; PSG, polysomnography.

Figure 2.

Patient disposition.CONSORT diagram of patient disposition. ON-SXB, once-nightly sodium oxybate. *Terminated.

Figure 3.

Change from baseline for the three coprimary endpoints (mITT population).A mixed-effects model for repeated measures was used for MWT and cataplexy analyses. A GLIMMEX model was used for CGI-I analysis. (A) LSM change from baseline in the MWT for patients receiving ON-SXB or matching placebo. (B) Percentage of patients rated much or very much improved on the CGI-I for patients receiving ON-SXB or matching placebo. (C) LSM change from baseline in mean number of cataplexy attacks for patients receiving ON-SXB or matching placebo. CGI-I, Clinical Global Impression of Improvement; LSM, least squares mean; LSMD, least squares mean difference; mITT, modified intent to treat; MWT, Maintenance of Wakefulness Test; ON-SXB, once-nightly sodium oxybate; OR, odds ratio.

Figure 4.

Change from baseline in ESS (mITT population).A mixed-effects model for repeated measures was used for the analysis. LSM change from baseline in the ESS for patients receiving ON-SXB or matching placebo. ESS, Epworth Sleepiness Scale; LSM, least squares mean; LSMD, least squares mean difference; mITT, modified intent to treat; ON-SXB, once-nightly sodium oxybate.

Figure 5.

Incidence of related TEAEs over time for ON-SXB.ON-SXB, once-nightly sodium oxybate; TEAE, treatment-emergent adverse event.