Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo-controlled trial with an active reference.

Background And Objectives: The orally active dual OXR and OXR antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults.

Patients And Methods: Prospective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated.

Results: From 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (-26.8 min and -19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo.

Conclusion: Almorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder. CLINICALTRIALS.

Gov Registration: NCT00608985.