Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening

Abstract

Study objectives: Our aim was to evaluate the effect of lemborexant versus zolpidem tartrate extended release 6.25 mg (ZOL) or placebo (PBO) on postural stability, auditory awakening threshold (AAT), and cognitive performance (cognitive performance assessment battery [CPAB]).

Methods: Healthy women (≥ 55 years) and men (≥ 65 years) were randomized, double-blind, to 1 of 4-period, single-dose crossover sequences, starting with lemborexant 5 mg (LEM5), 10 mg (LEM10), ZOL, or PBO. A ≥ 14-day washout followed all 4 treatments. Assessments were middle-of-the-night (MOTN) change from baseline in postural stability (primary prespecified comparison: LEM vs ZOL), AAT, absolute AAT, and CPAB for LEM5 and LEM10 versus ZOL and PBO; and morning change from baseline in postural stability and CPAB for LEM5 and LEM10 versus ZOL and PBO. Change from baseline measures were time-matched to a baseline night/morning when no study drug was administered.

Results: MOTN: Mean MOTN change from baseline in body sway was significantly higher for ZOL versus both lemborexant doses. There were no differences among the treatments regarding decibels required to awaken a participant. LEM5 was not statistically different from PBO on any CPAB domain; LEM10 and ZOL showed poorer performance on some tests of attention and/or memory. Morning: Body sway and cognitive performance following LEM5 or LEM10 did not differ from PBO; body sway was significantly higher for ZOL than PBO. Rates of treatment-emergent adverse events were low; there were no serious adverse events.

Conclusions: Lemborexant causes less postural instability than a commonly used sedative-hypnotic and does not impair the ability to awaken to auditory signals.

Clinical trials registration: Registry: ClinicalTrials.gov; Name: Crossover Study to Evaluate the Effect of Lemborexant Versus Placebo and Zolpidem on Postural Stability, Auditory Awakening Threshold, and Cognitive Performance in Healthy Subjects 55 Years and Older; URL: https://ichgcp.net/clinical-trials-registry/NCT03008447; Identifier: NCT03008447.

Keywords: attention; auditory awakening; lemborexant; memory; older adults; postural stability; zolpidem.

Conflict of interest statement

All authors have seen and approved the final manuscript. This study was sponsored by Eisai Inc. Medical writing assistance was provided by Samantha Forster, PhD, CMPP, of ProScribe, part of the Envision Pharma Group. Envision Pharma’s services complied with international guidelines for Good Publication Practice (GPP3). Patricia Murphy is a former employee of Eisai Inc. Dinesh Kumar and Margaret. The authors contributed to this paper as follows: Patricia Murphy, as Study Director, had full access to all study data and takes responsibility for all aspects of the study, including the integrity of the data and the accuracy of the data analysis. Patricia Murphy and Margaret Moline supervised the study. Patricia Murphy, Margaret Moline, Gary Zammit, and Russell Rosenberg were involved in the study concept and design. All authors were involved in the analysis and interpretation of data, the drafting of the manuscript, and in critical revision of the manuscript for important intellectual content. Dinesh Kumar conducted the statistical analysis; Patricia Murphy and Margaret Moline obtained funding. All authors have seen and approved the final manuscript. Moline are current employees of Eisai Inc. Gary Zammit is an employee and shareholder of Clinilabs Drug Development Corporation; has ownership interest in the Sleep Disorders Institute and Home Sleep and Respiratory Care; has served as a consultant for Eisai Inc., Janssen Pharmaceutical, Purdue, and Takeda; and has served on the speakers bureau for Merck. Russell Rosenberg has received grant/research support from Actelion Pharmaceuticals, Eisai Inc., Flamel Pharmaceuticals, Jazz Pharmaceuticals, Merck, and Philips Respironics.

© 2020 American Academy of Sleep Medicine.

Figures

Figure 1. Study design.

aAt screening visit 1, participants received a sleep diary, in which they provided information about the timing, quantity, and quality of the previous night’s sleep. Participants completed the sleep diary for at least 7 consecutive mornings within the first hour after morning waketime to confirm that the participant was a good sleeper without insomnia. At screening visit 2, an 8-hour PSG was performed at the participant’s mean habitual baseline to screen for symptoms of sleep apnea and/or periodic limb movement disorder. Participants were also introduced to the computerized CPAB for familiarization purposes. bBaseline assessments: 8-hour PSG with auditory awakening threshold, postural stability and CPAB at 4 hours postbedtime and postural stability and CPAB at 8 hours post bedtime. CPAB = cognitive performance test battery, PSG = polysomnography.

Figure 2. Change from baseline body sway.

Change from baseline body sway (A) in the middle of the night and (B) upon morning awakening. *P ≤ .0001, †P < .05, ‡P ≤ .001 vs placebo; §P ≤ .0001 vs zolpidem based on mixed-effect model repeated measurement analysis with treatment, sequence, period, baseline (time-matched), time (hours postdose), treatment × time, and baseline × time as fixed effects, and time with participant as a random effect and a repeated effect for time, with participant within sequence. aA unit of body sway is defined as 1/3 degree angle of arc movement of the ataxiameter. ER = extended release, LS = least squares, SE = standard error.

Figure 3. Percentage of participants in N2, other sleep stages, already awake, or not awakened by maximum decibel tone (awakened by technician).

AAT = auditory awakening threshold, ER = extended release, LS = least squares, N1/N2/N3 = nonrapid eye movement stage 1/2/3, REM = rapid eye movement, SE = standard error.

Figure 4. Return to sleep latency.

n = 51 for all groups owing to technical difficulties with polysomnography in 4 participants and 1 participant never awakened during the night in 1 treatment condition. *P ≤ .0001 vs. placebo; †P < .05 vs zolpidem based on an unstructured covariance matrix; model adjusted for treatment, sequence, and period as fixed effects, and a repeated effect of participant within sequence. ER = extended release, LS = least squares, SE = standard error.