title: Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.
  
  
  METHODS
  We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813.
  
  
  RESULTS
  322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (-18·0 min vs -8·4 min, difference -9·5, -14·6 to -4·5; p=0·0002).
  
  
  CONCLUSIONS
  Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance.
  
  
  BACKGROUND
  Merck & Co Inc.
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA. Electronic address: david_michelson@merck.com.
authors.forename: David
authors.initials: D
authors.lastname: Michelson
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Snyder
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Paradis
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Chengan-Liu
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Duane B
authors.initials: DB
authors.lastname: Snavely
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Hutzelmann
authors.affiliation: Sleep Medicine and Research Center, St Luke's Hospital, St Louis, MO, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Walsh
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krystal
authors.affiliation: University of Wisconsin, Madison, WI, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Benca
authors.affiliation: Omnitrials, Naples, FL, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Cohn
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lines
authors.affiliation: Henry Ford Hospital Sleep Center, Detroit, MI, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Roth
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ, USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Herring
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001381:Azepines / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000068796:Orexin Receptor Antagonists; D012189:Retrospective Studies; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D001381:Azepines; D006993:Hypnotics and Sedatives; D000068796:Orexin Receptor Antagonists; D014230:Triazoles; C551624:suvorexant