Efficacy and safety of lemborexant in midlife women with insomnia disorder

In the subgroup of perimenopausal-aged women with insomnia disorder who participated in the SUNRISE-2 trial, lemborexant improved subjective sleep parameters through 12 months. Lemborexant was well tolerated over the 12-month treatment, and most treatment-emergent adverse events were mild to moderate in severity in this population.

Abstract

Objective

Insomnia is common in midlife women. The efficacy and safety of lemborexant (LEM), a competitive dual orexin receptor antagonist, was assessed for 12 months in a subgroup of midlife women (age, 40-58 y) from Study E2006-G000-303 (Study 303; SUNRISE-2).

Methods

This was a randomized, double-blind, placebo (PBO)-controlled (first 6 mo) study of adults with insomnia disorder (N = 949). During treatment period 1 (TP1), participants received PBO or LEM 5 mg (LEM5) or 10 mg (LEM10). During TP2 (second 6 mo), LEM participants continued their assigned dose; PBO participants were rerandomized to LEM5 or LEM10. Assessments included patient-reported sleep- and fatigue-related measures and treatment-emergent adverse events.

Results

The midlife female subgroup comprised 280 of 949 participants (TP1: PBO, n = 90 of 318 [28.3%]; LEM5, n = 82 of 316 [25.9%]; LEM10, n = 108 of 315 [34.3%]). At 6 months, median changes from baseline in subjective sleep-onset latency (in minutes) were −17.9, −20.7, and − 30.4 for PBO, LEM5, and LEM10 (vs PBO: LEM5, P = not significant; LEM10, P = 0.0310). At 6 months, mean changes from baseline in subjective wake after sleep onset (in minutes) were −37.0 (59.6), −50.1 (74.5), and −54.5 (65.4) for PBO, LEM5, and LEM10 (vs PBO: LEM5 and LEM10, P = not significant), with benefits sustained through 12 months. Greater decreases from baseline (improvement) in Insomnia Severity Index total score and Fatigue Severity Scale total score were seen with LEM versus PBO at 6 months; benefits continued through 12 months. Most treatment-emergent adverse events were mild to moderate in severity.

Conclusions

Consistent with the total population, subjective sleep parameters improved, and improvement was sustained over time in midlife women. LEM was well tolerated, suggesting that LEM may be a potential treatment option for midlife women with insomnia.

Sleep disturbances are frequently reported by women during their midlife, including those in different stages of the menopausal transition.^1-4 The National Institutes of Health State-of-the-Science Conference Statement on management of menopause-related symptoms reported that the prevalence of sleep disturbance ranges from 16% during premenopause to 60% during postmenopause.⁵ A high prevalence of insomnia in perimenopausal women was also reported in a 10-year longitudinal analysis of the Study of Women’s Health Across the Nation (SWAN). The report found that among 3,302 multiethnic women aged 42 to 52 years and categorized as premenopausal or perimenopausal at baseline, 31% had symptoms of insomnia at year 1 and 42% at year 10.⁶ Therefore, insomnia may be frequently encountered in the gynecology setting.

Although intermittent awakening is the most common and among the most bothersome sleep complaints reported by perimenopausal women,^6–9 increased sleep-onset latency (SOL) and early morning awakenings are also frequent sleep disturbances.^4,6,10-12 As demonstrated by the SWAN study, the years-long transition to menopause is frequently associated with a greater prevalence of insomnia symptoms and impairment, such that a diagnosis of insomnia disorder may be warranted.⁶

The causes of insomnia during midlife and different stages of menopause are multifactorial and may be related to changing hormone levels, perimenopausal symptoms (hot flashes, night sweats), depression, joint and back pain, perceived poor health, and stress, which are frequently reported alongside insomnia.^8,9,13-16 Nocturnal hot flashes and other symptoms related to the perimenopausal state and older age may thus be factors for the development or exacerbation of preexisting insomnia.

Treatments of menopausal insomnia have been studied in clinical trials, including hormone therapy (HT) and hypnotics, but the results are mixed or unclear and somewhat limited.^17,18 The few efficacy studies assessing HT in midlife insomnia have been underwhelming, and even if HT had proven effective, it would likely be considered for limited duration because of potentially serious health risks associated with long-term use.^17,19-21 Eszopiclone has demonstrated efficacy in perimenopausal and early postmenopausal women with insomnia²²; however, data on the durability of therapeutic effect are unavailable. Dual orexin receptor antagonists (DORA), which target the orexin signaling pathway, are involved in sleep/wake regulation^23,24 and have the potential to effectively treat insomnia with fewer next-day residual effects than other sleep-promoting drugs with different mechanisms of action.²⁵ Recent findings demonstrated that the DORA suvorexant may be effective as a treatment of hot flash–associated insomnia in midlife women; however, the study duration was limited to 4 weeks.²⁶

