Effects of Eszopiclone and Lemborexant in People With OSA With a Low Arousal Threshold Who Have Difficulty Sleeping

Summary

Insomnia and obstructive sleep apnoea (OSA) are very common conditions, collectively estimated to affect 2 billion people globally, and share many of the same symptoms. It is also common for people to have both insomnia and sleep apnoea (COMISA). Indeed, 30 to 40% of patients with chronic insomnia also fulfil the diagnostic criteria for OSA. These people can be particularly challenging to treat with conventional therapy approaches. People get OSA for different reasons. One key cause is waking up too easily to minor airway narrowing episodes (a low arousal threshold). Accordingly, this study aims to increase the arousal threshold using a combination approach with a GABAergic and an orexin agent in appropriately selected individuals (i.e., the clinically relevant group of people with OSA with a low arousal threshold and difficulty maintain or initiating sleep). Sleep, breathing and next day performance will be compared across two monitored overnight sleep studies (placebo vs the study drugs).

Timeline

Start

2025-05-01

Primary completion

2027-05-01

Completion

2027-06-30

Publications

• Background Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800.
• Background Terauchi M, Cheng JY, Yardley J, Pinner K, Moline M, Malhotra M, Inabe K, Nishida M, Pappadopulos E. Efficacy and safety of lemborexant in midlife women with insomnia disorder. Menopause. 2023 Aug 1;30(8):839-848. doi: 10.1097/GME.0000000000002209. Epub 2023 Jun 20.
• Background Xue T, Wu X, Li J, Chen S, Wang Z, Tan X, Wang Z, Zhang J. Different doses of dual orexin receptor antagonists in primary insomnia: a Bayesian network analysis. Front Pharmacol. 2023 May 16;14:1175372. doi: 10.3389/fphar.2023.1175372. eCollection 2023.
• Background Habiba U, Waseem R, Shaikh TG, Waseem S, Ahmed SH, Asghar MS. Correction to: Comparative efficacy and safety of lemborexant 5 mg versus 10 mg for the treatment of insomnia: a systematic review. Neurol Sci. 2023 May;44(5):1833. doi: 10.1007/s10072-023-06626-x. No abstract available.
• Background Habiba U, Waseem R, Shaikh TG, Waseem S, Ahmed SH, Asghar MS. Comparative efficacy and safety of lemborexant 5 mg versus 10 mg for the treatment of insomnia: a systematic review. Neurol Sci. 2023 May;44(5):1533-1541. doi: 10.1007/s10072-023-06601-6. Epub 2023 Jan 12.
• Background Cheng JY, Lorch D, Lowe AD, Uchimura N, Hall N, Shah D, Moline M. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. J Clin Sleep Med. 2024 Jan 1;20(1):57-65. doi: 10.5664/jcsm.10788.
• Background Cheng JY, Filippov G, Moline M, Zammit GK, Bsharat M, Hall N. Respiratory safety of lemborexant in healthy adult and elderly subjects with mild obstructive sleep apnea: A randomized, double-blind, placebo-controlled, crossover study. J Sleep Res. 2020 Aug;29(4):e13021. doi: 10.1111/jsr.13021. Epub 2020 Mar 18.
• Background Eckert DJ, Malhotra A, Wellman A, White DP. Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. Sleep. 2014 Apr 1;37(4):811-9. doi: 10.5665/sleep.3596.
• Background Eckert DJ, Owens RL, Kehlmann GB, Wellman A, Rahangdale S, Yim-Yeh S, White DP, Malhotra A. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond). 2011 Jun;120(12):505-14. doi: 10.1042/CS20100588.
• Background Messineo L, Eckert DJ, Lim R, Chiang A, Azarbarzin A, Carter SG, Carberry JC. Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity. J Physiol. 2020 Oct;598(20):4681-4692. doi: 10.1113/JP280173. Epub 2020 Aug 30.
• Background Messineo L, Carter SG, Taranto-Montemurro L, Chiang A, Vakulin A, Adams RJ, Carberry JC, Eckert DJ. Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial. Respirology. 2021 Sep;26(9):878-886. doi: 10.1111/resp.14110. Epub 2021 Jun 23.
• Background Carter SG, Eckert DJ. Effects of hypnotics on obstructive sleep apnea endotypes and severity: Novel insights into pathophysiology and treatment. Sleep Med Rev. 2021 Aug;58:101492. doi: 10.1016/j.smrv.2021.101492. Epub 2021 Apr 22.
• Background Carter SG, Carberry JC, Grunstein RR, Eckert DJ. Randomized Trial on the Effects of High-Dose Zopiclone on OSA Severity, Upper Airway Physiology, and Alertness. Chest. 2020 Jul;158(1):374-385. doi: 10.1016/j.chest.2020.02.057. Epub 2020 Mar 18.
