Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial

Objective: To assess the effective dose range, safety, and tolerability of the novel selective orexin-2 receptor antagonist seltorexant in insomnia disorder.

Design, setting, and participants: This randomized, double-blind, active- and placebo-controlled, dose-finding, polysomnography study was conducted from November 2017 to April 2019 at 55 sites in 6 countries and analyzed in August 2019. The timeline for submission of this data for publication was impacted by internal strategic decision-making. Adults (aged 18-64 years) and older adults (aged 65-85 years) with insomnia (Insomnia Severity Index score ≥15) and no psychiatric comorbidity were included.

Interventions: Participants were randomized 1:1:1:1:1 to receive nightly oral-seltorexant (5 mg, 10 mg, or 20 mg), placebo, or zolpidem (5-10 mg) for 14 days.

Main outcomes and measures: Primary and key secondary outcomes included the dose-response relationship of night 1 latency to persistent sleep (LPS) and wake after sleep onset over the first 6 hours (WASO-6). Other secondary outcomes included night 13 LPS and WASO-6. Due to asymmetrical distributions of LPS and WASO-6 at baseline, log transformation was applied and results were expressed as back-transformed least-squares mean (LSM) ratios for comparisons between groups.

Results: Overall, 364 participants (mean [SD] age, 57.8 [12.4] years; 246 [67.6%] female) received seltorexant, 5 mg (n = 71), 10 mg (n = 74), or 20 mg (n = 71); placebo (n = 75); or zolpidem (n = 73). The night 1 dose-response relationship for LPS was significant (with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models), with greater improvements in seltorexant, 10 mg and 20 mg, vs placebo (10 mg: LSM ratio, 0.64; 90% CI, 0.51-0.81; 20 mg: LSM ratio, 0.51; 90% CI, 0.41-0.64) and in seltorexant, 20 mg, vs zolpidem (LSM ratio, 0.71; 90% CI, 0.57-0.88). The night 1 dose-response relationship for WASO-6 was also significant, with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models (seltorexant, 10 mg: LSM ratio, 0.68; 90% CI, 0.55-0.85; seltorexant, 20 mg: LSM ratio, 0.60; 90% CI, 0.48-0.74). Night 1 LPS and WASO-6 improvements were maintained on night 13 for seltorexant, 10 mg and 20 mg, but diminished for zolpidem. On night 13, compared with zolpidem, seltorexant, 10 mg and 20 mg, improved LPS by 30% and 28%, respectively, and seltorexant, 20 mg, improved WASO-6 by 31%. Treatment-emergent adverse events (TEAEs) were lower across the combined seltorexant doses (73/216 [33.8%]) relative to placebo (37/75 [49.3%]) and zolpidem (31/73 [42.5%]). Two participants experienced serious TEAEs during the double-blind phase (1 in the seltorexant, 20 mg, group and 1 in the zolpidem group). Three participants in the seltorexant, 5 mg, and 1 in the seltorexant, 20 mg, group experienced asymptomatic electrocardiogram-related TEAEs leading to discontinuation.

Conclusions and relevance: Among participants with insomnia in this study, seltorexant, 10 mg and 20 mg, improved sleep initiation and maintenance throughout 14 days of treatment. Seltorexant was generally well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT03375203.

Author/s:

Sofie Mesens, Andrew D Krystal, Rama Melkote, Haiyan Xu, Gahan Pandina, Jay B Saoud, Remy Luthringer, Adam Savitz, Wayne C Drevets

Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial

Erin Blanchette — Sun, 07 Jan 2024 19:56:39 +0000

Date Added:

January 7, 2024

Journal/Publication:

JAMA Network Open

Publisher:

American Medical Association

Publication Date:

December 28, 2023

Issue:

Volume:

URL:

Effect of Psychological and Medication Therapies for Insomnia on Daytime Functions: A Randomized Clinical Trial

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jamanetworkopen.2023.49638

Keywords

cognitive behavior therapy

PMID (1):

38153735

MeSH

behavior therapy

fatigue

sleep initiation and maintenance disorders

Cognitive behavioral therapy and zolpidem improve daytime functioning and symptoms equally. The combination further improves outcomes in those with inadequate response to either alone. James W. Mold, MD, MPH.

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Importance: Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted.

Objectives: To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted.

Design, setting, and participants: In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023.

Interventions: Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone).

Main outcomes and measures: Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components.

Results: Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences.

Conclusions and relevance: In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions.

Trial registration: ClinicalTrials.gov Identifier: NCT01651442.

Author/s:

Charles M Morin, Si-Jing Chen, Hans Ivers, Simon Beaulieu-Bonneau, Andrew D Krystal, Bernard Guay, Lynda Bélanger, Ann Cartwright, Bryan Simmons, Manon Lamy, Mindy Busby, Jack D Edinger