Key Points
Question
Does seltorexant, a selective orexin-2 receptor antagonist, provide clinical benefit in insomnia disorder?
Findings
In a randomized clinical trial including 364 adult participants with insomnia disorder, seltorexant showed a statistically significant dose-response relationship in latency to persistent sleep and wake after sleep onset over the first 6 hours on night 1 in the 10-mg and 20-mg groups vs placebo and in the 20-mg group vs zolpidem.
Meaning
Seltorexant, 10 mg and 20 mg, demonstrated efficacy in the initiation of sleep in participants with insomnia without psychiatric comorbidity.
This randomized clinical trial evaluates the safety and efficacy of seltorexant in insomnia disorder.
Abstract
Importance
Existing pharmacological treatments for insomnia have significant limitations.
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
Introduction
Insomnia disorder is the most common sleep disorder and is associated with increased risk of daytime sleepiness, accidents, depressive disorders, insulin resistance, and total health care expenditures, and decreased quality of life and work performance.1,2,3,4 The 2 most prescribed classes of US Food and Drug Administration–approved pharmacological treatment for insomnia, benzodiazepine and nonbenzodiazepine hypnotics (eg, zolpidem), have limitations, such as daytime drowsiness, dependence (including withdrawal symptoms), tolerance, and, especially in older individuals, increased risk of falls and cognitive impairment.5
While these pharmacologic treatments for insomnia act by promoting sleep drive through enhancing γ-aminobutyric acid receptor function, more recently approved agents, such as dual orexin receptor antagonists (DORAs) that act on both orexin-1 receptors (OX1Rs) and orexin-2 receptors (OX2Rs), have more directly targeted hyperarousal processes that play key roles in insomnia.6,7 The contribution of the orexin signaling to wakefulness is especially mediated by activation of OX2Rs in wake-active structures and selective blockade of OX2Rs is sufficient to initiate and prolong sleep.6,7,8 Moreover, in contrast with the effects of OX2R antagonists, administration of an OX1R antagonist in combination with an OX2R antagonist in rats induced a reduction in rapid eye movement (REM) sleep latency and an increase in REM sleep duration at the expense of the time spent in non-REM sleep.8 Thus, selective OX2R antagonists may afford advantages in the treatment of insomnia.9,10,11
Seltorexant (JNJ-42847922) is the first potent, selective antagonist of human OX2R to be studied clinically. In a phase 2 single- and multiple-dose study in adult participants with insomnia disorder, seltorexant, 40 mg, at bedtime was generally well tolerated and showed a more pronounced effect on sleep efficiency, latency to persistent sleep (LPS), and total sleep time (TST) with a modest effect on wake after sleep onset (WASO) compared with placebo.12 In another phase 2b, adaptive, dose-finding study in patients with major depressive disorder (MDD) with sleep disturbance (Insomnia Severity Index [ISI] scores ≥15), a larger treatment difference between seltorexant, 20 mg, and placebo was observed.13 Another exploratory study14 examined the effects of seltorexant, 10 mg, 20 mg, and 40 mg, on objective and subjective sleep parameters in patients with MDD who experienced insomnia. In this study, significant improvements were observed in sleep efficiency, LPS, and TST across all doses. However, a higher incidence of somnolence-related adverse events (AEs) was reported at the 40-mg dose.14 In a subsequent phase 1b study assessing the antidepressant treatment effect of seltorexant monotherapy (20 mg or 40 mg), the subgroup of patients with MDD who manifested subjective sleep disorder showed more prominent antidepressant treatment effects than the subgroups with lower levels of sleep disturbance.15 This study also identified a higher incidence of sleep-related AEs in the 40-mg group. Consequently, the seltorexant doses of 10 mg and 20 mg were selected for the present phase 2b study, as they were anticipated to have a significant impact on key sleep parameters while demonstrating better safety and tolerability compared to the 40-mg dose. Additionally, because older patients were included in the design of the present study, a lower dose of 5 mg of seltorexant was incorporated into this dose-ranging study to assess the minimum effective dose for this age group.
Methods
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. This study was conducted in accordance with ethical principles of the Declaration of Helsinki and adhered to the International Conference on Harmonization’s Good Clinical Practice guidelines and applicable regulatory requirements. A local institutional review board at each study site reviewed and approved the study protocol and amendments. All participants provided written informed consent prior to study enrollment. The trial protocol is in Supplement 1.
Participants
Participants met the DSM-5 criteria for insomnia disorder and had an ISI (7-item patient version) score of 15 or higher at screening. With amendment 2 of the protocol, further enrollment of women of childbearing potential was not permitted (eMethods in Supplement 2). Exclusion criteria included a recent history or current diagnosis of a psychiatric condition or hypersomnia or insomnia related to obstructive sleep apnea, restless leg syndrome, or parasomnias. For additional eligibility criteria and concomitant medication use, see the eMethods in Supplement 2. Participant race data were collected via self-reports and electronic health records to monitor the diversity of the study participants.
