The Optimal One-Month Dosing of Lemborexant for Moderate Obstructive Sleep Apnea (OSA) Patients With Low Arousal Threshold

One-Month Dosing of Lemborexant for Treatment of Moderate OSA Patients With Low Arousal Threshold, a Randomized, Double-blind, Crossover, Placebo-Controlled Trial

The goal of this clinical trial is to investigate the 1-month treatment effects of different dose of lemborexant in moderate OSA adult patients (18-65 years of age) with low arousal threshold.

The main questions it aims to answer are:

Primary outcome measure: Apnea/hypopnea index (AHI)

Secondary outcome measure:

1. Polysomnography parameters

   • Mean and nadir oxygen saturation
   • Sleep efficiency
   • Wake after sleep onset (WASO)
   • Sleep latency
   • Rapid eye movement (REM) latency
   • Percentage of time spent in Non-rapid eye movement (NREM) stage 1-3 and REM stage
   • Arousal index

2. Oxford Sleep Resistance Test (OSLER) test

3. Epworth Sleepiness Scale (ESS)

4. Functional Outcome of Sleep Questionnaire-short version (FOSQ-10T)

5. Pittsburgh Sleep Quality Index (PSQI)

6. Actigraphy parameters

   • Total sleep time
   • Sleep efficiency
   • Wake after sleep onset (WASO)
   • Sleep latency

7. Sleep diary parameters (Appendix 5)

   • Total sleep time
   • Sleep efficiency
   • Wake after sleep onset (WASO)
   • Sleep latency
   • Sleep quality

Researchers will compare placebo to see if there is a difference in AHI.

Participants will

• participate a total of 3 phases of study (3-crossover trial)
• each phrase the participants will receive either lemborexant 5 mg, lemborexant 10 mg, or placebo orally per day for 30 days with 2-week washout (depend on intervention arm whether the participants receive which intervention sequence)
• complete three overnight in-laboratory polysomnography (2-week washout) at day 30 of each phrase
• monitor actigraphy during day 1 to 29 of intervention of all periods
• record sleep diary during day 1 to 29 of intervention of all periods
• complete the OSLER test in the morning of the three overnight test
• complete questionnaires including: Epworth Sleepiness Scale (ESS), Functional Outcome of Sleep Questionnaire-short version (FOSQ-10T), Pittsburgh Sleep Quality Index (PSQI) at baseline (prior to intervention) and the night before overnight in-laboratory polysomnography

Inclusion criteria

Individuals are eligible for participation in this study if they have all of the followings:

1. Patient, aged 18 - 65 years at the time of informed consent
2. Voluntary agreement and capable for giving written informed consent
3. Diagnosis with OSA according to the criteria of the International Classification of Sleep Disorders, version 3 Text Revision
4. Baseline screening polysomnography (PSG) demonstrated apnea-hypopnea index 15 - 30 events/h of sleep (moderate severity)
5. Patients identified as low arousal threshold using previously recommended criteria which allocated a score of 1 to each criterion: apnea-hypopnea index < 30 events per hour, nadir oxygen saturation as measured by pulse oximetry > 82.5%, and fraction of hypopneas > 58.3%. A score of 2 or above defined a low arousal threshold.
6. Peripheral capillary oxygen saturation (SpO2) ≥ 94% measured during screening visit
7. Habitually sleeping ≥ 5.5 hours/night with usual bedtime falls within the range of 9:00 PM to 1:00 AM
8. Body mass index 18 - 40 kg/m2 Exclusion criteria

Individuals were not eligible for participation in this study if they have any of the followings:

1. Previous allergy or adverse effects with Lemborexant or other sedatives
2. Pregnant or breastfeeding
3. Significant medical comorbidities that could affect individual safety and study assessment results, regarding investigators' opinion
4. Uncontrolled cardiovascular or cerebrovascular diseases
5. Neuromuscular diseases
6. Nasal anatomical defect
7. Significant psychiatric comorbidities that could affect individual safety and study assessment results, regarding investigators' opinion
8. Active respiratory disorders other than OSA
9. Central respiratory events (CAHI) >25% of the total AHI
10. Diagnosis/symptoms of sleep-related disease other than OSA including narcolepsy, restless legs syndrome, periodic limb movement disorder, or circadian rhythm sleep-wake disorder
11. Severe hypersomnolence (ESS ≥16)
12. Peripheral capillary oxygen saturation (SpO2) < 80% for ≥ 5% of total sleep time measured during screening visit
13. Driving-related sleepiness accident or near misses in the past 12 months
14. Safety-critical occupation
15. Using CPAP or other dental devices within 2 weeks of screening polysomnography until the end of the study
16. Unable to tolerate equipment in this study
17. Taking any medication that affects sleep or other variable measured in this study
18. Taking any medication with cytochrome P450 Family 3A (CYP3A) inhibitors and all CYP3A inducers
19. Drug or alcohol use disorder within 2 years before the study initiation or current excessive alcohol intake
20. Excessive caffeine intake