The DORA lemborexant (LEM) is approved in several countries for the treatment for adults with insomnia. LEM is a competitive antagonist at orexin receptor types 1 and 2 and is thought to reduce wakefulness by attenuating orexin-mediated wake drive.²⁴ Clinical trials of LEM in patients with insomnia disorder demonstrate efficacy and a favorable safety profile.^27-29 In the pivotal phase 3 study E2006-G000-303 (Study 303; SUNRISE-2; NCT02952820), LEM treatment led to improvements in patient-reported parameters of sleep onset and sleep maintenance versus placebo (PBO) at the beginning (first 7 nights) and across 6 months of treatment, and was well tolerated.³⁰ The benefits of LEM were maintained up to 12 months after treatment.³¹ This additional treatment option is particularly important in primary care, as insomnia is an important concern and may be underestimated in this setting.³²

A post hoc analysis of the pivotal Study 303 was conducted to examine patient-reported efficacy and safety for up to 12 months in midlife women. In addition, the effect of LEM treatment on the severity of insomnia and fatigue using the participant-reported Insomnia Severity Index (ISI) and the Fatigue Severity Scale (FSS), respectively, was assessed, as well as participants’ perceptions of the effects of medication on their sleep using the Patient Global Impression—Insomnia (PGI-I) questionnaire.

METHODS

Study design

Details of the design and ethical standards of Study 303 have been previously published.^29,30 Briefly, Study 303 was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study. The study comprised a 6-month, PBO-controlled treatment period (TP1; day 1 through month 6) followed by a second 6-month treatment period (TP2; through month 12) that only included active treatment with LEM, which was designed to assess long-term safety data and persistence of effectiveness. During TP1, participants were randomized 1:1:1 to LEM 5 mg (LEM5), LEM 10 mg (LEM10), or PBO. During TP2, participants who received PBO in TP1 were rerandomized 1:1 to receive LEM5 or LEM10 (data for rerandomized participants are not presented here). Participants who received LEM5 or LEM10 during TP1 remained at the same dose of active drug in TP2. The present analysis only includes participants who continuously received LEM5 or LEM10 during TP1 and TP2 (or PBO for TP1).

Participants

Participants included in the overall study were women and men aged at least 18 years who met the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for insomnia disorder,³³ with subjective SOL (sSOL) of at least 30 minutes and/or subjective wake after sleep onset (sWASO) of at least 60 minutes occurring at least three times per week in the 4 weeks before enrollment in the study. Participants were also required to have an ISI total score of at least 15 at baseline. There were no specific inclusion criteria related to FSS score.

Individuals with comorbid sleep disorders (including sleep apnea, periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy) or a history of complex sleep-related behavior and those with a diagnosis of a major medical or psychiatric disorder or a disorder that was not adequately treated (in the opinion of the investigator) were excluded from the study. Additional exclusion criteria included a history of abnormal nocturnal behaviors, nocturia, excessive caffeine consumption, history of drug or alcohol dependency or abuse, positive drug screen, recent use of insomnia treatment, and suvorexant treatment failure.

The Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory were administered once at screening, and exclusionary scores were higher than 19 on the BDI-II and higher than 15 on the Beck Anxiety Inventory. Concomitant antidepressant medication use was permitted (except for moderate or strong cytochrome P450 [CYP3A] inhibitors or CYP3A inducers). Participants with a history of depression and/or mild depression (BDI-II score 14-19) were eligible for study participation, provided that any medication for depression did not pose a risk for drug–drug interactions. Participants with other medical and psychiatric disorders were eligible to participate if their condition was adequately managed, their treatment regimen was stable, and they were taking any concomitant medications that were not prohibited. A complete list of inclusion and exclusion criteria is published elsewhere.³⁰

The midlife female subgroup reported in this article was aged 40 to 58 years at the time of the first screening visit. This age range would be expected to capture the greatest number of midlife women in the study because, in the United States, the median age of menopause is 52 years, with a perimenopausal age range of 40 to 58 yr.⁵

Efficacy outcomes

Patient-reported (subjective) sleep parameters were calculated for all participants using data from electronic sleep diaries completed each day within 1 hour of morning awakening. For all sleep diary endpoints, the reported values were the means of the final 7 nights before a given study visit. Endpoints reported here include sSOL (subjectively estimated time [minutes] from the time the participant attempted to fall asleep until sleep onset), subjective sleep efficiency (sSE; total time spent asleep divided by time in bed, which was calculated using sleep diary entries), sWASO (subjectively estimated sum of time [minutes] of wake during night after initial sleep onset), and subjective total sleep time (sTST; derived minutes of sleep from sleep onset until getting out of bed). Improvements in subjective sleep parameters were indicated by decreases in change from baseline of sSOL and sWASO and by increases in change from baseline sSE and sTST.

Participants’ perceptions of their insomnia severity were assessed using the validated seven-item self-report ISI questionnaire.³⁴ Each of the seven items in the questionnaire is assessed on a 5-point Likert scale (ranging from 0 [no problem] to 4 [very severe problem]), yielding a maximum score of 28. Higher scores on the scale indicate greater severity of insomnia.