Study Design
This was a multicenter, randomized, double-blind, parallel-group, active- and placebo-controlled, dose-finding polysomnography (PSG) study in adult (18-64 years, inclusive) and older adult (65-85 years, inclusive) participants with insomnia. The study was conducted at 55 sites in the US, Belgium, France, Germany, Poland, and Japan from November 2017 to April 2019 and analyzed in August 2019. The timeline for submission of this data for publication was impacted by internal strategic decision-making. The study consisted of a 2-part screening phase (≤35 days), a double-blind treatment phase (≤17 days), and a posttreatment follow-up phase (7-10 days) (eFigure 1 in Supplement 2). Part 1 of the screening phase (day −35 to −15) consisted of assessments of general health and subjective insomnia symptoms; participants who met protocol-specified sleep criteria entered part 2 of the screening, which consisted of an insomnia assessment by PSG recording conducted consecutively over 2 nights (day −14 to −1). In the double-blind phase, eligible participants were randomized (1:1:1:1:1) to receive oral placebo; seltorexant, 5 mg, 10 mg, or 20 mg; or zolpidem (5 mg or 10 mg, per the local label) once daily at bedtime for 14 consecutive nights. To meet the local label (package insert) or prescription guidelines for zolpidem dose selection at study sites in different countries, in the US, all female participants and older male participants (aged 65-85 years) received 5-mg doses while male participants aged 18 to 64 years received 10-mg doses; in the European countries, all adults aged 18 to 64 years received 10-mg doses while adults aged 65 to 85 years received 5-mg doses; and in Japan, all participants received a 5-mg dose.
Blinded treatment was administered 15 minutes prior to lights-out on nights when PSG was recorded at the study site (nights 1 and 13) or at normal bedtime on non-PSG nights (nights 2-12 and 14). For formulations of all study drugs, randomization, and blinding information, see the eMethods in Supplement 2.
Study Evaluations
The primary efficacy end point was LPS on night 1, measured by PSG and calculated as time from lights-out to the first 10 minutes of continuous sleep.
The key secondary efficacy end point was WASO over the first 6 hours (WASO-6) on night 1. LPS and WASO-6 on night 13 were additional secondary end points. For analyses of other PSG end points, subjective sleep parameters, and clinical assessments, see the eMethods in Supplement 2.
The safety and tolerability of seltorexant and zolpidem were evaluated throughout the study by monitoring treatment-emergent adverse events (TEAEs). TEAEs of special interest that were prospectively defined and evaluated included falls, cataplexy, sleep paralysis, and parasomnias. For additional safety evaluations, see the eMethods in Supplement 2.
Statistical Analysis
It was estimated that a sample size of 360 participants would be needed (eMethods in Supplement 2). There were 3 analysis sets: (1) the all-randomized analysis set included all randomized participants, regardless of whether treatment was received; (2) the full analysis set included all randomized participants who received 1 or more dose of the study drug; and (3) the safety analysis set was the same as the full analysis set.
The primary and key secondary end points were evaluated at 1-sided significance level of .05 using multiple comparison procedure modeling, with linear, maximum effect, exponential, and sigmoid maximum effect included as candidate models, to test for dose response. For early phase studies in drug development, statistical testing is commonly performed at a level of significance that is higher than the conventional 2-sided .05 to increase the chance of detecting signal, after which the signal (if detected at this significance level) is further evaluated under the more rigorous setting of phase 3 confirmatory studies at a significance level of .05 (2-sided). Consequently, the design of this phase 2b study used a significance level of .10 (2-sided) (alternatively, a 1-sided significance level of .05) for sample size estimation and hypothesis testing, but for the purpose of reporting the results in the scientific literature the analyses for the primary and key secondary end points were also assessed at the conventional 2-sided significance level of .05.
The treatment effect for each dose of seltorexant was estimated using the analysis of covariance (ANCOVA) model with log-transformed data. The model included treatment group, region, and age group as factors and baseline value as a continuous covariate. Due to asymmetrical distributions (right-skewed) of LPS and WASO-6 at baseline, log-transformation was applied to normalize the data, and the results were expressed as back-transformed least-squares mean (LSM) ratios to allow valid comparisons between treatment groups. The multiple comparison procedure modeling approach was applied to the back-transformed LSM estimates obtained from the ANCOVA model. Pairwise comparison between each seltorexant dose group and placebo on night 1 was performed using the appropriate contrasts from the ANCOVA using observed data and on night 1 and night 13 using mixed model for repeated measures (MMRM). Treatment comparisons under ANCOVA or MMRM were performed based on the expectation that the model residuals are normally distributed. For sensitivity and subgroup analyses and CIs and significance level, see the eMethods in Supplement 2.
Results
Participant Characteristics
Of 1327 participants screened, 365 were randomized 1:1:1:1:1 to receive placebo (n = 75); seltorexant, 5 mg (n = 71), 10 mg (n = 74), or 20 mg (n = 71); or zolpidem (n = 73) in the double-blind phase (Figure 1). Of the 365 randomized participants who received at least 1 dose of study agent, 347 (95.1%) completed the double-blind treatment phase; 363 participants entered and 348 (95.9%) completed the follow-up phase. Demographics and baseline characteristics of the participants included in the full analysis set were comparable between groups (mean [SD] age, 57.8 [12.4] years; 246 [67.6%] women and 118 [32.4%] men; 126 [34.6%] older adults; 3 [0.8%] American Indian or Alaska Native, 30 [8/2%] Asian, 73 [20.1% Black or African American, 4 [1.1%] Native Hawaiian or Other Pacific Islander, and 251 [69.0%] White) (Table 1).
Figure 1. Flow Diagram of Participant Disposition.
aSome participants were excluded who both did not meet both inclusion criteria and met exclusion criteria.
bReceived at least 1 dose of study drug.
cOne participant who was randomized in error did not receive any study agent and discontinued from the study; this participant was not included in the summary of discontinuation.
dThe full and safety analysis sets consist of all participants who were randomly assigned to study drug and received at least 1 dose of study drug.
eOne participant in the safety analysis set who was randomized to the 10-mg group received 5 mg of seltorexant. This participant was summarized under the 10-mg treatment group for disposition.
