Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials

Abstract

Background: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults.

Methods: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance.

Results: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years.

Conclusions: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia.

Trial registration numbers and dates of registration: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

Fig. 1

Sleep onset and maintenance in patients aged ≥ 65 years from Study 304: a LPS, b WASO, c WASO2H, and d SE. Estimates based on a repeated mixed-effects model with factors for region, treatment, visit (nights 1 and 2 and nights 29 and 30), and treatment-by-visit interaction as fixed effects, and baseline LPS, WASO, WASO2H, or SE as a covariate. Missing values were not imputed and assumed to be missing at random. The repeated mixed-effects model for LPS used log transformation of LPS. *p < 0.0001, ^†p < 0.001, ^‡p < 0.01, ^§p < 0.05 versus PBO, ‖p < 0.0001, ^¶p < .001, ^#p < 0.01, ^¶¶p < 0.05 versus ZOL. BL baseline, LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, LPS latency to persistent sleep, LSM least squares mean, PBO placebo, SD standard deviation, SE standard error, WASO wake after sleep onset, WASO2H wake after sleep onset in the second half of the night, ZOL zolpidem tartrate extended-release 6.25 mg

Fig. 2

Postural stability, as measured by body sway, in subjects aged ≥ 65 years: a Study 304 at days 2 and 3 and days 30 and 31 of treatment and b Study 108 4 h and 8 h post dose. For Study 304, changes from baseline were assessed using a repeated mixed-effects model analysis with factors for region, visit (time point), and treatment-by-visit interaction as fixed effects, and baseline body sway as a covariate. For Study 108, mean change from baseline and associated 95% CIs were calculated for body sway and CPAB domains for 4 h post dose (middle of the night) and 8 h post dose (morning). ^aA unit of body sway is defined as 1/3° angle of arc movement of the ataxiameter. A higher value represents more body sway and less postural stability. ^‡p < 0.01 versus PBO; ^#p < 0.01, ^¶¶p < 0.05 versus ZOL. BL baseline, CI confidence interval, CPAB cognitive performance assessment battery, LEM5 lemborexant 5 mg, LEM10 lemborexant 10 mg, LSM least squares mean, PBO placebo, ZOL zolpidem tartrate extended-release 6.25 mg

Fig. 3

Change from baseline in cognitive performance as measured by CPAB in subjects aged ≥ 65 years from Study 304 for the domains a power of attention, b continuity of attention, c quality of memory, and d speed of memory retrieval. For power of attention and speed of memory retrieval, lower values reflect better performance; for continuity of attention and quality of memory, higher values reflect better performance. ^‡p < 0.01, ^§p < 0.05 versus PBO; ^¶p < 0.001, ^#p < 0.01, ^¶¶p < 0.05 versus ZOL. Changes from baseline were analyzed using a repeated mixed-effects model with factors for region, visit (days 2 and 3 and days 30 and 31), and treatment-by-visit interactions as fixed effects, and baseline CPAB domain as a covariate. Missing values were not imputed and assumed to be missing at random. BL baseline, CPAB cognitive performance assessment battery, LEM5, lemborexant 5 mg, LEM10 lemborexant 10 mg, LSM least squares mean, PBO placebo, SE standard error, ZOL zolpidem tartrate extended-release 6.25 mg

Fig. 4

Mean (SD) RSL in subjects aged ≥ 65 years from Study 108. * p < 0.05, ^†p < 0.01 versus PBO; ^‡p < 0.05 versus ZOL. ER extended release, PBO placebo, RSL return-to-sleep latency, SD standard deviation, ZOL zolpidem tartrate extended-release 6.25 mg