The impact of fatigue on participants’ daily functioning and quality of life was assessed using the nine-item, self-reported FSS questionnaire.³⁵ Each item in the questionnaire is assessed on a 7-point scale (ranging from 1 [strongly disagree] to 7 [strongly agree]), yielding a maximum score of 63, where higher scores indicate more severe fatigue. Scores of at least 36 are considered clinically significant.³⁶

Participants’ perceptions of the effects of medication on their sleep were assessed using the four-item PGI-I questionnaire.³⁷ The PGI-I contains three items related to study medication effects on sleep, rated on a 3-point scale (negative, neutral, positive), during or at the end of treatment, relative to the participant’s sleep before the initiation of study treatment. Item 4 is related to perceived appropriateness of study medication strength, rated as too strong, just right, or too weak.

Safety outcomes

Safety assessments included monitoring and recording treatment-emergent adverse events (TEAE), clinical laboratory measures, vital signs, weight, electrocardiograms, suicidality, and physical examinations.

Statistical analyses

All statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC) or other validated software. Efficacy analyses included all randomized midlife female participants who received at least one dose of study drug and had at least one postdose primary efficacy assessment. Safety analyses included all randomized midlife female participants who received at least one dose of study drug and had at least one postdose safety assessment. Data were analyzed at prespecified time points: week 1, month 3, and month 6. Changes from study baseline in subjective sleep parameters during TP1 were analyzed using a mixed-effects model of repeated-measures (MMRM) analysis. Changes from baseline for sSOL, sSE, sWASO, and sTST were analyzed using MMRM analysis, with region, visit, treatment, and treatment-by-visit interaction as fixed effects and baseline value for the relevant variable as a covariate. Because sSOL values were not normally distributed, log transformation was used and between-group differences were compared via least squares geometric means (LSGM), standard procedure for sleep latency variables in insomnia trials.^38,39 Missing values of sSOL, sSE, and sWASO were imputed using complete case missing value pattern imputation and assumed to be missing not at random. Missing values of sTST were not imputed and assumed to be missing at random. Between-group differences were compared using least squares mean (LSM). Between-group comparisons were not performed for TP2. Changes from study baseline in ISI and FSS were analyzed using the same methodology as sTST and summarized descriptively for TP1 and TP2. The midlife female subgroup analyses were not controlled for multiplicity or powered for the detection of statistically significant differences.

RESULTS

Participant disposition and baseline characteristics

Full results for the overall population (N = 949) have been published.^30,31 A total of 280 participants (29.5%) from the overall population were included in the subgroup of midlife women (PBO, n = 90; LEM5, n = 82; LEM10; n = 108; Table 1). Participant disposition during both treatment periods is shown (Supplemental Digital Content 1, http://links.lww.com/MENO/B137, and Supplemental Digital Content 2, http://links.lww.com/MENO/B138). Baseline demographics, subjective sleep measures, mean ISI scores, and mean FSS scores were similar among treatment groups (Tables 1, 2). The mean age in the subgroup was 50 years and most participants were White (70%).

TABLE 1.

Baseline demographics and characteristics of female participants 40-58 years of age

	Placebo (n = 90)	LEM5 (n = 82)	LEM10 (n = 108)
Age, y
Mean (SD)	50.0 (5.4)	49.2 (5.8)	50.2 (5.2)
Median (range)	50.0 (40-58)	50.0 (40-58)	51.0 (40-58)
Race, n (%)a
White	62 (68.9)	60 (73.2)	74 (68.5)
lack or African American	11 (12.2)	7 (8.5)	10 (9.3)
Japanese	16 (7.8)	11 (13.4)	17 (15.7)
Chinese	0	1 (1.2)	1 (0.9)
Other Asian	1 (1.1)	1 (1.2)	2 (1.9)
American Indian or Alaska Native	0	1 (1.2)	2 (1.9)
Otherb	0	1 (1.2)	2 (1.9)
BMI mean (SD), kg/m2	27.5 (6.7)	27.2 (7.0)	27.5 (5.6)
ISI, mean (SD)	19.3 (2.8)	20.1 (3.0)	19.5 (3.7)
FSS total score, mean (SD)	35.5 (14.0)	39.8 (12.6)	36.6 (13.5)

BMI, body mass index; FSS, Fatigue Severity Scale; ISI, Insomnia Severity Index; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg.

^aPercentages may not add up to 100 because of rounding errors.

^bThree participants identified as “Caucasian and African American,” “Puerto Rican,” and “American Indian and White.”

TABLE 2.