Table 1. Summary of Demographic and Baseline Characteristicsa.
| Characteristic | Placebo (n = 75) | Seltorexant | Zolpidem (n = 73) | Total (N = 364) | |||
|---|---|---|---|---|---|---|---|
| 5 mg (n = 71) | 10 mg (n = 74) | 20 mg (n = 71) | Combined (n = 216) | ||||
| Age, mean (SD), y | 58.6 (11.49) | 56.9 (13.85) | 57.6 (12.90) | 57.6 (11.88) | 57.4 (12.85) | 58.5 (12.03) | 57.8 (12.40) |
| Adult (18-64 y), No. (%) | 50 (66.7) | 45 (63.4) | 48 (64.9) | 47 (66.2) | 140 (64.8) | 48 (65.8) | 238 (65.4) |
| Older adult (65-85 y), No. (%) | 25 (33.3) | 26 (36.6) | 26 (35.1) | 24 (33.8) | 76 (35.2) | 25 (34.2) | 126 (34.6) |
| Sex, No. (%) | |||||||
| Female | 45 (60.0) | 48 (67.6) | 51 (68.9) | 50 (70.4) | 149 (69.0) | 52 (71.2) | 246 (67.6) |
| Male | 30 (40.0) | 23 (32.4) | 23 (31.1) | 21 (29.6) | 67 (31.0) | 21 (28.8) | 118 (32.4) |
| Race, No. (%)b | |||||||
| American Indian/Alaska Native | 1 (1.3) | 1 (1.4) | 0 | 0 | 1 (0.5) | 1 (1.4) | 3 (0.8) |
| Asian | 8 (10.7) | 5 (7.0) | 7 (9.5) | 4 (5.6) | 16 (7.4) | 6 (8.2) | 30 (8.2) |
| Black/African American | 11 (14.7) | 15 (21.1) | 20 (27.0) | 18 (25.4) | 53 (24.5) | 9 (12.3) | 73 (20.1) |
| Native Hawaiian/Other Pacific Islander | 1 (1.3) | 0 | 0 | 3 (4.2) | 3 (1.4) | 0 | 4 (1.1) |
| White | 54 (72.0) | 49 (69.0) | 46 (62.2) | 45 (63.4) | 140 (64.8) | 57 (78.1) | 251 (69.0) |
| Multiple | 0 | 0 | 1 (1.4) | 0 | 1 (0.5) | 0 | 1 (0.3) |
| Missing | 0 | 1 (1.4) | 0 | 1 (1.4) | 2 (0.9) | 0 | 2 (0.5) |
| Baseline ISI total score, mean (SD) | 19.8 (3.33) | 20.5 (3.09) | 20.7 (3.42) | 20.2 (3.36) | 20.5 (3.29) | 20.1 (2.88) | 20.2 (3.22) |
| Baseline LPS, mean (SD) min | 88.7 (53.41) | 85.9 (49.85) | 92.0 (57.15) | 82.4 (46.88) | 86.8 (51.47) | 87.9 (54.37) | 87.4 (52.33) |
| Baseline WASO-6, mean (SD) min | 83.1 (39.01) | 72.7 (37.06) | 81.6 (48.57) | 84.8 (38.60) | 79.7 (41.94) | 74.5 (37.53) | 79.4 (40.48) |
Abbreviations: ISI, Insomnia Severity Index; LPS, latency to persistent sleep; PSG, polysomnography; WASO-6, wake after sleep onset over first 6 hours.
The baseline measurement is defined as the closest measurement taken prior to or at the time of the first dose of study drug, with the exception of the baseline values for PSG parameters LPS and WASO-6, which are defined as the mean of values collected on the 2 screening PSG nights.
Participant race data were collected via self-reports and electronic health records to monitor the diversity of the study participants.f
Primary Efficacy End Point
In the multiple comparison procedure modeling analysis, all 4 prespecified candidate models showed a significant dose-response relationship in log-transformed LPS on night 1 (with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models) (eFigure 2 in Supplement 2). The linear and sigmoid maximum effect models showed the best fit for the data with the largest and comparable t statistic (linear: 5.34; sigmoid maximum effect: 5.17).
Based on ANCOVA, the back-transformed LSM ratio was 0.64 (90% CI, 0.51-0.81) for the 10-mg group and 0.51 (90% CI, 0.41-0.64) for the 20-mg group (Table 2), indicating 36% and 49% improvements in LPS on night 1 compared with placebo, respectively. Compared with zolpidem, there was a 29% improvement in LPS on night 1 in the seltorexant, 20 mg, group (back-transformed LSM ratio, 0.71; 90% CI, 0.57-0.88).
Table 2. Latency to Persistent Sleep (LPS) on Nights 1 and 13a.
