Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial

Abstract

Introduction: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia.

Methods: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4.

Results: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients.

Discussion: Suvorexant improved TST in patients with probable AD dementia and insomnia.

Trial registration: ClinicalTrials.gov NCT02750306.

Keywords: Alzheimer's disease; insomnia; randomized clinical trial; suvorexant.

Conflict of interest statement

W.J.H., P.C., E.S., K.B., J.H., J.S., C.L., and D.M. are current or former employees of Merck Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and they own or owned stock options in Merck & Co., Inc., Kenilworth, NJ, USA. D.B. has acted as a consultant for Merck & Co., Inc. (Kenilworth, NJ USA), Jazz, Eisai, and Ferring.

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.

Figures

Figure 1

Trial design. Polysomnography (PSG) was recorded overnight (8‐hours duration) in a sleep laboratory. The Mini‐Mental State Exam and Digit Symbol test were administered the morning after PSG recording nights. The patient's partner completed an e‐diary of the patient's sleep each morning throughout the treatment period, and the Sleep Disorders Inventory weekly in the e‐diary starting at visit 4. Partners rated their own sleep using the single‐item Sleep Quality Scale at visits 4, 5, and 6. The Neuropsychiatric Inventory was completed by an interview with the partner and scored by a qualified trained rater at visits 4 and 6. Clinicians completed the Clinical Global Impression–Severity for insomnia at visits 4, 5, and 6

Figure 2

Patient disposition. aThere were 43 reasons for exclusion, and an individual patient could be excluded for multiple reasons. The main reasons for exclusions were the following: underlying pathology of sleep identified during the screening polysomnography (PSG) night, N = 116; Mini‐Mental State Exam outside the 12 to 26 range, N = 19; total sleep time (TST) >6.5 hours during the screening PSG night, N = 19; and mean TST over the screening and baseline PSG nights >6 hours, N = 15. bThe number of patients in the full‐analysis‐set for the primary endpoint of change from baseline in TST at week 4. In the suvorexant group, seven patients were excluded due to missing PSG data. In the placebo group, two patients were excluded due to missing PSG data and two patients were excluded due to Good Clinical Practice noncompliance issues at one site

Figure 3

Change from baseline in total sleep time (TST) and wake after persistent sleep onset (WASO) by thirds of the night (first, middle, and last) with baseline values in minutes

Figure 4

Subgroup analyses based on patient characteristics at baseline: point estimates and 95% confidence intervals for the difference between suvorexant and placebo in change from baseline in total sleep time (TST; minutes) at week 4. aRegions were North America, Europe, and Other. The confidence interval for Europe was not calculated because there were fewer than 20 participants per treatment group. Abbreviations: AHI, Apnea/Hypopnea Index (number of apneas or hypopneas per hour assessed during PSG); APOE ɛ4, apolipoprotein ɛ4 gene variant; MMSE, Mini‐Mental State Exam