Summary of sleep diary endpoints in female participants 40-58 years of age

	Placebo (n = 90)		LEM5 (n = 82)		LEM10 (n = 108)
sSOL, min	n	Median (1st and 3rd quartiles)	n	Median (1st and 3rd quartiles)	n	Median (1st and 3rd quartiles)
Baseline	90	57.5 (35.7, 79.6)	82	51.1 (31.4, 73.6)	105	54.0 (37.9, 80.8)
Week 1	89	49.3 (28.8, 74.5)	80	33.3 (20.4, 59.9)	107	37.9 (22.9, 61.6)
Change from baseline at week 1	89	−5.7 (−21.4, 4.1)	80	−11.1 (−26.4, 0.0)	104	−12.9 (−30.0, −0.6)
Month 3	82	29.5 (15.7, 57.0)	67	20.7 (14.3, 40.0)	92	24.1 (13.6, 39.8)
Change from baseline at month 3	82	−17.6 (−32.1, −3.0)	67	−18.6 (−41.6, −6.7)	90	−29.3 (−49.9, −13.3)
Month 6	71	24.3 (14.0, 51.4)	63	20.7 (11.7, 33.6)	77	20.0 (10.0, 32.1)
Change from baseline at month 6	71	−17.9 (−40.0, −2.9)	63	−20.7 (−39.1, −10.3)	76	−30.4 (−55.0, −17.6)
LSGM treatment ratio: LEM/PBO (95% CI)		—		0.87 (0.65 to 1.16)		0.74 (0.57 to 0.97)
P		—		0.3464		0.0310
Month 9		—	57	20.0 (10.0, 34.2)	73	19.2 (10.0, 40.7)
Change from baseline at month 6		—	57	−23.6 (−46.4, −10.7)	72	−32.8 (−52.8, −21.2)
Month 12		—	49	19.2 (10.7, 29.4)	73	15.8 (10.0, 34.3)
Change from baseline at month 6		—	49	−27.7 (−46.4, −13.3)	72	−33.9 (−55.7, −19.7)

sSE, %	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Baseline	88	59.9 (16.7)	80	60.7 (20.0)	102	61.2 (17.5)
Week 1	85	63.4 (18.0)	79	67.9 (20.3)	105	68.8 (17.8)
Change from baseline at week 1	85	3.0 (11.8)	78	6.9 (10.5)	101	7.4 (10.3)
Month 3	80	74.0 (16.7)	65	77.9 (16.0)	91	75.1 (17.4)
Change from baseline at month 3	79	13.0 (14.3)	65	15.1 (15.8)	86	14.3 (13.5)
Month 6	71	72.8 (19.3)	63	78.3 (16.3)	77	78.0 (17.8)
Change from baseline at month 6	70	12.5 (15.0)	62	15.9 (17.0)	73	17.2 (14.7)
LSM treatment difference: LEM-PBO (95% CI)		—		2.19 (−2.36 to 6.74)		3.28 (−1.11 to 7.67)
P		—		0.3463		0.1428
Month 9		—	57	78.6 (17.7)	73	78.9 (16.9)
Change from baseline at month 6		—	56	16.1 (19.5)	69	17.9 (15.6)
Month 12		—	49	82.1 (11.2)	73	79.8 (16.7)
Change from baseline at month 6		—	49	17.6 (18.2)	69	19.1 (14.8)

sWASO, min	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Baseline	90	134.9 (70.8)	82	142.4 (86.5)	105	136.5 (84.4)
Week 1	89	135.5 (90.2)	80	120.7 (90.1)	107	117.7 (82.8)
Change from baseline at week 1	89	0.7 (56.3)	80	−21.4 (43.7)	104	−17.9 (44.5)
Month 3	82	97.2 (83.4)	67	87.5 (80.6)	92	96.9 (86.9)
Change from baseline at month 3	82	−37.3 (60.3)	67	−49.7 (67.7)	90	−38.6 (66.0)
Month 6	71	95.0 (74.8)	63	83.8 (73.4)	77	83.1 (79.7)
Change from baseline at month 6	71	−37.0 (59.6)	63	−50.1 (74.5)	76	−54.5 (65.4)
LSM treatment difference: LEM-PBO (95% CI)		—		−12.43 (−31.95 to 7.09)		−9.94 (−28.18 to 8.30)
P		—		0.2119		0.2853
Month 9		—	57	79.7 (78.9)	73	77.3 (73.9)
Change from baseline at month 6		—	57	−54.7 (86.9)	72	−59.5 (74.6)
Month 12		—	49	65.8 (52.5)	73	73.9 (69.7)
Change from baseline at month 6		—	49	−59.1 (76.7)	72	−66.2 (64.9)

sTST, min	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Baseline	88	294.9 (83.9)	80	300.6 (101.5)	102	302.6 (90.5)
Week 1	85	316.5 (89.8)	79	338.9 (103.2)	105	343.8 (92.8)
Change from baseline at week 1	85	19.2 (60.4)	78	35.9 (53.0)	101	40.0 (55.1)
Month 3	80	369.0 (94.8)	65	386.7 (85.2)	91	374.8 (93.9)
Change from baseline at month 3	79	68.9 (88.7)	65	76.2 (80.2)	86	74.3 (72.8)
Month 6	71	354.0 (97.5)	63	389.6 (83.4)	77	391.0 (97.5)
Change from baseline at month 6	70	59.9 (80.4)	62	80.6 (87.9)	73	90.6 (80.1)
LSM treatment difference: LEM-PBO (95% CI)		—		11.23 (−14.42 to 36.87)		24.07 (−0.33 to 48.47)
P		—		0.3892		0.0531
Month 9		—	57	384.2 (92.3)	73	389.8 (88.8)
Change from baseline at month 6		—	56	73.9 (98.5)	69	86.3 (79.0)
Month 12		—	49	398.8 (58.2)	73	391.5 (90.5)
Change from baseline at month 6		—	49	78.1 (93.6)	69	91.6 (77.3)

CI, confidence interval; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; LSGM, least squares geometric mean; LSM, least squares mean; PBO, placebo, sSE, subjective sleep efficiency; sSOL, subjective sleep-onset latency; sTST, subjective total sleep time; sWASO, subjective wake after sleep onset.

