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

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).

• Change in nadir overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in mean overnight hypoxemia (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in time below 90% blood arterial oxygen saturation (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in sleep efficiency (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in arousal index (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in respiratory control (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in the respiratory arousal threshold (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in airway collapsibility (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in pharyngeal muscle response (eszopiclone and lemborexant night vs. placebo night) [Time frame: Two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Baseline OSA endotype and whether they are associated with changes in OSA severity [Time frame: Baseline sleep study]
• Change in next morning balance (eszopiclone and lemborexant night vs. placebo night) [Time frame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]
• Change in perceived sleepiness (eszopiclone and lemborexant night vs. placebo night) [Time frame: Next morning following two non-consecutive single night sleep studies (eszopiclone and lemborexant night vs. placebo night) up to one month apart.]