Phase 3 REST-ON Analysis Provides Insights Into Hypnagogic and Hypnopompic Hallucinations of Narcolepsy

A newly presented post-hoc analysis of the phase 3 REST-ON study (NCT02720744)–the trial that led to once-nightly sodium oxybate’s (ON-SXB; Lumyrz; Avadel Pharmaceuticals) FDA approval–examined the incidence of hypnagogic/hypnopompic hallucination (HH) rates among treated patients with narcolepsy. Overall, the baseline HH rates were low, a strong placebo effect was observed, and the findings provided insights in the different HH types participants experienced.¹

In the trial, the modified intent-to-treat (mITT) population with HH present at baseline comprised 112 participant who were randomly assigned 1:1 to either ON-SXB (week 1, 4.5 g; weeks 2-3, 6 g; weeks 4-8, 7.5 g; weeks 9-13, 9 g) or placebo. Nocturnal HH types were evaluated through 6 yes/no questions, recorded daily through diaries, whereas daytime HHs were not assessed. Coming into the trial, the baseline mean number of HH events/day was 0.60 (SD, 0.35) and 0.66 (SD, 0.35) in the ON-SXB and placebo groups, respectively.

Led by Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore, respective mean change from baseline in HH events/day to weeks 3, 8, and 13 was –0.16 (95% CI, –0.21 to –0.11), –0.28 (95% CI, –0.37 to –0.19) and –0.29 (95% CI, –0.40 to –0.18) with ON-SXB (all P <.001). In comparison, investigators recorded mean changes of –0.14 (95% CI, –0.20 to –0.08), –0.18 (95% CI, –0.26 to –0.10), and –0.24 (95% CI, –0.33 to –0.14).

Among the 12,455 HH events recorded, 7762 (62%) were hypnagogic, and 4683 (38%) were hypnopompic. Through the daily diaries, there were several different HH types identified, including (1) feeling that shadows or objects are moving/distorting (total number of events: ON-SXB: 1693; placebo: 2133), (2) feeling another presence in the room (ON-SXB: 1362; placebo: 1839), (3) feeling that you are about to be attacked (ON-SXB: 655; placebo: 1232), (4) feeling that you are flying through the air (ON-SXB: 543; placebo: 1351), (5) feeling that you will soon fall into a hole (ON-SXB: 448; placebo: 914), and (6) feeling caught in a fire (ON-SXB: 123; placebo: 152).

HHs, found in patients with various sleep disorders, are very vivid, dreamlike experiences that occur during the transition between wake and sleep. The content of the hallucinations varies, but in general it has been described as unpleasant and frightening. In 85% of the hallucinations, multiple senses are simultaneously involved: visual, auditory, and tactile. Some hallucinations appear so realistically that patients have difficulty telling them apart from real events after waking up.²

There are distinct differences between hypnagogic hallucinations and dreams: dreams typically have a storyline, whereas hypnagogic hallucinations are typically brief images or sounds. Unlike dreams or nightmares, which are typically recognized upon waking, HHs occur while a patient is still awake and may take longer to distinguish from reality.

The original REST-ON study featured 222 patients with narcolepsy type 1 or 2, all aged 16 years or older, who received ON-SXB or placebo over a 3-week screening period, 13-week treatment period, and 1-week follow-up. Overall, the trial met all 3 of its primary end points of change in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement, and weekly cataplexy attacks within the 6-, 7.5-, and 9-g groups.³

In the research, data from REST-ON showed a significantly greater increase in sleep latency with ON-SXB treatment at week 3 for the 6-g dose group (8.1 vs 3.1 min, respectively; least-squares mean difference [LSMD], 4.98; 95% CI, 2.90-7.05; P <.001); at week 8 for the 7.5-g dose group (9.6 vs 3.3 min, respectively; LSMD, 6.21; 95% CI, 3.84-8.58; P <.001); and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min, respectively; LSMD, 6.13; 95% CI, 3.52-8.75; P <.001).