Subjective sleep onset

At baseline, the median sSOL values were 57.5, 51.1, and 54.0 minutes in the PBO, LEM5, and LEM10 treatment groups, respectively (Table 2). Participants treated with LEM10 had a greater decrease in sSOL from baseline versus PBO at each time point in TP1, beginning as early as week 1 (Table 2; Supplemental Digital Content 3A, http://links.lww.com/MENO/B139, which shows change from baseline in subjective sleep parameters over time). The differences in change from baseline versus PBO were generally less pronounced with LEM5 than with LEM10 during TP1.

At month 6, the median changes from baseline in sSOL were −17.9 minutes with PBO, −20.7 minutes with LEM5, and −30.4 minutes with LEM10. The LSGM treatment ratios showed a significantly greater reduction from baseline in sSOL for LEM10 versus PBO (LSGM treatment ratio [95% confidence interval {CI}], 0.74 [0.57 to 0.97]; P = 0.0310) and a numerically, but not significantly, greater reduction for LEM5 (0.87 [0.65 to −1.16]; Table 2; Fig. 1A). These findings in midlife women are generally consistent with the overall study population in which reductions in sSOL were observed from baseline to month 6 for both doses of LEM compared with PBO (Fig. 1A).³⁰

FIG. 1.

Forest plot for LSGM or LSM treatment ratio for change from baseline to 6 months in (A) sSOL, (B) sSE, (C) sWASO, and (D) sTST for LEM versus PBO in the midlife female subgroup and among all participants (all participant data have been previously published).²⁹ (A) Estimates and 95% CI based on MMRM analysis with log transformation of sSOL and factors for age group, region, visit (for all participants: treatment), and treatment-by-visit interaction as fixed effects and baseline value as a covariate. (B to D) Based on MMRM analysis with factors of age group, region, visit, and treatment-by-visit interaction as fixed effect and baseline value as a covariate. (A, B, C, and D) Midlife female subgroup: age group was not included as a factor in the MMRM analysis. Missing values were imputed using multiple imputation and assumed to be missing not at random. (D) Midlife female subgroup: missing values were not imputed and were assumed to be missing at random. (A, B, and C) All participants: missing values were imputed using multiple imputation and assumed to be missing not at random. (D) All participants: missing values were not imputed and assumed to be missing at random. CI, confidence interval; LEM, lemborexant; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; LSGM, least squares geometric mean; LSM, least squares mean; ML, midlife female subgroup; MMRM, mixed-effects model of repeated-measures; PBO, placebo; sSE, subjective sleep efficiency; sSOL, subjective sleep-onset latency; sTST, subjective total sleep time; sWASO, subjective wake after sleep onset.

During TP2, the decrease from baseline in median sSOL was maintained through 12 months in the LEM5 and LEM10 treatment groups (Table 2; Supplemental Digital Content 3A, http://links.lww.com/MENO/B139).

Subjective sleep maintenance and total sleep

Mean sSE (%) was similar among midlife women in the PBO (59.9), LEM5 (60.7), and LEM10 (61.2) treatment groups at baseline (Table 2). Both LEM doses were associated with numerically greater increases in sSE versus PBO at all time points in TP1 (Table 2). At month 6, sSE increased from baseline by 15.9% and 17.2% with LEM5 and LEM10, respectively, compared with 12.5% with PBO (Table 2). LSM treatment differences (LEM-PBO) from baseline to month 6 were all in the direction that favored LEM5 (LSM difference [95% CI], 2.19 [−2.36 to 6.74]) and LEM10 (3.28 [−1.11 to 7.67]) versus PBO, but differences were not statistically significant (Table 2; Fig. 1B).

At baseline, mean sWASO values were 134.9, 142.4, and 136.5 minutes in the PBO, LEM5, and LEM10 groups, respectively. Numerically greater improvements (ie, larger mean decrease from baseline) in sWASO for LEM5 and LEM10 versus PBO were apparent at all time points in TP1, beginning as early as week 1 (Table 2). The mean changes from baseline in sWASO at month 6 were −50.1 minutes with LEM5, −54.5 minutes with LEM10, and −37.0 minutes with PBO (Table 2). LSM treatment differences (LEM-PBO) from baseline to month 6 again were all in the direction that favored LEM5 (LSM difference [95% CI], −12.43 [−31.95 to 7.09]) and LEM10 (−9.94 [−28.18 to 8.30]) versus PBO; however, these differences did not reach statistical significance (Table 2; Fig. 1C).