• Background Carter SG, Carberry JC, Cho G, Fisher LP, Rollo CM, Stevens DJ, D'Rozario AL, McKenzie DK, Grunstein RR, Eckert DJ. Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial. Eur Respir J. 2018 Jul 19;52(1):1800149. doi: 10.1183/13993003.00149-2018. Print 2018 Jul.
• Background Carter SG, Berger MS, Carberry JC, Bilston LE, Butler JE, Tong BK, Martins RT, Fisher LP, McKenzie DK, Grunstein RR, Eckert DJ. Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea. Sleep. 2016 Apr 1;39(4):757-66. doi: 10.5665/sleep.5622.
• Background Edwards BA, Eckert DJ, McSharry DG, Sands SA, Desai A, Kehlmann G, Bakker JP, Genta PR, Owens RL, White DP, Wellman A, Malhotra A. Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2014 Dec 1;190(11):1293-300. doi: 10.1164/rccm.201404-0718OC.
• Background Eckert DJ. Phenotypic approaches to obstructive sleep apnoea - New pathways for targeted therapy. Sleep Med Rev. 2018 Feb;37:45-59. doi: 10.1016/j.smrv.2016.12.003. Epub 2016 Dec 18.
• Background Gray EL, McKenzie DK, Eckert DJ. Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype. J Clin Sleep Med. 2017 Jan 15;13(1):81-88. doi: 10.5664/jcsm.6394.
• Background Zinchuk A, Edwards BA, Jeon S, Koo BB, Concato J, Sands S, Wellman A, Yaggi HK. Prevalence, Associated Clinical Features, and Impact on Continuous Positive Airway Pressure Use of a Low Respiratory Arousal Threshold Among Male United States Veterans With Obstructive Sleep Apnea. J Clin Sleep Med. 2018 May 15;14(5):809-817. doi: 10.5664/jcsm.7112.
• Background Ghadiri M, Grunstein RR. Clinical side effects of continuous positive airway pressure in patients with obstructive sleep apnoea. Respirology. 2020 Jun;25(6):593-602. doi: 10.1111/resp.13808. Epub 2020 Mar 24.
• Background Patil SP, Ayappa IA, Caples SM, Kimoff RJ, Patel SR, Harrod CG. Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. J Clin Sleep Med. 2019 Feb 15;15(2):301-334. doi: 10.5664/jcsm.7638.
• Background Rotenberg BW, Murariu D, Pang KP. Trends in CPAP adherence over twenty years of data collection: a flattened curve. J Otolaryngol Head Neck Surg. 2016 Aug 19;45(1):43. doi: 10.1186/s40463-016-0156-0.
• Background Baillieul S, Tamisier R, Eckert DJ, Pepin JL. Current Knowledge and Perspectives for Pharmacological Treatment in OSA. Arch Bronconeumol. 2022 Oct;58(10):681-684. doi: 10.1016/j.arbres.2021.12.013. Epub 2022 Jan 6. No abstract available. English, Spanish.
• Background Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013 Oct 15;188(8):996-1004. doi: 10.1164/rccm.201303-0448OC.
• Background Thomas E, Micic G, Adams R, Eckert DJ. Pharmacological management of co-morbid obstructive sleep apnoea and insomnia. Expert Opin Pharmacother. 2023 Sep-Dec;24(18):1963-1973. doi: 10.1080/14656566.2023.2292186. Epub 2024 Jan 5.
• Background Sweetman A, Lack L, McEvoy RD, Antic NA, Smith S, Chai-Coetzer CL, Douglas J, O'Grady A, Dunn N, Robinson J, Paul D, Eckert D, Catcheside PG. Cognitive behavioural therapy for insomnia reduces sleep apnoea severity: a randomised controlled trial. ERJ Open Res. 2020 May 17;6(2):00161-2020. doi: 10.1183/23120541.00161-2020. eCollection 2020 Apr.
• Background Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, Nunez CM, Patel SR, Penzel T, Pepin JL, Peppard PE, Sinha S, Tufik S, Valentine K, Malhotra A. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019 Aug;7(8):687-698. doi: 10.1016/S2213-2600(19)30198-5. Epub 2019 Jul 9.
• Background Sweetman A, Lack L, McEvoy RD, Smith S, Eckert DJ, Osman A, Carberry JC, Wallace D, Nguyen PD, Catcheside P. Bi-directional relationships between co-morbid insomnia and sleep apnea (COMISA). Sleep Med Rev. 2021 Dec;60:101519. doi: 10.1016/j.smrv.2021.101519. Epub 2021 Jun 23.
• Background Meira E Cruz M, Kryger MH, Morin CM, Palombini L, Salles C, Gozal D. Comorbid Insomnia and Sleep Apnea: mechanisms and implications of an underrecognized and misinterpreted sleep disorder. Sleep Med. 2021 Aug;84:283-288. doi: 10.1016/j.sleep.2021.05.043. Epub 2021 Jun 8.

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