Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension.

STUDY OBJECTIVES: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. METHODS: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. RESULTS: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P < .0001) at months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. CONCLUSIONS: Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919.