At baseline, the mean sTST values were 294.9, 300.6, and 302.6 minutes in the PBO, LEM5, and LEM10 treatment groups (Table 2). Mean increases in sTST were apparent throughout TP1, beginning as early as week 1 (Table 2). At month 6, numerically greater mean increases in sTST from baseline were observed for LEM5 (80.6 min) and LEM10 (90.6 min) compared with PBO (59.9 min; Table 2). As with the other sleep parameters, the LSM treatment differences (LEM-PBO) from baseline to month 6 in sTST were in a direction that favored LEM5 (LSM difference [95% CI], 11.23 [−14.42 to 36.87]) and LEM10 (24.07 [−0.33 to 48.47]) versus PBO, but did not reach statistical significance (Table 2; Fig. 1D).

The observations that LSM treatment differences from baseline to month 6 favored both LEM doses versus PBO for each of the sleep maintenance (sSE and sWASO) and sTST endpoints in this small population of midlife women are consistent with results from the overall study population, in which significant improvements in sSE, sWASO, and sTST were observed for both doses of LEM compared with PBO (Fig. 1B-D).³⁰

Across the subjective sleep maintenance and total sleep time parameters, the improvements from baseline observed at month 6 in the LEM5 and LEM10 groups were maintained through 12 months during TP2 (Table 2; Supplemental Digital Content 3B-D, http://links.lww.com/MENO/B139).

Insomnia Severity Index

Mean ISI scores at baseline were 19.3, 20.1, and 19.5 in the PBO, LEM5, and LEM10 groups, respectively (Table 3). At 6 months, numerically greater decreases from baseline (improvement) in mean ISI scores were observed with LEM5 (−9.8) and LEM10 (−10.7) versus PBO (−8.3) (Table 3). Improvements in ISI score persisted through TP2 with both LEM doses.

TABLE 3.

Summary of Insomnia Severity Index total score and Fatigue Severity Scale total score endpoints in female participants 40-58 years of age

	Placebo (n = 90)		LEM5 (n = 82)		LEM10 (n = 108)
	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
ISI (total score)
aseline	90	19.3 (2.8)	82	20.1 (3.0)	108	19.5 (3.7)
Month 1	85	12.9 (5.1)	80	14.0 (6.2)	99	12.2 (6.1)
Change from baseline at month 1	85	−6.4 (5.8)	80	−6.1 (5.3)	99	−7.4 (7.0)
Month 3	79	11.6 (5.3)	69	12.1 (6.6)	91	10.4 (6.1)
Change from baseline at month 3	79	−7.4 (6.1)	69	−7.8 (6.2)	91	−9.3 (6.6)
Month 6	72	10.9 (5.4)	65	10.1 (6.5)	82	8.8 (5.9)
Change from baseline at month 6	72	−8.3 (6.0)	65	−9.8 (6.2)	82	−10.7 (6.9)
LSM treatment difference: LEM-PBO (95% CI)		—		−0.5 (−2.5 to 1.4)		−1.8 (−3.6 to 0)
P		—		0.5876		0.0558
Month 9	—	—	57	9.3 (5.9)	73	7.5 (5.5)
Change from baseline at month 9	—	—	57	−10.5 (5.8)	73	−12.0 (6.3)
Month 12	—	—	52	7.9 (6.1)	70	7.7 (5.6)
Change from baseline at month 12	—	—	52	−11.8 (5.8)	70	−11.6 (6.3)
FSS (total score)
aseline	90	35.5 (14.0)	82	39.8 (12.6)	108	36.6 (13.5)
Month 1	85	30.9 (13.7)	80	35.0 (13.0)	99	30.1 (14.0)
Change from baseline at month 1	85	−4.6 (12.4)	80	−4.7 (12.2)	99	−6.4 (13.7)
Month 3	79	30.1 (12.8)	69	33.5 (13.9)	91	28.9 (14.5)
Change from baseline at month 3	79	−5.2 (11.3)	69	−6.3 (10.7)	91	−7.5 (13.4)
Month 6	72	28.5 (14.2)	65	29.8 (14.8)	82	27.1 (14.3)
Change from baseline at month 6	72	−7.4 (12.8)	65	−9.9 (12.9)	82	−9.0 (14.5)
LSM treatment difference: LEM-PBO (95% CI)				−0.4 (−4.4 to 3.7)		−1.4 (−5.2 to 2.4)
P				0.8520		0.4677
Month 9	—	—	57	29.0 (13.0)	73	23.8 (13.2)
Change from baseline at month 9	—	—	57	−11.4 (12.5)	73	−11.1 (14.6)
Month 12	—	—	52	25.6 (12.6)	70	25.1 (14.2)
Change from baseline at month 12	—	—	52	−14.5 (13.1)	70	−9.8 (15.7)

FSS, Fatigue Severity Scale; ISI, Insomnia Severity Index; LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo; SD, standard deviation.

Fatigue Severity Scale

Mean FSS total scores at baseline were 35.5, 39.8, and 36.6 in the PBO, LEM5, and LEM10 groups, respectively (Table 3). At 6 months, numerically greater decreases from baseline (improvement) in mean FSS scores were observed with LEM5 (−9.9) and LEM10 (−9.0) versus PBO (−7.4; Table 3). Improvements in FSS score persisted through TP2 with both LEM doses.