| Time point | Placebo | Seltorexant | Zolpidem | ||
|---|---|---|---|---|---|
| 5 mg | 10 mg | 20 mg | |||
| Baseline | |||||
| No. | 75 | 71 | 74 | 71 | 73 |
| Mean (SD) | 88.75 (53.42) | 85.85 (49.85) | 92.02 (57.15) | 82.43 (46.88) | 87.87 (54.37) |
| Median (range) | 72.0 (26.3 to 280.8) | 74.8 (25.0 to 235.8) | 74.4 (25.0 to 320.3) | 70.0 (25.8 to 270.8) | 73.3 (26.5 to 297.3) |
| Night 1 | |||||
| No. | 75 | 71 | 73 | 71 | 73 |
| Mean (SD) | 73.51 (80.63) | 55.94 (47.64) | 42.38 (36.86) | 34.73 (40.10) | 47.14 (44.91) |
| Median (range) | 48.0 (2.5 to 480.0) | 40.5 (3.5 to 204.5) | 29.0 (1.0 to 179.5) | 20.0 (1.5 to 222.5) | 30.0 (3.0 to 271.5) |
| Night 13 | |||||
| No. | 69 | 69 | 73 | 69 | 69 |
| Mean (SD) | 66.03 (69.11) | 58.57 (62.83) | 38.13 (39.95) | 41.91 (56.06) | 56.11 (58.57) |
| Median (range) | 48.5 (2.0 to 454.5) | 40.5 (3.5 to 356.5) | 24.5 (0.0 to 257.0) | 23.5 (0.0 to 297.0) | 34.5 (1.0 to 285.5) |
| Night 1 change from baseline | |||||
| No. | 75 | 71 | 73 | 71 | 73 |
| Mean (SD) | −15.24 (78.59) | −29.92 (49.05) | −49.49 (53.22) | −47.69 (48.42) | −40.74 (54.40) |
| Median (range) | −18.0 (−152.5 to 422.0) | −29.8 (−186.5 to 71.8) | −43.0 (−246.5 to 66.8) | −37.8 (−183.3 to 64.5) | −34.3 (−268.3 to 191.5) |
| Night 13 change from baseline | |||||
| No. | 69 | 69 | 73 | 69 | 69 |
| Mean (SD) | −23.74 (61.79) | −27.12 (54.73) | −53.99 (60.29) | −41.19 (59.71) | −30.94 (60.24) |
| Median (range) | −26.5 (−146.3 to 267.5) | −27.0 (−198.0 to 128.3) | −44.5 (−299.3 to 61.5) | −32.3 (−222.8 to 203.5) | −28.3 (−269.3 to 174.5) |
| Night 1 ANCOVA vs placebob | |||||
| LSM difference in change from baselinec | NA | −16.38 | −32.21 | −36.62 | NA |
| 2-Sided P valueb,d | NA | .35 | .001 | <.001 | NA |
| Back-transformed LSM ratio (90% CI)d | NA | 0.88 (0.70 to 1.10) | 0.64 (0.51 to 0.81) | 0.51 (0.41 to 0.64) | NA |
| Back-transformed LSM ratio (95% CI)d,e | NA | 0.88 (0.67 to 1.15) | 0.64 (0.49 to 0.84) | 0.51 (0.39 to 0.67) | NA |
| Night 13 MMRM vs placebof | |||||
| LSM difference in change from baselineg | NA | −5.22 | −28.64 | −21.02 | NA |
| Back-transformed LSM ratio (90% CI)d | NA | 0.93 (0.72 to 1.20) | 0.57 (0.44 to 0.73) | 0.58 (0.45 to 0.75) | NA |
| Back-transformed LSM ratio (95% CI)e | NA | 0.93 (0.68 to 1.26) | 0.57 (0.42 to 0.76) | 0.58 (0.43 to 0.79) | NA |
| Night 1 ANCOVA vs zolpidemb | |||||
| LSM difference in change from baselinec | 26.16 | 9.73 | −6.01 | −10.52 | |
| Back-transformed LSM ratio (90% CI)d | 1.39 (1.11 to 1.72) | 1.22 (0.98 to 1.52) | 0.89 (0.72 to 1.11) | 0.71 (0.57 to 0.88) | NA |
| Back-transformed LSM ratio (95% CI)d,e | 1.39 (1.07 to 1.80) | 1.22 (0.93 to 1.59) | 0.89 (0.69 to 1.16) | 0.71 (0.54 to 0.92) | NA |
| Night 13 MMRM vs zolpidemf | |||||
| LSM difference in change from baselineg | 8.97 | 3.72 | −19.62 | −12.13 | NA |
| Back-transformed LSM ratio (90% CI)d | 1.24 (0.96 to 1.60) | 1.15 (0.89 to 1.49) | 0.70 (0.54 to 0.90) | 0.72 (0.56 to 0.93) | NA |
| Back-transformed LSM ratio (95% C)e | 1.24 (0.92 to 1.68) | 1.15 (0.85 to 1.56) | 0.70 (0.52 to 0.95) | 0.72 (0.53 to 0.98) | NA |
Abbreviations: ANCOVA, analysis of covariance; LPS, latency to persistent sleep; LSM, least-squares mean; MMRM, mixed-model for repeated measures; NA, not applicable; PSG, polysomnography.
Negative changes in LPS indicate improvement. Baseline for PSG parameters is defined as the mean of values collected on the 2 screening PSG nights. ANCOVA only uses paired data, which are represented by change from baseline. LPS indicates the total observation time (in minutes) for participants who did not sleep at all during the observation period.
Based on ANCOVA model using log-transformed LPS with treatment, region, and age group as factors, and log-transformed baseline LPS as a continuous covariate.
LSM difference compared to reference based on ANCOVA model using change in LPS from baseline with treatment, region, and age group as factors, and baseline LPS as a continuous covariate.
Pairwise comparison: P values and confidence intervals without multiplicity adjustment.
95% CIs were determined post hoc and are provided as additional information.
Based on MMRM model using log-transformed LPS with treatment, time, region, age group, and time-by-treatment interaction as factors and baseline log-transformed LPS as a covariate.
LSM difference compared to reference based on MMRM model using change in LPS with treatment, time, region, age group, and time by treatment interaction as factors, and baseline LPS as a covariate.
Results of the sensitivity analysis (LPS on night 1 with age as a continuous covariate) were consistent with the primary analysis (eTable 1 in Supplement 2). Subgroup analyses of LPS on night 1 are provided in eFigure 3 in Supplement 2.
Secondary Efficacy End Points
Key Secondary Efficacy End Point: WASO-6 on Night 1
Based on the multiple comparison procedure modeling analysis, all 4 prespecified models showed a significant dose-response relationship in log-transformed WASO-6 on night 1 (with trend test t statistics ≥3.99 and adjusted P values <.001 for all 4 prespecified models) (eFigure 4 in Supplement 2). The linear model showed the best fit for the data with the largest t statistic (4.03).
