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

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J Clin Sleep Med


STUDY OBJECTIVES: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in non-elderly 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 re-randomized 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 versus 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-min increase in average nightly total sleep time was observed for esmirtazapine versus 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 versus 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: "A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002)" (NCT00631657; https://clinicaltrials.gov/ct2/show/NCT00631657) and "Twenty-six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007)" (NCT00750919; https://clinicaltrials.gov/ct2/show/NCT00750919).

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ePub ahead of print