Patient Global Impression—Insomnia

A summary of the percentages of participants reporting positive, neutral, or negative effects of study drug (items 1-3 of the PGI-I questionnaire) during TP1 and TP2 is presented in Figure 2A-C. At month 6, numerically higher percentages of participants treated with LEM5 and LEM10 versus PBO reported positive medication effects on sleep (60.9% and 72.8% vs 50.7%, respectively), time to fall asleep (70.3% and 74.1% vs 49.3%), and total sleep time (54.7% and 64.2% vs 43.7%). At months 9 and 12, most participants in both LEM treatment groups continued to report positive effects of their medication on sleep (70.0%-80.0%), time to fall asleep (67.3%-85.3%), and total sleep time (60.0%-70.7%; Fig. 2A-C).

FIG. 2.

Percentage of participants reporting a positive, neutral, or negative effect of study drug for PGI-I items 1 (A), 2 (B), and 3 (C) and reporting too weak, too strong, or just right medication strength for item 4 (D). LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; PBO, placebo; PGI-I, Patient Global Impression—Insomnia.

A numerically greater percentage of participants receiving LEM5 and LEM10 compared with PBO reported that their study medication strength was “just right” in response to item 4 during TP1 (Fig. 2D). At the end of month 6, 50.0% and 51.9% of participants in the LEM5 and LEM10 treatment groups, respectively, reported that their medication strength was “just right” compared with 40.8% in the PBO group; 42.2% and 42.0% of participants in the LEM5 and LEM10 treatment groups, respectively, reported that their medication strength was “too weak.” These proportions were somewhat higher compared with the overall population (LEM5, 40.1%; LEM10, 39.7%).⁴⁰ At months 9 and 12 during TP2, most participants in the LEM5 (53.3% and 63.3%, respectively) and LEM10 (61.3% and 56.5%, respectively) treatment groups reported that their study medication was “just right” (Fig. 2D). The proportions of participants who reported their study medication was “too weak” at months 9 and 12 for LEM5 were 38.3% and 34.7%, respectively, and for LEM10, values were 34.7% and 34.8%, respectively. These values were also higher compared with corresponding values at months 9 and 12 for the overall population (month 9: 34.4% for LEM5, 30.3% for LEM10; month 12: 34.1% for LEM5, 32.8% for LEM10).⁴⁰

Safety

Over TP1, similar proportions of TEAE were reported across treatment groups (LEM5, 64.6%; LEM10, 58.9%; PBO, 64.4%), and more TEAE cases were reported with LEM5 (57.8%) than LEM10 (44.7%) during TP2 (Table 4). Overall, TEAE cases were generally mild to moderate in severity during both study periods. The most common TEAE cases (occurring in >10% of participants in any treatment group and period) were somnolence, nasopharyngitis, and headache (Table 4).

TABLE 4.

TEAE (safety analysis set^a) in female participants 40-58 years of age

	Treatment Period 1 (1st 6 mo)			Treatment Period 2 (2nd 6 mo)
	Placebo (n = 90)	LEM5 (n = 82)	LEM10 (n = 107)	LEM5-LEM5 (n = 64)	LEM10-LEM10 (n = 76)
TEAEb	58 (64.4)	53 (64.6)	63 (58.9)	37 (57.8)	34 (44.7)
Treatment-related	14 (15.6)	22 (26.8)	33 (30.8)	8 (12.5)	5 (6.6)
Severe	4 (4.4)	1 (1.2)	2 (1.9)	2 (3.1)	1 (1.3)
Serious	2 (2.2)	1 (1.2)	3 (2.8)	1 (1.6)	1 (1.3)
Leading to study drug withdrawal	5 (5.6)	3 (3.7)	9 (8.4)	3 (4.7)	1 (1.3)
Leading to interruption of study drug	5 (5.6)	4 (4.9)	2 (1.9)	3 (4.7)	0
Death	0	0	0	0	0
TEAE reported in >5% of participants in any treatment group
Somnolence	1 (1.1)	8 (9.8)	13 (12.1)	1 (1.6)	1 (1.3)
Nasopharyngitis	13 (14.4)	8 (9.8)	10 (9.3)	9 (14.1)	7 (9.2)
Headache	10 (11.1)	11 (13.4)	8 (7.5)	4 (6.3)	4 (5.3)
Influenza	5 (5.6)	4 (4.9)	6 (5.6)	0	1 (1.3)
Upper respiratory tract infection	2 (2.2)	5 (6.1)	4 (3.7)	4 (6.3)	2 (2.6)

All data are presented as n (%).

LEM5, lemborexant 5 mg; LEM10, lemborexant 10 mg; TEAE, treatment-emergent adverse event.

^aSafety analysis set was defined as all randomized participants who received at least one dose of study drug and had at least one postdose safety assessment.

^bA TEAE was defined as an adverse event with onset date on or after the first dose of study drug up to 14 days after the last dose of study drug. Within each treatment period, participants with at least two adverse events with the same preferred term are counted only once for that preferred term.