Based on ANCOVA, the back-transformed LSM ratio for WASO-6 on night 1 was 0.68 (90% CI, 0.55-0.85) in the seltorexant, 10 mg, group and 0.60 (90% CI, 0.48-0.74) in the seltorexant, 20 mg, group (eTable 2 in Supplement 2), indicating an improvement of 32% and 40%, respectively, compared with placebo. The improvements in WASO-6 on night 1 for the 3 seltorexant groups were comparable with that for zolpidem. Subgroup analyses of WASO-6 on night 1 are provided in eFigure 5 in Supplement 2.
Other Secondary Efficacy End Points: PSG Parameters
Based on the MMRM analysis, the improvements observed in LPS on night 1 in the seltorexant, 10 mg and 20 mg, groups compared with placebo were maintained on night 13 (43% and 42% improvement, respectively, based on the back-transformed LSM ratios) (Table 2). There was a 30% and 28% improvement in LPS on night 13 in the seltorexant, 10 mg and 20 mg, groups, respectively, compared with zolpidem (Figure 2).
Figure 2. Back-Transformed Least-Squares Mean (LSM [SE]) Over Time.
The figure displays the mixed-model repeated-measures (MMRM) observed case analysis on log-transformed data for latency to persistent sleep (LPS) and wake after sleep onset over the first 6 hours (WASO-6). Negative changes in LPS and WASO-6 indicate improvement.
aComparison vs zolpidem: α = 0.10.
bThe estimates are back-transformed from the values obtained from MMRM on log-transformed data with treatment (placebo, seltorexant dose groups, and zolpidem), time, region (US or Europe and Japan), age group (adult [18-64 years] and older adult [65-85 years]), and time-by-treatment interaction as factors and log-transformed baseline value as a covariate. Results are not adjusted for multiple comparisons.
Based on the MMRM analysis, the improvements in WASO-6 on night 1 compared with placebo were maintained on night 13 in the seltorexant, 10 mg and 20 mg, groups (25% and 40% improvement, respectively, based on the back-transformed LSM ratios) (eTable 2 in Supplement 2). Compared with zolpidem, there was a 31% improvement in WASO-6 on night 13 for the seltorexant, 20 mg, group (Figure 2).
Mean changes in LPS and WASO-6 at day 13 for both doses of zolpidem (5 mg and 10 mg) were smaller than in the seltorexant, 10 and 20 mg, dose groups (eTable 3 in Supplement 2). For sleep efficiency, TST during the first 6 hours and wake during the total sleep period, greater improvements vs placebo were observed in all 3 seltorexant groups on night 1 (eTable 4 in Supplement 2); these improvements were maintained on night 13 in the 10-mg and 20-mg groups. The supplement contains additional PSG end points (eTable 4-7 in Supplement 2).
Other Secondary Efficacy End Points: Subjective Sleep Parameters and Clinical Assessments
All 3 seltorexant groups showed improvements in subjective sleep diary assessments, including subjective sleep onset latency, subjective WASO, subjective refreshed feeling on waking, and subjective quality of sleep (5 mg and 10 mg only), compared with placebo, at all time points examined (eTables 8-9 in Supplement 2). On day 14, compared with zolpidem, seltorexant, 10 mg and 20 mg, showed greater improvements in subjective sleep onset latency and subjective refreshed feeling on waking, while seltorexant, 5 mg and 10 mg, showed improvements in subjective quality of sleep. Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) and PROMIS-Sleep Related Impairment (PROMIS-SRI) results are shown in eTable 10, Patient Global Impression-Severity (PGI-S) and PGI-Improvement (PGI-I) in eTable 11, and ISI total scores in eTable 12 (Supplement 2). Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scores are shown in eTable 13 in Supplement 2.
Safety
Adverse Events
TEAE incidence was lower with seltorexant (73/216 [33.8%] in combined dose group) than with placebo (37/75 [49.3%]) and zolpidem (31/73 [42.5%]) (Table 3). The most common TEAE (>5% of participants) in the combined seltorexant group was headache (17/216 [7.9%] vs 8/75 [10.7%] in the placebo and 8/73 [11.0%] in the zolpidem groups). Most TEAEs were mild or moderate in severity.
Table 3. Safety Summary.
| Variable | No. (%) | |||||
|---|---|---|---|---|---|---|
| Placebo (n = 75) | Seltorexant | Zolpidem (n = 73) | ||||
| 5 mg (n = 72a) | 10 mg (n = 73a) | 20 mg (n = 71) | Combined (n = 216) | |||
| Any TEAE | 37 (49.3) | 29 (40.3) | 23 (31.5) | 21 (29.6) | 73 (33.8) | 31 (42.5) |
| Most common TEAEs (>5% of participants in any treatment group) | ||||||
| Headache | 8 (10.7) | 7 (9.7) | 4 (5.5) | 6 (8.5) | 17 (7.9) | 8 (11.0) |
| Fatigue | 8 (10.7) | 4 (5.6) | 3 (4.1) | 2 (2.8) | 9 (4.2) | 2 (2.7) |
| Somnolence | 1 (1.3) | 1 (1.4) | 0 | 4 (5.6) | 5 (2.3) | 4 (5.5) |
| Nasopharyngitis | 1 (1.3) | 4 (5.6) | 1 (1.4) | 0 | 5 (2.3) | 1 (1.4) |
| Disturbance in attention | 4 (5.3) | 2 (2.8) | 1 (1.4) | 1 (1.4) | 4 (1.9) | 4 (5.5) |
| Restlessness | 4 (5.3) | 0 | 2 (2.7) | 2 (2.8) | 4 (1.9) | 1 (1.4) |
| Nausea | 2 (2.7) | 1 (1.4) | 2 (2.7) | 0 | 3 (1.4) | 5 (6.8) |
| Urinary tract infection | 4 (5.3) | 0 | 1 (1.4) | 1 (1.4) | 2 (0.9) | 0 |
| Myalgia | 3 (4.0) | 1 (1.4) | 1 (1.4) | 0 | 2 (0.9) | 4 (5.5) |
| Diarrhea | 3 (4.0) | 0 | 0 | 1 (1.4) | 1 (0.5) | 4 (5.5) |
| Dizziness | 1 (1.3) | 0 | 0 | 0 | 0 | 5 (6.8) |
| TEAEs leading to discontinuation | 2 (2.7) | 3 (4.2) | 0 | 2 (2.8) | 5 (2.3) | 2 (2.7) |
| Serious TEAEs | 0 | 0 | 0 | 1 (1.4) | 1 (0.5) | 1 (1.4) |
Abbreviation: TEAE, treatment-emergent adverse event.
