Once-Nightly Sodium Oxybate for Narcolepsy - Episode 1
Dr Clete Kushida discusses the results of a phase 3 clinical trial that examined once-nightly sodium oxybate in patients with narcolepsy.
Clete Kushida, MD, PhD: Hi. It’s my pleasure to discuss this study, which is the “Once-Nightly Sodium Oxybate (FT218) Demonstrated Improvement of Symptoms in a Phase 3 Randomized Clinical Trial in Patients with Narcolepsy.” My name is Dr Clete Kushida at the Stanford University School of Medicine in Palo Alto, California.
Narcolepsy is a neurologic problem in which the brain isn’t able to control the sleep-wake cycle, as shown on this slide. And one of the key features is it causes a sudden, irresistible sleepiness during almost any time of the day. And it is prevalent in about 1 of every 2000 people and does affect men and women equally. Some of the common signs and symptoms are illustrated here. There’s cataplexy, a sudden decrement in muscle tone that’s frequently associated with strong emotions such as laughter, anger, surprise. Then there are hallucinations, which are at the onset of sleep or coming out of sleep, and these hallucinations can be auditory, visual, or somatic. And oftentimes they’re accompanied by sleep paralysis or an inability to move voluntary muscles. Excessive daytime sleepiness is one of the key features of this condition, and it also tends to disrupt nocturnal sleep. There are 2 subtypes of narcolepsy. Narcolepsy type 1 [NT1] and narcolepsy type 2 [NT2]. The key distinguishing features between these 2 types are that NT1 is associated with cataplexy and low levels of hypocretin-1 orexin-A, whereas [with] NT2 cataplexy’s absent and levels of hypocretin-1 and orexin are not as low as found in NT1.
So REST-ON was a phase 3, double-blind, 2 arm, multi-center, randomized clinical trial that was designed to investigate the efficacy and safety of ON-SXB, which is once-nightly sodium oxybate for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. The trial comprised a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period. Randomization was 1:1 to either once-nightly sodium oxybate or placebo and was stratified by narcolepsy type NT1 or NT2. Participants initially received 4.5 grams for 1 week, followed by 6 grams per weeks 2 to 3, 7.5 grams for weeks 4 to 8, and then 9 grams for weeks 9 to 13. The Maintenance of Wakefulness Test, or MWT; as well as the number of cataplexy attacks, the Epworth Sleepiness Scale, which tests subjective daytime sleepiness; and the PSG, which is the polysomnography sleep study, where it sets that baseline at weeks 3, 8, and 13 of treatment. Now, the number of cataplexy attacks, hypnagogic hallucinations, which are hallucinations as a person is going to sleep, and sleep paralysis events were recorded daily in sleep symptom diaries which were reviewed at weeks 3, 8, and 13. The clinical global impression of severe, or CGI-S, for sleepiness was recorded at baseline. The clinical global impression of improvement, or CGI-I, was recorded at weeks 3, 8, and 13. Adverse events were documented at weeks 3, 8, and 13, but could be recorded at any time during the trial.
So this shows the patient demographics and baseline characteristics. Baseline demographics were well-balanced between the once-nightly sodium oxybate and placebo arms. The mean age was 31 and 32 years in the once-nightly sodium oxybate and placebo arms, respectively. Most participants were women. For the once-nightly sodium oxybate it was 64.5% women and for placebo it was 71.4% women. Also, most participants were white; In the once-nightly sodium oxybate arm it was 74.8% and in the placebo arm it was 76.2%. Geographic distribution of the participants in the U.S. and the rest of the world were equally distributed in the placebo group and the once-nightly sodium oxybate group, but slightly greater for the U.S. in the once-nightly sodium oxybate group.
Median and mean body mass indices for the 2 groups were similar. Approximately 75%, or three-quarters of participants had NT1. It’s important to note that hypertension was not an exclusion criterion. Approximately 8% of participants enrolled had a medical history of hypertension.
Regarding efficacy, the mean sleep latency on the MWT was similar between the once-nightly sodium oxybate and placebo arms at baseline. The actual values were 5 and 4.7 minutes, respectively. The increase in sleep latency was significantly greater with the once-nightly sodium oxybate versus placebo at week 3 for the 6-gram dose. The least square mean changed from baseline was 8.1 versus 3.1 minutes, respectively. At week 8, for the 7.5-gram dose, you can see that it was 9.6 versus 3.3 minutes, respectively. And at week 13, for the 9-gram dose, it was 10.8 versus 4.7 minutes, respectively. Now, the mean baseline CGI-severity was 5.1 in both treatment arms, indicating that participants were markedly impaired. A significantly greater proportion of participants in the once-nightly sodium oxybate treatment arm versus placebo were rated much or very much improved on the CGI-I scale at week 3 for the 6-gram dose. The values were 40.1% for the once-nightly sodium oxybate arm versus 6.1% in the placebo arm, respectively. At week 8, for the 7.5-gram dose, the values were 62.6% for the once-nightly sodium oxybate arm versus 22.8% in the placebo arm, respectively. And at week 13, for the 9-gram dose, it was 72% versus 31.6%, respectively. The mean baseline number weekly cataplexy attacks were similar in the once-nightly sodium oxybate and placebo arms. It was 18.9 versus 19.8, respectively. The decrease in least square mean changes from baseline, in the number of weekly cataplexy attacks, was significantly greater with the once-nightly sodium oxybate arm versus placebo at week 3 for the 6-gram dose. It was minus-7.4 versus minus-2.6, respectively. Then, at week 8, for the 7.5-gram dose, it was minus-10 versus minus-3.7, respectively. And at week 13, for the 6-gram dose, it was minus-11.5 for the once-nightly sodium oxybate arm versus minus-4.9 for the placebo arm.
At baseline, the Epworth Sleepiness Scale score was similar in the once-nightly sodium oxybate and placebo arms. The values were 16.6 and 17.5, respectively. The decrease in the least square mean change from baseline was significantly greater with the once-nightly sodium oxybate versus placebo at week 3 for the 6-gram dose. It was minus-3.5 versus minus-1.4, respectively. At week 8, at the 7.5 gram dose, it was minus-5.3 versus minus-2.2, respectively. And at week 13, for the 9-gram dose, it was minus-6.5 for the once-nightly sodium oxybate arm versus minus-2.7 for our placebo arm.
In the safety population, 83, or 77.6% and 49, or 46.7% of the participants in the once-nightly sodium oxybate and placebo arms, respectively, experienced a treatment-emergent adverse event. The most frequently reported treatment-emergent adverse events for all participants treated with once-nightly sodium oxybate at rates higher than placebo were nausea at 22.4%, headache at 18.7%, vomiting at 17.8%, dizziness at 15.9%, decreased appetite at 12.1%, anxiety at 7.5%, hyperhidrosis at 5.6%, and decreased weight at 5.6%. No participant in the once-nightly sodium oxybate arm and 1 participant in the placebo arm discontinued the study due to a treatment-emergent adverse event of worsening sleep or worsening of sleep apnea. A serious treatment-emergent adverse event was reported by 7 participants, or 3.3%, overall. And that included 5 in the once-nightly sodium oxybate arm, or 4.7%, and 2 in the placebo arm, or 1.9%. Only the serious adverse event in the 9-gram dose group, which was suicidal ideation, was considered treatment-related.
In the once-nightly sodium oxybate arm, when you look at the 3 dosing periods, rates of known sodium oxybate adverse events, such as nausea, vomiting, somnolence, dizziness, and enuresis were generally low, and, as shown here, there was no dose response relationship except for enuresis.
Transcript edited for clarity.