Tasimelteon for non-24-hour sleep–wake disorder in totally blind people (SET and RESET): two multicentre, randomised, double-masked, placebo-controlled phase 3 trials

• Published in: The Lancet (British edition) 2015-10, Vol.386 (10005), p.1754-1764
• Main Authors: Lockley, Steven W, Dr, Dressman, Marlene A, PhD, Licamele, Louis, PhD, Xiao, Changfu, PhD, Fisher, Dennis M, MD, Flynn-Evans, Erin E, PhD, Hull, Joseph T, PhD, Torres, Rosarelis, PhD, Lavedan, Christian, PhD, Polymeropoulos, Mihael H, MD
• Format: Article
• Language: English
• Subjects: Benzofurans - therapeutic use; Biological clocks; Blind people; Blindness; Blindness - complications; Brain research; Circadian rhythm; Circadian Rhythm - drug effects; Cyclopropanes - therapeutic use; Double-Blind Method; Evidence-based medicine; Female; Gene expression; Humans; Internal Medicine; Male; Melatonin; Middle Aged; Receptors, Melatonin - agonists; Sleep; Sleep and wakefulness; Sleep disorders; Sleep Disorders, Circadian Rhythm - drug therapy; Sleep Disorders, Circadian Rhythm - etiology; Treatment Outcome; Voice response technology
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(15)60031-9

Summary Background Most totally blind people have non-24-hour sleep–wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist. Methods We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18–75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non-entrained patients, assessed in the intention-to-treat population. Safety assessments included adverse events and clinical laboratory measures, assessed in all treated patients. These trials are registered with ClinicalTrials.gov , numbers NCT01163032 and NCT01430754. Findings Between Aug 25, 2010, and July 5, 2012, we screened 391 totally blind patients for SET, of whom 84 (22%) were assigned to receive tasimelteon (n=42) or placebo (n=42). Two patients in the tasimelteon group and four