The incidence of serious TEAE was low during TP1 in the LEM5 and LEM10 groups (1.2% and 2.8%, respectively) and similar to the incidence in the PBO group (2.2%; Table 4); findings for LEM5 and LEM10 were similar in TP2 (1.6% and 1.3%, respectively). Study drug withdrawals and study drug interruptions due to TEAE occurred at similarly low rates in the LEM5, LEM10, and PBO groups in TP1 and TP2 (Table 4). No deaths occurred during the study.

DISCUSSION

In this post hoc analysis of 280 midlife women enrolled in a large phase 3 trial of LEM for insomnia disorder, LEM treatment demonstrated consistent changes in the direction of improvement in all sleep diary–based outcomes for sSE, sSOL, sWASO, and sTST versus PBO for up to 6 months. Although the differences between active treatment and PBO were often not significant, what can be noted is that the changes were consistently in direction of improvement for both sleep onset and sleep maintenance variables, which would not be expected if changes were random but would be expected when analyzing smaller subgroups. The benefits of LEM were observed as early as week 1 and were sustained through 12 months, demonstrating the long-term effectiveness of LEM in this population. Although both doses of LEM improved sleep parameters numerically versus PBO at all times assessed, some differences were observed by dose. Compared with LEM5, LEM10 seemed to show greater improvement in all sleep parameters at most time points evaluated, particularly regarding sSOL, suggesting that LEM10 may be particularly valuable for midlife women with sleep-onset problems. Unexpectedly, the robust improvement in sSOL observed with LEM10 was not similarly observed with LEM5; sSOL improvements with LEM5 were similar to those in the PBO group.

Although reasons for less robust improvement with LEM5 are not entirely understood, the PBO response in midlife women in this study was higher than previously observed,³¹ which could explain why LEM5 did not differentiate from PBO. Nevertheless, the mean changes from baseline in sSOL at 6 months for LEM5 and LEM10 in this subgroup were comparable with those observed in the overall population.³⁰ Moreover, many participants in the LEM5 group still reported positive effects on sleep onset on the PGI-I. Mean changes from baseline at 6 months in sWASO were also numerically greater for both LEM treatment groups compared with PBO. It should be noted that this fixed-dose study design does not allow for upward or downward titration, and thus, treatment was not optimized for each participant individually. This is supported by the relatively higher proportion of participants in this study who reported their medication strength as being “too weak” at months 6, 9, and 12 on item 4 of the PGI-I, compared with the overall population, and this may account for the findings in the efficacy outcomes.⁴⁰ Having this potential difference in treatment response is not an issue from the dosing perspective because LEM5 is the approved starting dose for all adult patients, with the opportunity to titrate up to LEM10 depending on response in countries where the higher dose has been approved.

The observed differences from PBO in patient-reported ISI and FSS scores with LEM suggest that LEM reduces both insomnia and fatigue severity in the midlife female subgroup. Because these reductions in insomnia and fatigue severity coincided with improvements in sleep, these findings suggest that improving sleep symptoms may contribute to improved daytime function and reduced fatigue. This is particularly important because fatigue is a major complaint among midlife women.⁴¹ The benefits of LEM on sleep and fatigue outcomes were also supported by participants’ positive perceptions of their medication. The majority of participants receiving LEM5 or LEM10 reported that their study medication helped them to sleep, decreased the time to fall asleep, and increased the total sleep time compared with PBO at 12 months, sustaining similar positive effects for LEM achieved earlier in treatment. The majority of participants also reported their medication strength as “just right” at 12 months. Given that ratings of LEM being “too weak” generally decreased through month 1 to month 12, it seems that tolerance to LEM did not occur.

LEM was well tolerated over the 12-month treatment period, with a safety profile consistent with that observed in the overall population.³⁰ In these studies, somnolence, headache, influenza, and upper respiratory tract infection were among the most commonly reported TEAE, and TEAE cases were generally mild to moderate (≤5% of TEAE cases were severe in any treatment group).³⁰ There were no new safety signals when treatment was continued beyond 6 months in the midlife female subgroup. Of note, the incidence of most TEAE with LEM, and for somnolence in particular, was lower during TP2, suggesting that the frequency of TEAE may decrease over time with LEM.

Limitations

There are some limitations to consider in interpreting this subgroup analysis. Because the midlife female subgroup in our post hoc analysis was defined by sex and age only, our analyses will have included some postmenopausal women.⁴² The relatively small population of midlife women gave insufficient power to demonstrate statistical differences in change from baseline in sleep parameters between treatment groups, although it is notable that the direction of changes in all parameters was towards improvement, matching the overall population. There was also attrition during the study (although generally not from lack of therapeutic effect) from all treatment groups. In addition, because the overall study was a fixed-dose design, optimization of outcomes through dose adjustment was not an option.

CONCLUSIONS

These analyses provide evidence that LEM may provide benefit and is well tolerated in midlife women with insomnia disorder through 12 months. In conjunction with participant-reported reductions in insomnia and fatigue severity with LEM, both critical factors associated with sleep disturbance in this patient population, these data suggest that LEM may be a potential treatment option for midlife women with insomnia.

Supplementary Material

meno-30-839-s001.docx ^{(128.6KB, docx)}