One participant who was randomized to seltorexant, 10 mg, received 5 mg of seltorexant. This participant is summarized under the 5-mg group.
The incidence of somnolence TEAEs was slightly higher in the combined seltorexant dose group (5/216 [2.3%]) compared to the placebo group (1/75 [1.3%]). A higher percentage of participants in the seltorexant, 20 mg (4/271 [5.6%]), and zolpidem (4/73 [5.5%]) groups reported a somnolence TEAE compared with the seltorexant, 5 mg (1/72 [1.4%]) and 10 mg (0/73), groups.
No TEAEs resulting in death occurred during the study. Treatment-emergent serious AEs (SAEs) were reported for 2 participants during the double-blind phase, 1 in the seltorexant, 20 mg, group (cerebral hemorrhage and hematoma, leading to treatment discontinuation) and 1 in the zolpidem group (cognitive disorder followed by seizure in the days following treatment discontinuation), which are detailed in eTable 14 in Supplement 2.
The incidences of participants with TEAEs leading to discontinuation of study medication were comparable in the combined seltorexant (5/216 [2.3%]), placebo (2/75 [2.7%]), and zolpidem (2/73 [2.7%]) groups (eTable 15 in Supplement 2). Three participants in the seltorexant, 5 mg, group experienced TEAEs leading to discontinuation (atrial fibrillation: 2; electrocardiogram (ECG) PR prolongation: 1). Two participants in the seltorexant, 20 mg, group experienced TEAEs leading to discontinuation (arrythmia and cerebral hemorrhage/hematoma).
The incidences of TEAEs of special interest in the seltorexant groups (5 mg: 1/74 [1.4%]; 10 mg: 2/73 [2.7%]; 20 mg: 1/71 [1.4%]) were comparable with that in the placebo group (2/75 [2.7%]), but lower than that in the zolpidem group (4/73 [5.5%]) (eTable 16 in Supplement 2). There were no cases of cataplexy or sleep paralysis. One fall was reported in the seltorexant, 20 mg, group.
The incidence of TEAEs was higher in participants aged 65 to 85 years in all treatment groups compared with participants aged 18 to 64 years: 13 of 25 (52.0%) vs 24 of 50 (48.0%) (placebo), 30 of 76 (39.5%) vs 43 of 140 (30.7%) (combined seltorexant dose), and 12 of 25 (48.0%) vs 19 of 48 (39.6%) (zolpidem) (eTable 17 in Supplement 2).
Residual Effects
There was little difference in the pattern of changes in body sway between the treatment groups (eFigure 6 in Supplement 2). The most notable decline in stability occurred with zolpidem on day 15 when awakened in the middle of the night. The mean changes in Karolinska Sleepiness Scale scores from evening 1 to morning 2 and from evening 13 to morning 14 showed small increases in next-day sleepiness that were comparable across treatment groups (eTable 18 in Supplement 2).
Additional Safety Observations
Apart from the previously described 4 participants in the seltorexant, 5 mg and 20 mg, groups who discontinued because of AEs related to ECG changes, there was no clinically relevant change in clinical laboratory tests, vital sign measurements, physical examinations, or ECG results in any group (data not shown). See Supplement 2 for cognitive function (computerized cognitive test battery [eFigures 7-11] and modified PROMIS-Applied Cognition Abilities [eTable 19]), withdrawal symptoms (20-item Physician Withdrawal Checklist [eTable 20] and Benzodiazepine Withdrawal Symptom Questionnaire [eTable 21]), and suicidality (Columbia Suicide Severity Rating Scale [eTable 22]) results.
Discussion
This randomized clinical trial assessed the dose-response of 3 doses of seltorexant (5 mg, 10 mg, and 20 mg) compared to placebo on an objective measure of sleep onset in participants with insomnia. Based on the multiple comparison procedure modeling analysis, all 4 prespecified models showed a significant dose-response relationship in log-transformed LPS and WASO-6 on night 1. The results of the primary (LPS on night 1) and key secondary (WASO-6 on night 1) end points demonstrated statistically significant and clinically meaningful improvements for the seltorexant, 10 mg and 20 mg, groups compared with placebo, and these effects were maintained on night 13, without showing evidence of tolerance across this time frame. These data indicate that 10 mg and 20 mg of seltorexant are efficacious doses for participants with insomnia.
Zolpidem immediate release (5 mg or 10 mg according to the local label) was chosen as active comparator and showed a greater improvement compared with placebo for both LPS and WASO-6 on night 1, but not night 13.16 Compared with zolpidem, seltorexant, 20 mg, showed greater improvement in LPS on night 1 and in LPS and WASO-6 on night 13.
