Daridorexant for Sleep Disturbance in Adults With Liver Cirrhosis

• Daridorexant (Drug): Daridorexant tablets administered orally once nightly for 30 days at a dose of 25 mg or 50 mg according to liver function and the study protocol. The maximum dose for participants with Child-Pugh class B liver function is 25 mg per night.
• Placebo (Drug): Matching placebo administered orally once daily for 30 days.

Primary outcomes

• Percent Improvement From Baseline in Sleep Efficiency at Day 30 [Baseline and Day 30]: Sleep efficiency (SE) is measured by overnight polysomnography (PSG) and expressed as the percentage of time in bed spent asleep. PSG is performed at baseline and on Days 7, 14, and 30. The primary outcome is the relative percent change in SE from baseline to Day 30.

Secondary outcomes

• Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Total Score at Day 30 [Baseline and Day 30]: The Pittsburgh Sleep Quality Index (PSQI) total score ranges from 0 to 21, with higher scores indicating poorer sleep quality. The outcome is the change in the PSQI total score from baseline to Day 30.
• Change From Baseline in Polysomnography-Measured Sleep Latency at Day 30 [Baseline and Day 30]: Sleep latency is measured by overnight polysomnography (PSG), in minutes, from lights out to sleep onset. PSG is performed at baseline and on Days 7, 14, and 30. This outcome is calculated as Day 30 sleep latency minus baseline sleep latency; negative values indicate a shorter time to fall asleep.
• Change From Baseline in Total Sleep Time at Day 30 [Baseline and Day 30]: Total sleep time is the total duration of sleep recorded during overnight polysomnography (PSG), expressed in minutes. PSG is performed at baseline and on Days 7, 14, and 30. This outcome is calculated as Day 30 total sleep time minus baseline total sleep time; positive values indicate a longer sleep duration.
• Change From Baseline in Slow-Wave Sleep Percentage at Day 30 [Baseline and Day 30]: Slow-wave sleep (SWS) is defined as stage N3 sleep measured by overnight polysomnography (PSG). SWS percentage is calculated as N3 sleep time divided by total sleep time, multiplied by 100. PSG is performed at baseline and on Days 7, 14, and 30. This outcome is the Day 30 SWS percentage minus the baseline SWS percentage, expressed in percentage points.
• Change From Baseline in Rapid Eye Movement Sleep Percentage at Day 30 [Baseline and Day 30]: Rapid eye movement (REM) sleep is measured by overnight polysomnography (PSG). REM sleep percentage is calculated as REM sleep time divided by total sleep time, multiplied by 100. PSG is performed at baseline and on Days 7, 14, and 30. This outcome is the Day 30 REM sleep percentage minus the baseline REM sleep percentage, expressed in percentage points.
• Change From Baseline in Microarousal Frequency at Day 30 [Baseline and Day 30]
• Change From Baseline in Psychometric Hepatic Encephalopathy Score During Treatment [Baseline, Day 7, Day 14, and Day 30]: The Psychometric Hepatic Encephalopathy Score (PHES) ranges from -15 to +5, with higher scores indicating better cognitive performance. The outcome is the change in PHES during the study.
• Change From Baseline in Stroop EncephalApp Performance at Day 30 [Baseline and Day 30]
• Change From Baseline in Epworth Sleepiness Scale Total Score at Day 30 [Baseline and Day 30]
• Proportion of Participants With Reversal of Minimal Hepatic Encephalopathy by Day 30 [Baseline through Day 30]
• Proportion of Participants With New-Onset Minimal Hepatic Encephalopathy Through Day 30 [Baseline through Day 30]
• Incidence of Overt Hepatic Encephalopathy by Day 30 [From baseline through Day 30]
• Proportion of Participants With Adverse Events [From treatment initiation through Day 30]
• Proportion of Participants With Serious Adverse Events [From treatment initiation through Day 30]
• Proportion of Participants Discontinuing Study Treatment Due to Adverse Events [From treatment initiation through Day 30]

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

1. Age 18-60 years.
2. Confirmed liver cirrhosis based on imaging, pathology, or clinical diagnosis.
3. Child-Pugh class A or B liver function; participants with hepatic encephalopathy must have covert hepatic encephalopathy (minimal hepatic encephalopathy \[MHE\]) or West-Haven grade I hepatic encephalopathy.
4. Insomnia supported by both subjective and objective evidence, including a Pittsburgh Sleep Quality Index (PSQI) total score >5 and objective polysomnography (PSG) or actigraphy findings.
5. Provision of written informed consent.

Exclusion Criteria:

1. Age <18 years or >60 years.
2. Child-Pugh class C liver function.
3. Overt hepatic encephalopathy of West-Haven grade II or higher.
4. Concomitant use of strong CYP3A4 inhibitors, such as itraconazole or ketoconazole, or strong CYP3A4 inducers, such as carbamazepine or rifampin.
5. Severe respiratory insufficiency or uncontrolled severe obstructive sleep apnea.
6. Pregnancy or breastfeeding.
7. Narcolepsy.
8. Known hypersensitivity to daridorexant or any of its excipients.
9. Concomitant use of central nervous system depressants, including alcohol, benzodiazepines, or opioids, that may increase sedation or somnolence.
10. Active severe psychiatric disorders, such as depression with suicidal ideation or a history of suicidal ideation, or a history of substance abuse.
11. Any contraindication to daridorexant.