Suvorexant in Patients with Insomnia: Pooled Analyses of Three-Month Data from Phase-3 Randomized Controlled Clinical Trials

Abstract

Study Objectives: Suvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials. Methods: Prespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints. Results: Suvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use.

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications

“…(), and the results of pooled data across the two studies combined for the approved 20/15 mg doses are reported in Herring, Connor, Snyder, et al. (). Across the two studies, a total of 775 patients were randomized to 40/30 mg, 494 to 20/15 mg, and 772 to placebo.…”

“…Fourth, suvorexant tended to show greater efficacy on objective measures than subjective measures; for example, standardized effect sizes for sleep maintenance measures with suvorexant 20/15 mg at Month‐3 were 54% for WASO and 29% for sTST (Herring, Connor, Snyder, et al., ).…”

“…The global benefits of the improvements in sleep measures over 3 months were reflected in patient and clinician global assessments of insomnia severity and improvement, and in a variety of “responder” analyses (Herring, Connor, Ivgy‐May, et al., ; Herring, Connor, Snyder, et al., ). For example, the percentage of responders on the patient‐rated Insomnia Severity Index (Bastien, Vallieres, & Morin, ), classified as those showing ≥ 6 point improvement (Yang, Morin, Schaefer, & Wallenstein, ) at 3 months, was 56% for suvorexant 20/15 mg versus 42% for placebo with an odds ratio of 1.8, indicating that patients taking suvorexant were nearly twice as likely to be a responder than patients taking placebo (Herring, Connor, Snyder, et al., ).…”

“…In the pooled analysis of the two pivotal Phase 3 trials, most patients completed the planned 3 months of treatment, and relatively few discontinued treatment due to adverse events (3.0% for 20/15 mg versus 5.2% for placebo; Herring, Connor, Snyder, et al., ). The most common adverse event associated with suvorexant was somnolence (6.7% for 20/15 mg versus 3.3% for placebo), which mostly occurred early during treatment (within 1–2 weeks), was generally mild‐to‐moderate in severity, and rarely resulted in discontinuation.…”

Hypothalamic Dysfunction and Multiple Sclerosis: Implications for Fatigue and Weight Dysregulation

“…Currently, Suvorexant, the dual orexin receptor antagonist (DORA), is the only FDA-approved orexin antagonist therapy available. In a phase III trial of 1260 patients with insomnia, individuals in the treatment group ( n = 493) experienced prolonged sleep maintenance and decreased sleep onset compared to placebo controls ( n = 767) [127]. The relationship between insomnia and fatigue in MS must be better understood in order to justify use of DORAs.…”