ArticlesTasimelteon for non-24-hour sleep–wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials
Introduction
Much of human physiology and behaviour is dominated by 24 h rhythms in hormone production, temperature and metabolic regulation, and sleep–wake cycles. These internal, intrinsic rhythms are spontaneously generated by an endogenous oscillator in the suprachiasmatic nuclei with a period of close to but not exactly 24 h, on average. The major environmental time cue that synchronises (entrains) this pacemaker with the Earth's 24 h day is the light–dark cycle (appendix), detected exclusively by the eyes via specialised photosensitive retinal ganglion cells. In most totally blind individuals, circadian photoreception is abolished, and the suprachiasmatic nuclei revert to their internal near-24-h circadian period (τ), which is usually longer than 24 h (23·8–25·1 h).1
The link between blindness and rhythm disruption was described more than 60 years ago2 and was associated with altered corticosteroid rhythms, renal function, and glucose regulation.1 Today, melatonin and cortisol are more typically used as highly reliable markers of internal circadian phase and period in people with and without visual impairment.3, 4, 5, 6, 7, 8, 9 Whereas circadian desynchrony affects multiple systems, a common patient complaint is sleep–wake cycle disruption, including insomnia, daytime sleepiness, or both.10 The symptoms occur when an individual's non-24-h circadian sleep propensity rhythm is misaligned from the socially imposed 24 h sleep–wake pattern. As these two rhythms oscillate in and out of phase, patients can experience cyclic episodes of good sleep, followed by episodes of daytime sleepiness, or night-time sleep disruption, or both, that repeat every 3–26 weeks, depending on an individual's circadian period.11, 12, 13, 14 The resulting non-24-hour sleep–wake disorder (non-24),15, 16 sometimes referred to as free-running disorder, also causes cyclic changes in alertness and mood levels17 and difficulties maintaining school, work, or social schedules. The cyclic nature of the disorder means that traditional measures of sleep (eg, total sleep time) are not appropriate to capture the rhythmic symptoms, and other measures, such the timing and duration of daytime naps or measures that attempt to capture only the most disruptive part of the cycle, are therefore necessary.14 The cyclic nature of the disorder is often apparent in individuals with a long circadian period (thereby taking fewer calendar days to cycle around the clock), whereas cyclic symptoms are harder to discern in people with a shorter period and may present as intermittent insomnia or excessive daytime sleepiness without prompting a non-24 diagnosis. The prevalence of non-entrained rhythms in totally blind individuals is 55–70%.4, 6, 13, 18, 19
The suprachiasmatic nuclei contain two types of G-protein-coupled seven-transmembrane receptors for the pineal hormone melatonin, MT1 and MT2. Treatment with synthetic pharmaceutical-grade melatonin was previously shown to entrain the circadian pacemaker in a small number of totally blind patients with non-24.20, 21 Tasimelteon is a novel dual-melatonin receptor agonist with specificity and high affinity for MT1 and MT2 receptors, reaches peak plasma concentrations 0·5–3·0 h after administration, and has a 1·3 h half-life.22 Oral administration (10–100 mg) phase-shifts circadian rhythms in sighted patients,23 and daily injections entrain non-24-h circadian activity rhythms in rats.24
Here we present the results of two phase 3 clinical trials to determine the efficacy and safety of daily tasimelteon administration for totally blind patients with non-24.
Section snippets
Study design and patients
The safety and efficacy of tasimelteon to treat non-24 in totally blind individuals was assessed in two phase 3, randomised, placebo-controlled, double-masked, multicentre trials, SET (Safety and Efficacy of Tasimelteon) and RESET (Randomised withdrawal study of the Safety and Efficacy of Tasimelteon).
These trials were completed in 27 US and six German clinical research centres and sleep centres. The studies were approved by central and local Institutional Review Boards (the Ethics Committees
Results
Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET. The screening phase lasted 7–25 weeks (mean 12·7 weeks, SD 4·2 weeks). 84 (22%) patients had circadian period of 24·25 h or longer, met the inclusion criteria, and were enrolled; 52 (13%) patients with ineligible τ value entered the open-label tasimelteon study (figure 1). After randomisation in the tasimelteon group, two patients (5%) withdrew because of adverse events before a sufficient number of samples
Discussion
In our two phase 3 clinical trials of blind patients with non-24, daily treatment with 20 mg tasimelteon was more effective than placebo to entrain and maintain entrainment of the circadian pacemaker with the 24 h day. Tasimelteon treatment resulted in clinically meaningful improvements in the duration of night-time sleep and reduced undesired daytime sleep during the worst quartile of sleep disruption, improved sleep stability, and improved physicians' ratings of patient functioning.
References (40)
- et al.
Disturbance of sleep in blindness
Am J Ophthalmol
(1998) - et al.
Circadian rhythm sleep disorders: lessons from the blind
Sleep Med Rev
(2001) - et al.
Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials
Lancet
(2009) - et al.
Tasimelteon: a selective and unique binding profile
Neuropharmacology
(2015) - et al.
Feasibility and validation of a computer-automated Columbia–Suicide Severity Rating Scale using interactive voice response technology
J Psychiatr Res
(2010) - et al.
Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans
Brain Res
(1995) - et al.
Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin
Brain Res
(2001) - et al.
Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms
Sleep Med
(2015) - et al.
Comparison of melatonin products against USP's nutritional supplements standards and other criteria
J Am Pharm Assoc (Wash)
(1999) - et al.
Visual impairment and circadian rhythm disorders
Dialogues Clin Neurosci
(2007)
Untersuchungen an Blinden ueber die 24-Stunden-Rhythmik
Monatsblaetter fuer Augenheilkunde
Stability, precision, and near-24-hour period of the human circadian pacemaker
Science
Different types of melatonin circadian secretory rhythms in some blind subjects
J Clin Endocrinol Metab
Melatonin rhythms and the sleep-wake cycle in blind subjects
J Interdiscipl Cycle Res
Circadian rhythm abnormalities in totally blind people: incidence and clinical significance
J Clin Endocrinol Metab
Relationship between napping and melatonin in the blind
J Biol Rhythms
Correlation between urinary cortisol and 6-sulphatoxymelatonin rhythms in field studies of blind subjects
Clin Endocrinol
Circadian rhythm disorders and melatonin production in 127 blind women with and without light perception
J Biol Rhythms
Blind man living in normal society has circadian rhythms of 24·9 hours
Science
Chronic non-24-hour circadian rhythm sleep disorder in a blind man with a regular 24-hour sleep-wake schedule
Sleep
Cited by (91)
Circadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine
2024, Neuroscience and Biobehavioral ReviewsSleep and Circadian Disturbances in Children With Neurodevelopmental Disorders
2023, Seminars in Pediatric NeurologyRecent advances in the study of circadian rhythm disorders that induce diabetic retinopathy
2023, Biomedicine and PharmacotherapyA brief history of circadian rhythm sleep disorders
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionAdjunctive and alternative treatments of circadian rhythm sleep disorders
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionCircadian medicine for aging attenuation and sleep disorders: Prospects and challenges
2023, Progress in Neurobiology
- †
Contributed equally