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

Phase 2

Not yet recruiting

• Conditions: OSA - Obstructive Sleep Apnea
• Interventions: Drug: Eszopiclone 3 mg; Drug: Placebo; Drug: Lemborexant 10mg

• Registration Number: NCT06928766
• Lead Sponsor: Flinders University

Brief 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).

Detailed Description

Background:

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.

OSA is characterised by repeated narrowing and closure of the upper airway during sleep, desaturation in oxygen levels, and fragmented sleep. OSA is a heterogeneous disease, with anatomical crowding of the upper airway and at least three distinct non-anatomical endotypes. The non-anatomical OSA endotypes include high loop gain (unstable control of breathing), poor upper airway dilator muscle function, and a low arousal threshold (ArTH- waking up too easily to minor airway narrowing events). Each OSA endotype represents a novel therapeutic target. Adding to the complexity of OSA, more than one endotype can contribute to a person's OSA. While the first line treatment for OSA, continuous positive airway pressure (CPAP) is efficacious, long-term compliance is only 40 to 70%. Those with a low ArTH endotype have markedly lower CPAP uptake and compliance.

Indeed, people with a low ArTH endotype experience frequent cortical arousals (awakenings) leading to fragmented and non-restorative sleep. Frequent cortical arousals prevent transitioning into deeper sleep states that are characterised by more stable breathing. Thus, strategies to increase the arousal threshold to stabilise breathing and reduce OSA severity in people who wake up easily (low ArTH) have been investigated as a novel therapeutic target. For example, commonly used hypnotic agents such as eszopiclone and trazodone can increase the arousal threshold and reduce OSA severity in people with a low ArTH. More recently, we have shown that 50mg quetiapine also improves sleep and reduces OSA severity in people with OSA who report difficulty maintaining sleep. However, the extent to which common hypnotic agents increase the arousal threshold in people with OSA is modest at best (\~20%). This limits the therapeutic efficacy for people with OSA.

Orexin has been identified as an important sleep wake modulator. Accordingly, new orexin antagonists have been developed as novel sleep promotion aids for the treatment of insomnia. For example, the orexin antagonist, Lemborexant, has been shown to be safe and efficacious for the treatment of insomnia including in the elderly and people with OSA.

Given that current monotherapy approaches to increase the arousal threshold in people with OSA have only modestly increased the threshold for arousal with correspondingly modest reductions in OSA severity, there is a need to investigate the potential role for combination hypnotic therapy. Accordingly, this study aims to target two key sleep/wake mechanisms (the GABAergic and orexin systems) to determine if this combination approach yields greater therapeutic benefit than previous attempts with monotherapy in appropriately selected individuals (i.e., the clinically relevant group of people with OSA with a low ArTH and difficulty maintain or initiating sleep).

Study Timeline

• Status Verified: 2025-04
• Study First Submitted: 2025-04-07
• Study First Submitted QC: 2025-04-07
• Study First Posted: 2025-04-15
• Last Update Submitted: 2025-04-15
• Last Update Posted: 2025-04-18
• Study Start: 2025-05-01
• Primary Completion: 2027-05-01
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Moderate or more difficulty "staying or initiating asleep" score on the Insomnia Severity Index questionnaire
• Obstructive Sleep Apnoea (OSA), Apnoea Hypopnea Index ≥ 10 events/hour
• Low arousal respiratory threshold OSA endotype
• BMI ≤35 kg/m2

Exclusion Criteria

• Concomitant medications that interact or are contraindicated with eszopiclone, zopiclone, and Lemborexant
• Concomitant medications known to influence breathing, sleep, arousal, or muscle physiology
• Current pregnancy or breast-feeding
• Current or recent other medical conditions likely to affect results or safety

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Eszopiclone 3mg and lemborexant 10mg	Eszopiclone 3 mg	Both Eszopiclone 3mg and Lemborexant 10mg in the form of capsules taken before bedtime. Dosages is taken on one instance for one night only.
Eszopiclone 3mg and lemborexant 10mg	Lemborexant 10mg	Both Eszopiclone 3mg and Lemborexant 10mg in the form of capsules taken before bedtime. Dosages is taken on one instance for one night only.
Placebo	Placebo	Placebo capsules that look exactly like the study drugs, taken before bedtime. Dosage is taken on one instance for one night only.

Primary Outcome Measures

Name	Time	Method
Change in OSA severity (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	OSA severity as measured by the apnoea hypopnea index (units: number of respiratory events/h sleep) during overnight in-laboratory polysomnography.

Secondary Outcome Measures

Name	Time	Method
Change in nadir overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Nadir overnight oxygen saturation during sleep (units: %) measured via pulse oximetry during overnight in-laboratory polysomnography.
Change in mean overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Mean overnight oxygen saturation during sleep (units: %) measured via pulse oximetry during overnight in-laboratory polysomnography.
Change in time below 90% blood arterial oxygen saturation (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Percent time asleep spent below an arterial oxygen saturation of 90% measured via pulse oximetry during overnight in-laboratory polysomnography.
Change in sleep efficiency (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Percent time spent asleep divided by the recording time from lights out to lights on during overnight in-laboratory polysomnography
Change in arousal index (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Number of cortical arousals per hour of sleep during overnight in-laboratory polysomnography.
Change in respiratory control (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Loop gain and the ventilatory response to arousal (units: % eupnea) during overnight in-laboratory polysomnography.
Change in the respiratory arousal threshold (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Threshold to arousal (units: % eupnea) during overnight in-laboratory polysomnography.
Change in airway collapsibility (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Vpassive (units: % eupnea) during overnight in-laboratory polysomnography.
Change in pharyngeal muscle response (eszopiclone and lemborexant night vs. placebo night)	Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Vcompensation (units: % eupnea) during overnight in-laboratory polysomnography.
Baseline OSA endotype and whether they are associated with changes in OSA severity	Baseline sleep study	Exploratory analysis to determine if baseline OSA endotypes as defined above (outcomes 7-10) are associated with changes in OSA severity as measured via the AHI- outcome 1 (eszopiclone and lemborexant night vs. placebo night)
Change in next morning balance (eszopiclone and lemborexant night vs. placebo night)	Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Stand on AMTI AccuSway Balance Board, eyes open and eyes closed 1 minute each. To evaluate balance in the next morning after eszopiclone and lemborexant night vs. placebo night (units: distance from center in cm)
Change in perceived sleepiness (eszopiclone and lemborexant night vs. placebo night)	Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Next day perceived sleepiness assessed via the Karolinska Sleepiness Scale (10 point scale where 1=extremely alert and 10=extremely sleepy)
Change in driving simulator performance (eszopiclone and lemborexant night vs. placebo night)	Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Next day alertness as measured via the Australian-developed (AusEd) driving simulator performance task (units: SD of steering deviation from median line).
Change in psycho-motor vigilance (eszopiclone and lemborexant night vs. placebo night)	Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.	Next day alertness as measured via the psychomotor vigilance test (PVT) (units m/s) higher values indicate worse performance.

Trial Locations

Locations (1)

Flinders University, Adelaide Institute for Sleep Health; 🇦🇺 Bedford Park, South Australia, Australia