In the secondary PSG-based efficacy end points of sleep efficiency, TST during the first 6 hours and wake during total sleep period, greater improvement vs placebo was seen in all 3 seltorexant groups on night 1. These effects were maintained on night 13 in the 10-mg and 20-mg groups.
Notably, the subjective sleep improvements observed with seltorexant in sleep diary reports have not been found with DORAs.17,18 Also, at day 14, all 3 seltorexant groups showed improvements in PROMIS-SD, PROMIS-SRI, PGI-S (5 mg and 10 mg only), PGI-I, ISI, CGI-S, and CGI-I, compared with placebo.
Seltorexant, 10 mg and 20 mg, showed similar improvements in both REM and non-REM sleep, which were maintained over time (eTable 5 in the Supplement 2). Known changes in sleep architecture observed with DORAs, which increased REM sleep without affecting or decreasing non-REM sleep, were not observed with seltorexant, suggesting a difference between the effects of a selective OX2R antagonist vs the DORAs on sleep architecture that has not previously been reported.19
Overall, seltorexant was generally well tolerated at all doses tested for both adult and older participants, consistent with prior studies in both insomnia and MDD.12,13,14,20 There was no clear dose-related increase in AEs. Seltorexant showed favorable tolerability relative to zolpidem (the incidence of TEAEs was 33.8% in the combined seltorexant group vs 42.5% in the zolpidem group), including lower incidences of disturbance in attention and somnolence in the combined seltorexant group. There were no reports of sleep paralysis or cataplexy, and overall reporting of TEAEs of special interest was lower in the combined seltorexant group compared with zolpidem. One fall (considered probably related to external cause by the site investigator) and 1 serious TEAE of cerebral hemorrhage (without clear confirmation of cause) were reported in the seltorexant, 20 mg, group. These observations are contextualized by additional safety data from all completed short- and long-term trials of seltorexant involving healthy control individuals, as well as patients with insomnia or MDD, in which the overall incidence of falls was relatively low, and showed no significant imbalance between seltorexant and placebo groups.12,13,15
Four seltorexant participants discontinued the study because of AEs related to ECG changes, but overall there were no clinically significant changes in ECG parameters (heart rate, PR interval, or QT interval) or cardiovascular trends of concern. All ECG-related TEAEs leading to study drug discontinuation were reported in older adult patients based on observations from the ECG monitoring performed onsite, and none of these patients showed any clinical symptoms related to these observations. Subsequent studies13,15 of seltorexant did not identify any further safety concerns based on ECG data or cardiovascular related TEAEs. A cardiac safety study21 in a broader seltorexant MDD safety dataset did not identify any specific trends for cardiovascular abnormalities.
Additional safety observations (clinical laboratory testing, vital sign measurement, physical examination, suicidality, sleepiness, etc) were comparable across treatment groups. For some outcomes, like body sway and withdrawal effect (Benzodiazepine Withdrawal Symptom Questionnaire), seltorexant showed more favorable profile compared to zolpidem.
One strength of this study was the inclusion of both adult and older adult participants, a large subpopulation of those with insomnia. There were no clinically meaningful differences in seltorexant effects and improvements in sleep parameters between these age subgroups. TEAE incidence was slightly higher in older adults (39.5% vs 30.7%) in the combined seltorexant dose group; however, the incidence of TEAEs in older participants in the combined seltorexant group was lower than that among older participants from the zolpidem group (39.5% vs 48.0%). Another strength of the study was the comparison vs zolpidem, which increased the clinical meaningfulness of the data given the widespread use of zolpidem for clinical management of insomnia.
Limitations
Limitations of this study included that the participants composed a subpopulation with insomnia (those without psychiatric comorbidities) and that fewer than 3% of the participants in this study were women of childbearing potential, who make up a substantial proportion of patients with insomnia.22 However, the aggregate data from other completed and ongoing studies of seltorexant, which include relatively large numbers of women of childbearing potential, have supported the generalizability of the observed safety and efficacy data to this population.
Conclusions
In this randomized clinical trial, 10 mg and 20 mg of seltorexant, a novel, selective OX2R antagonist, demonstrated efficacy in both initiation and maintenance of sleep in adults and older adults with insomnia without psychiatric comorbidity. Seltorexant, 10 mg and 20 mg, maintained efficacy over the 14-day treatment period, while efficacy with zolpidem diminished. Seltorexant, up to 20 mg, appeared to be generally better tolerated than zolpidem (5-10 mg) in both adult and older adult populations.
