Clinical trial NCT06928766: Effects of Eszopiclone and Lemborexant in People With OSA With a Low Arousal Threshold Who Have Difficulty Sleeping
Official title: Effects of Eszopiclone and Lemborexant in People With Obstructive Sleep Apnoea (OSA) With a Low Arousal Threshold Who Have Difficulty Maintaining or Falling Asleep (ELOSA): A Double-blind, Placebo-controlled, Randomised, Trial.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: OSA - Obstructive Sleep Apnea
Keywords: sleep disordered breathing
arousal
COMISA
Lead sponsor: Flinders University
Sponsor class: OTHER
First posted: 2025-04-15
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Oral capsules (Eszopiclone 3mg and lemborexant 10mg) taken together or placebo equivalent , order is randomized. After at least a week washout the opposite agent will be given.
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: Change in OSA severity (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
Secondary outcomes:
measure: Change in nadir overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in mean overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in time below 90% blood arterial oxygen saturation (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in sleep efficiency (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in arousal index (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in respiratory control (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in the respiratory arousal threshold (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in airway collapsibility (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in pharyngeal muscle response (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Baseline OSA endotype and whether they are associated with changes in OSA severity
timeFrame: Baseline sleep study
measure: Change in next morning balance (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in perceived sleepiness (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in driving simulator performance (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
measure: Change in psycho-motor vigilance (eszopiclone and lemborexant night vs. placebo night)
timeFrame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.
Other outcomes:
Locations:
city: Bedford Park
country: Australia
facility: Flinders University, Adelaide Institute for Sleep Health
state: South Australia
Study officials:
affiliation: Flinders University
name: Danny J Eckert, PhD
role: PRINCIPAL_INVESTIGATOR
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