Affect of Melatonin on Sleep and Cognition in Cirrhosis

Study Objectives

This project aims to determine the impact of melatonin supplementation on sleep physiology in patients with cirrhosis and HE.

Hypothesis: Melatonin supplementation will improve sleep physiology, and REM specifically.

Background and Significance

Hepatic encephalopathy (HE) affects approximately 50% of patients with cirrhosis, causing lasting cognitive and quality of-life impairments even with therapy. Most HE cases are covert, significantly increasing risks of hospitalization, mortality, and progression to overt HE (OHE) within three years (\>50%). Guidelines recommend screening all patients for covert HE (CHE) using neurocognitive tools such as the Psychomotor Hepatic Encephalopathy Score (PHES). However, low screening and treatment rates persist due to the need for specialized training, equipment, and significant time commitments. Even in patients receiving HE therapy, clinicians are hesitant to escalate treatment absent overt confusion, largely due to the cost and poor tolerability of rifaximin and lactulose. These limitations contribute to frequent hospital readmissions and high short-term mortality in those with prior OHE. Improved recognition and management strategies are critical to advancing HE outcomes.

Sleep changes in HE are frequently described, often as disturbances in the sleep-wake cycle. The pathophysiology is likely multifactorial, including adenosine mediated hyperammonemic effects on arousal and alterations in endogenous melatonin metabolism in cirrhosis with resultant circadian rhythm dysfunction. Prior research confirms that patients with CHE likewise suffer from suboptimal sleep with associated quality of life reduction, and our research and others have noted reduced REM sleep, and increased sleep fragmentation. There may also be a bi-directional relationship between sleep decline and cognitive impairment in progressive OHE. Traditional gold-standard assessment of sleep physiology utilizes polysomnography (PSG), which requires on-site monitoring, application of multiple cumbersome leads, and costs up to $2000 for a night's study, making it impractical for routine assessment of disturbed sleep in cirrhosis. Consumer wearables have drastically increased in popularity for personal sleep assessment. Their ease of use, affordability, and promising performance in validation studies with PSG make them an attractive target for research. Utilization of wearables in cirrhosis may make sleep a more approachable target for monitoring in CHE. Melatonin is an endogenous pineal hormone with a known role in circadian maintenance with reduced hepatic metabolism and higher baseline serum levels in cirrhosis, perhaps contributing to circadian dysfunction. Prior research suggests that supplementing melatonin in patients with REM sleep disorders, poor subjective sleep, and cirrhosis improves subjective or objective sleep and wellbeing, but have never assessed the impact on cognitive function or CHE. Data suggests melatonin can improve REM sleep duration, sleep latency, and sleep disturbances, while being safe and affordable with high tolerability, but objective data is lacking in cirrhosis and large-scale randomized trials have not been done to date.

Overall Design

This study is a pilot randomized double-blinded, crossover study of melatonin. This design allows participants to serve as their own controls, reducing sample size needed, minimizing inter-individual sleep variability and permitting 1:1 randomization, provided proper washout and analysis for period effect, addressed below. Randomization will be performed in Stata, with a single unblinded coordinator. Each participant will have a 2-week run in for baseline home sleep assessment, 4 weeks on 3 mg nightly melatonin or 100 mg thiamine, a 1-week washout, and a 4-week period on the alternate therapy for a total of 11 weeks in the study. The washout period was chosen from previously published washouts of melatonin. Thiamine was chosen to approximate placebo due to its identical taste/appearance, affordability and lack of hepatotoxicity. After a two-week lead in, the investigational pharmacy will give participants an identical 30-day supply of either 3 mg melatonin tablets or 100 mg thiamine tablets who will be instructed to take it nightly 30-60 min before intended bedtime. A MEDLINE search does not identify any published reports of thiamine impacting melatonin secretion, sleep physiology or sleep quality. Both melatonin and thiamine are dietary supplements and do not require an investigational new drug application (IND) for assessment of sleep physiologic effects. After the first sleep study is completed the bottle will be collected and the alternative therapy will be given, with instructions to start after a one-week washout. Sleep will be tracked throughout the entire study period via the Oura ring.

• Mean change in total sleep time measured by polysomnography [Срок оценки: Approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment.]
• Mean change in deep sleep time measured by polysomnography [Срок оценки: Approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment]
• Mean change in percentage sleep efficiency measured by polysomnography [Срок оценки: approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment]
• Mean change in wake after sleep onset (WASO) measured by polysomnography [Срок оценки: approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment]
• Mean change in resting and mean heart rate during sleep measured by polysomnography [Срок оценки: approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment]
• Mean change in total sleep time measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Mean change in rapid eye movement (REM) sleep as a percentage of total sleep measured by Oura 3.0 ring after melatonin vs thiamine [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Mean change in deep sleep time measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Mean change in percentage sleep efficiency measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Mean change in average and resting heart rate during sleep measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Mean change in sleep midpoint as measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]
• Variation in sleep midpoint as measured by Oura 3.0 [Срок оценки: Entire duration of study period (visit 1-3). Approximately week 0-9]