Trial protocol
eMethods
eTable 1. Sensitivity Analysis: LPS on Night 1 (ANCOVA Observed Case Analysis Based on Log-transformed Data, Age as Continuous Covariate)
eTable 2. WASO-6 at Night 1 and Night 13
eTable 3. LPS and WASO-6: Mean (SD) change from baseline at Day 13
eTable 4. Secondary PSG Endpoints: Sleep Efficiency, TST-6, TST-8, WASO-8, Wake During Total Sleep Period, Time to First Awakening After Sleep
eTable 5. Secondary PSG Endpoints: nNAW and Wake After Final Awakening
eTable 6. Secondary PSG Endpoints: Sleep Architecture
eTable 7. Secondary Efficacy Endpoint: Proportion of Participants With Sleep Onset REM Over Time
eTable 8. Secondary Efficacy Endpoints: CSD-M sFRESH and sQUAL (Odds Ratio for Better Condition at Double-Blind Endpoint)
eTable 9. Secondary Efficacy Endpoints: CSD-M sSOL and sWASO
eTable 10. Secondary Efficacy Endpoints: PROMIS-SD and -SRI
eTable 11. Secondary Efficacy Endpoints: PGI-S and PGI-I (Odds Ratio for Better Condition at Day 14)
eTable 12. Secondary Efficacy Endpoint: ISI Total Score
eTable 13. Secondary Efficacy Endpoints: CGI-S and CGI-I (Odds Ratio for Better Condition at Day 14)
eTable 14. Treatment-Emergent Serious Adverse Events Vignettes
eTable 15. Number of Pts with TEAEs Leading to Discontinuation of Study Agent by System Organ Class and Preferred Term
eTable 16. Number of Pts with TEAEs of Special Interest by Special Interest Category and Preferred Term
eTable 17. Number of Pts with TEAEs by System Organ Class and Preferred Term by age Group
eTable 18. KSS: Change From Day 1 to Morning 2 and Evening 13 to Morning 14
eTable 19. PROMIS-ACA T-Score: Means and Mean Changes from Baseline
eTable 20. PWC-20: Most Frequently Reported New or Worsened Symptoms (≥5% Participants in Any Treatment Group) at Day 17 Telephone Contact (as Compared to Day 14) in the Post-treatment Follow-up Period
eTable 21. BWSQ: Summary of Total Score
eTable 22. C-SSRS: Most Severe Postbaseline Potentially Suicide-Related Category vs. Baseline During the Double-blind Phase
eFigure 1. Study Design
eFigure 2. LPS on Night 1: MCP-Mod Treatment Effects and ANCOVA Treatment Effects and 90% CI On Log-Transformed Data
eFigure 3. LPS on Night 1: Back-Transformed Least-squares Mean Ratio (90% Confidence Interval) ANCOVA by Subgroup
eFigure 4. WASO-6 on Night 1: MCP-Mod Treatment Effects and ANCOVA Treatment Effects and 90% CI on Log-Transformed Data
eFigure 5. WASO-6 on Night 1: Back-Transformed Least-squares Mean Ratio (90% CI) ANCOVA by Subgroup
eFigure 6. Mean Change from Baseline for Body Sway
eFigure 7. Mean Change from Baseline for Power of Attention
eFigure 8. Mean Change from Baseline for Continuity of Attention
eFigure 9. Mean Change from Baseline for Quality of Working Memory
eFigure 10. Mean Change from Baseline for Quality of Episodic Secondary Memory
eFigure 11. Mean Change from Baseline for Speed of Memory
eReferences
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eMethods
eTable 1. Sensitivity Analysis: LPS on Night 1 (ANCOVA Observed Case Analysis Based on Log-transformed Data, Age as Continuous Covariate)
eTable 2. WASO-6 at Night 1 and Night 13
eTable 3. LPS and WASO-6: Mean (SD) change from baseline at Day 13
eTable 4. Secondary PSG Endpoints: Sleep Efficiency, TST-6, TST-8, WASO-8, Wake During Total Sleep Period, Time to First Awakening After Sleep
eTable 5. Secondary PSG Endpoints: nNAW and Wake After Final Awakening
eTable 6. Secondary PSG Endpoints: Sleep Architecture
eTable 7. Secondary Efficacy Endpoint: Proportion of Participants With Sleep Onset REM Over Time
eTable 8. Secondary Efficacy Endpoints: CSD-M sFRESH and sQUAL (Odds Ratio for Better Condition at Double-Blind Endpoint)
eTable 9. Secondary Efficacy Endpoints: CSD-M sSOL and sWASO
eTable 10. Secondary Efficacy Endpoints: PROMIS-SD and -SRI
eTable 11. Secondary Efficacy Endpoints: PGI-S and PGI-I (Odds Ratio for Better Condition at Day 14)
eTable 12. Secondary Efficacy Endpoint: ISI Total Score
eTable 13. Secondary Efficacy Endpoints: CGI-S and CGI-I (Odds Ratio for Better Condition at Day 14)
eTable 14. Treatment-Emergent Serious Adverse Events Vignettes
eTable 15. Number of Pts with TEAEs Leading to Discontinuation of Study Agent by System Organ Class and Preferred Term
eTable 16. Number of Pts with TEAEs of Special Interest by Special Interest Category and Preferred Term
eTable 17. Number of Pts with TEAEs by System Organ Class and Preferred Term by age Group
eTable 18. KSS: Change From Day 1 to Morning 2 and Evening 13 to Morning 14
eTable 19. PROMIS-ACA T-Score: Means and Mean Changes from Baseline
eTable 20. PWC-20: Most Frequently Reported New or Worsened Symptoms (≥5% Participants in Any Treatment Group) at Day 17 Telephone Contact (as Compared to Day 14) in the Post-treatment Follow-up Period
eTable 21. BWSQ: Summary of Total Score
eTable 22. C-SSRS: Most Severe Postbaseline Potentially Suicide-Related Category vs. Baseline During the Double-blind Phase
eFigure 1. Study Design
eFigure 2. LPS on Night 1: MCP-Mod Treatment Effects and ANCOVA Treatment Effects and 90% CI On Log-Transformed Data
eFigure 3. LPS on Night 1: Back-Transformed Least-squares Mean Ratio (90% Confidence Interval) ANCOVA by Subgroup
eFigure 4. WASO-6 on Night 1: MCP-Mod Treatment Effects and ANCOVA Treatment Effects and 90% CI on Log-Transformed Data
eFigure 5. WASO-6 on Night 1: Back-Transformed Least-squares Mean Ratio (90% CI) ANCOVA by Subgroup
eFigure 6. Mean Change from Baseline for Body Sway
eFigure 7. Mean Change from Baseline for Power of Attention
eFigure 8. Mean Change from Baseline for Continuity of Attention
eFigure 9. Mean Change from Baseline for Quality of Working Memory
eFigure 10. Mean Change from Baseline for Quality of Episodic Secondary Memory
eFigure 11. Mean Change from Baseline for Speed of Memory
eReferences
Data sharing statement
