Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder
Abstract
Objective
To assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO).
Methods
Elderly (≥65 years) participants (n = 58) with insomnia were randomly allocated (Latin square design) to receive 5 treatments (5, 10, 25, and 50 mg daridorexant and placebo) during 5 treatment periods, each consisting of 2 treatment nights followed by a 5- to 12-day washout period. Main efficacy endpoints were the absolute change from baseline in WASO (primary) and latency to persistent sleep (LPS; secondary) to days 1 and 2 (mean of 2 treatment nights assessed by polysomnography) in each period. Safety and tolerability were also assessed.
Results
Of 58 participants included, 67% were female, and the median age was 69 years (range 65–85 years). WASO and LPS were dose-dependently reduced from baseline to days 1 and 2 after daridorexant administration (multiple comparison procedure modeling, p < 0.0001 and p = 0.004, respectively); reductions were statistically significant for doses ≥10 mg compared with placebo (WASO: −32.0, −45.1, −61.4 minutes; LPS: −44.9, −43.8, −45.4 minutes for 10, 25, and 50 mg, respectively, p ≤ 0.025). Treatment-emergent adverse events were similar for daridorexant and placebo; the most frequent were fatigue, nasopharyngitis, gait disturbance, and headache (≤7% in any group).
Conclusions
Daridorexant was well tolerated. Dose-dependent improvements in WASO and LPS were statistically significant (dose range 10–50 mg) in elderly people with insomnia disorder.
ClinicalTrials.gov identifier:
NCT02841709.
Classification of evidence
This study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.
Get full access to this article
View all available purchase options and get full access to this article.
References
1.
Dam TT, Ewing S, Ancoli-Israel S, et al. Association between sleep and physical function in older men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2008;56:1665–1673.
2.
Blackwell T, Yaffe K, Ancoli-Israel S, et al. Poor sleep is associated with impaired cognitive function in older women: the Study of Osteoporotic Fractures. J Gerontol Ser A Biol Sci Med Sci 2006;61:405–410.
3.
Stone KL, Blackwell TL, Ancoli-Israel S, et al. Sleep disturbances and risk of falls in older community-dwelling men: the Outcomes of Sleep Disorders in Older Men (MrOS sleep) study. J Am Geriatr Soc 2014;62:299–305.
4.
Spira AP, Covinsky K, Rebok GW, Stone KL, Redline S, Yaffe K. Objectively measured sleep quality and nursing home placement in older women. J Am Geriatr Soc 2012;60:1237–1243.
5.
Jaussent I, Bouyer J, Ancelin ML, et al. Insomnia and daytime sleepiness are risk factors for depressive symptoms in the elderly. Sleep 2011;34:1103–1110.
6.
Nakazaki C, Noda A, Koike Y, Yamada S, Murohara T, Ozaki N. Association of insomnia and short sleep duration with atherosclerosis risk in the elderly. Am J Hypertens 2012;25:1149–1155.
7.
Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep 2007;30:213–218.
8.
Brandt J, Leong C. Benzodiazepines and Z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D 2017;17:493–507.
9.
Abad VC, Guilleminault C. Insomnia in elderly patients: recommendations for pharmacological management. Drugs Aging 2018;35:791–817.
10.
Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017;13:307–349.
11.
Schroeck JL, Ford J, Conway EL, et al. Review of safety and efficacy of sleep medicines in older adults. Clin Ther 2016;38:2340–2372.
12.
Chow M, Cao M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep 2016;8:81–86.
13.
Muehlan C, Heuberger J, Juif PE, Croft M, van Gerven J, Dingemanse J. Accelerated development of the dual orexin receptor antagonist ACT-541468: integration of a microtracer in a first-in-human study. Clin Pharmacol Ther 2018;104:1022–1029.
14.
Treiber A, de Kanter R, Roch C, et al. The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468. J Pharmacol Exp Ther 2017;362:489–503.
15.
Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J. 0007 Multiple-ascending-dose study of ACT-541468, a novel dual orexin receptor antagonist: characterization of its multiple-dose pharmacokinetics, pharmacodynamics, safety, and tolerability. Sleep 2018;41:A3.
16.
Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J. 0008 Night-time administration of ACT-541468, a novel dual orexin receptor antagonist: characterization of its pharmacokinetics, next-day residual effects, safety, and tolerability. Sleep 2018;41:A3.
17.
Muehlan C, Zuiker R, Brooks S, Gerven JV, Dingemanse J. 0377 Clinical pharmacology of the dual orexin receptor antagonist act-541468 in elderly subjects. Sleep 2019;42:A153.
18.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington: American Psychiatric Association; 2013.
19.
Morin CM, Belleville G, Belanger L, Ivers H. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep 2011;34:601–608.
20.
Hindmarch I. Psychomotor function and psychoactive drugs. Br J Clin Pharmacol 1980;10:189–209.
21.
McLeod DR, Griffiths RR, Bigelow GE, Yingling J. An automated version of the Digit Symbol Substitution Test (DSST). Behav Res Methods Instrumentation 1982;14:463–466.
22.
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol 1996;11(suppl 3):89–95.
