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

Flinders University

Status and phase: Not yet enrolling; Phase 2

Conditions: OSA - Obstructive Sleep Apnea

Treatments: Drug: Lemborexant 10mg; Drug: Placebo; Drug: Eszopiclone 3 mg

Study type: Interventional

Funder types: Other

Identifiers

NCT06928766

7849

1196261 (Other Grant/Funding Number)

Details and patient eligibility

About

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).

Full 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).

Enrollment: 15 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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15 participants in 2 patient groups, including a placebo group

Eszopiclone 3mg and lemborexant 10mg

Experimental group

Description:

Both Eszopiclone 3mg and Lemborexant 10mg in the form of capsules taken before bedtime. Dosages is taken on one instance for one night only.

Treatment:

Drug: Eszopiclone 3 mg

Drug: Lemborexant 10mg

Placebo

Placebo Comparator group

Description:

Placebo capsules that look exactly like the study drugs, taken before bedtime. Dosage is taken on one instance for one night only.

Treatment:

Drug: Placebo