23.
Akerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J Neurosci 1990;52:29–37.
24.
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies combining multiple comparisons and modeling procedures. J Biopharm Stat 2006;16:639–656.
25.
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics 2005;61:738–748.
26.
Berry RB, Brooks R, Gamaldo CE, et al. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, Version 2.2. Darien: American Academy of Sleep Medicine; 2015.
27.
Cooke JR, Ancoli-Israel S. Normal and abnormal sleep in the elderly. Handb Clin Neurol 2011;98:653–665.
28.
Mander BA, Winer JR, Walker MP. Sleep and human aging. Neuron 2017;94:19–36.
29.
Winkler A, Rief W. Effect of placebo conditions on polysomnographic parameters in primary insomnia: a meta-analysis. Sleep 2015;38:925–931.
30.
Bianchi MT, Williams KL, McKinney S, Ellenbogen JM. The subjective-objective mismatch in sleep perception among those with insomnia and sleep apnea. J Sleep Res 2013;22:557–568.
31.
Herring WJ, Connor KM, Snyder E, et al. Suvorexant in elderly patients with insomnia: pooled analyses of data from phase III randomized controlled clinical trials. Am J Geriatr Psychiatry 2017;25:791–802.
32.
Stone KL, Ensrud KE, Ancoli-Israel S. Sleep, insomnia and falls in elderly patients. Sleep Med 2008;9(suppl 1):S18–S22.
33.
Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53:955–962.
34.
Dauvilliers Y. Insomnia in patients with neurodegenerative conditions. Sleep Med 2007;8(suppl 4):S27–S34.
35.
Mayer G, Jennum P, Riemann D, Dauvilliers Y. Insomnia in central neurologic diseases: occurrence and management. Sleep Med Rev 2011;15:369–378.
36.
Dauvilliers Y, Zammit G, Fietze I, et al. Daridorexant, a New Dual Orexin Receptor Antagonist to Treat Insomnia Disorder. Ann Neurol 2020;87:347–356.
Information & Authors
Information
Published In
Copyright
© 2020 American Academy of Neurology.
Publication History
Received: July 8, 2019
Accepted: January 28, 2020
Published online: April 27, 2020
Published in print: May 26, 2020
Disclosure
G. Zammit is an employee of Clinilabs, a company that has received grants from Idorsia Pharmaceuticals Ltd and other biomedical companies. Y. Dauvilliers reports board membership, consultancy, and lecture activity with UCB Pharma, Jazz, Idorsia, Takeda, Harmony Biosciences, and Bioprojet. S. Pain and D. Sebök Kinter are current employees of Idorsia Pharmaceuticals Ltd and were employees of Actelion Pharmaceuticals Ltd at the time of conduct of the study. Y. Mansour is a current employee of Idorsia Pharmaceuticals Ltd. D. Kunz reports consultancy for Actelion and Idorsia, a grant from German Ministry of Research, and ownership of Intellux GmbH. Go to Neurology.org/N for full disclosures.
Study Funding
This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.
Authors
Metrics & Citations
Metrics
Citation information is sourced from Crossref Cited-by service.
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Nighttime safety of daridorexant: Evaluation of responsiveness to an external noise stimulus, postural stability, walking, and cognitive function, Journal of Psychopharmacology, (2024).https://doi.org/10.1177/02698811241293997
- Treatment of Insomnia, The American Psychiatric Association Publishing Textbook of Psychopharmacology, (2024).https://doi.org/10.1176/appi.books.9781615375523.as58
- Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease, Annual Review of Pharmacology and Toxicology, 64, 1, (359-386), (2024).https://doi.org/10.1146/annurev-pharmtox-040323-031929
- Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: Results from phase 1 and 2 studies, Journal of Sleep Research, 34, 1, (2024).https://doi.org/10.1111/jsr.14302
- Effect of daridorexant on sleep architecture in patients with chronic insomnia disorder: a pooled post hoc analysis of two randomized phase 3 clinical studies, SLEEP, 47, 11, (2024).https://doi.org/10.1093/sleep/zsae098
- DARIDOREXANT, Prescriber's Guide, (207-210), (2024).https://doi.org/10.1017/9781009464772.033
- Daridorexant in Japanese patients with insomnia disorder: A phase 3, randomized, double-blind, placebo-controlled study, Sleep Medicine, 122, (27-34), (2024).https://doi.org/10.1016/j.sleep.2024.07.037
- Dose-response of daridorexant in insomnia disorder: An analysis of Phase 2 and 3 studies, Sleep Medicine, 121, (315-325), (2024).https://doi.org/10.1016/j.sleep.2024.07.019
- Clinical safety of daridorexant in insomnia treatment: Analysis of FDA adverse event reports, Journal of Affective Disorders, 362, (552-559), (2024).https://doi.org/10.1016/j.jad.2024.07.034
- Bioactive compounds from Ocimum tenuiflorum and Poria cocos: A novel natural Compound for insomnia treatment based on A computational approach, Computers in Biology and Medicine, 175, (108491), (2024).https://doi.org/10.1016/j.compbiomed.2024.108491
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.