An interventional study of Melatonin tablet 3 mg once daily and Thiamine in Hepatic Encephalopathy, Covert Hepatic Encephalopathy and Cirrhosis, sponsored by Weill Medical College of Cornell University. Recruiting at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-07-29.
Sponsored by Weill Medical College of Cornell University · Not applicable, Interventional, and Treatment
The goal of this clinical trial is to learn the affect of melatonin on sleep, cognitive function, and quality of life (QoL) in patients with cirrhosis and a complication called hepatic encephalopathy (HE). The main questions this study aims to answer are:
This is a pilot study, where participants will:
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.
225 studies on the registry are indexed under Hepatic Encephalopathy; 53 are open to participants now.
This study's planned enrollment of 18 is below the median of 60 across 154 interventional studies indexed under Hepatic Encephalopathy.
Browse Hepatic Encephalopathy studies →Weill Medical College of Cornell University is the lead sponsor of 892 studies on the registry; 165 are open to participants now.
Of its 123 completed or terminated interventional studies of FDA-regulated products, 94 (76%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Heavy current alcohol use (>7 drinks weekly for women and 14 drinks weekly for men)'
-- >40
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This group will take one month of melatonin, followed by a one week washout period, then one month of thiamine. They will have the primary outcomes assessed at each month, and will also undergo continuous sleep monitoring via a wearable tracker during all phases of the arm.
Dietary Supplement: Melatonin tablet 3 mg once daily · Dietary Supplement: Thiamine
This group will take one month of melatonin, followed by a one week washout period, then one month of thiamine. They will have the primary outcomes assessed at each month, and will also undergo continuous sleep monitoring via a wearable tracker during all phases of the arm.
Dietary Supplement: Melatonin tablet 3 mg once daily · Dietary Supplement: Thiamine
Participants will be instructed to take 3 mg regular acting (not orally dissolving) melatonin 30 minutes before their anticipated bedtime, nightly for the 30 days preceding analysis of study endpoints.
Participants will be instructed to take 100 mg regular acting (not orally dissolving) thiamine 30 minutes before their anticipated bedtime, nightly for the 30 days preceding analysis of study endpoints.
Mean change in rapid eye movement (REM) sleep as a percentage of total sleep measured by polysomnography after melatonin vs thiamine
Prior research by the investigators and other groups have suggested that patients with hepatic encephalopathy have reduced REM sleep, which is a critical sleep phase that contributes to daytime attention, cognition, and mental/emotional wellbeing. Melatonin has been noted in small studies to increase the amount of nightly REM sleep but is understudied in cirrhosis. The primary outcome of this study will be to determine whether relative to thiamine, use of melatonin increases the absolute nightly amount of REM sleep and the percentage of nightly sleep spent in REM. This outcome will be measured by polysomnography, the gold standard for sleep stage determination..
Time frame: 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 polysomnography
The mean difference in individuals in total sleep duration after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in total deep sleep duration and as a percentage of total sleep duration after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in sleep efficiency, as measured by % of total time in bed spent asleep after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in WASO, as measured by duration (min) of wake time after initial sleep onset after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in heart rate (bpm), as measured by average during a whole sleep period and lowest recorded rate after initial sleep onset after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in total sleep duration after use of melatonin or thiamine
Time frame: 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
Throughout the study, participants will also wear a wearable sleep tracker that is commercially available, the Oura 3.0 ring. This ring performs sleep staging nightly with prior studies suggesting significant agreement with polysomnography, but is inadequately validated against PSG in cirrhosis. REM as a median nightly duration and median percentage of nightly sleep will be measured and compared between each treatment arm for the full 30 day duration.
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Mean change in deep sleep time measured by Oura 3.0
The mean difference in individuals in total deep sleep duration and as a percentage of total sleep duration after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Mean change in percentage sleep efficiency measured by Oura 3.0
The mean difference in individuals in sleep efficiency, as measured by % of total time in bed spent asleep after use of melatonin or thiamine
Time frame: 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
The mean difference in individuals in heart rate (bpm), as measured by average during a whole sleep period after initial sleep onset after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Mean change in sleep midpoint as measured by Oura 3.0
The mean difference in individuals in sleep midpoint (midpoint between sleep onset and awakening) after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Variation in sleep midpoint as measured by Oura 3.0
The mean variability (standard deviation) in individuals in overnight sleep midpoint after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Variation in body temperature as measured by Oura 3.0
The mean variability (standard deviation) in individuals in overnight peripheral body temperature (degrees Celsius) after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Mean change in sleep onset time as measured by Oura 3.0
The mean difference in individuals in sleep onset after use of melatonin or thiamine
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Mean change in cognitive performance as measured by Psychometric Hepatic Encephalopathy Score (PHES)
Change in PHES as assessed prior to polysomnography after treatment with melatonin or thiamine. The Psychometric Hepatic Encephalopathy Score (PHES) is a validated, paper-and-pencil neuropsychological battery used to detect minimal or covert hepatic encephalopathy. It evaluates multiple cognitive domains including psychomotor speed, attention, visual perception, and visuomotor coordination. Each test is scored and converted to standardized z-scores based on age- and education-adjusted normative data. The total PHES score is the sum of the standardized scores from all five subtests. Total scores range from -18 to +6. A score of +6 indicates optimal cognitive performance. A score of -4 or below is commonly used as the threshold for covert (minimal) hepatic encephalopathy.
Time frame: At time of polysomnography (Approximately week 4 and week 9)
Mean difference in subjective sleep quality as measured by Pittsburgh Sleep Quality Index (PSQI)
Change in PSQI as assessed prior to polysomnography after treatment with melatonin or thiamine. The Pittsburgh Sleep Quality Index (PSQI) is a widely used, validated self-report questionnaire that assesses subjective sleep quality over the past month. There are 7 components: Subjective sleep quality. Sleep latency, Sleep duration, Habitual sleep efficiency, Sleep disturbances, Use of sleeping medication, Daytime dysfunction Each component is scored from 0 (no difficulty) to 3 (severe difficulty), and the component scores are summed to yield a global PSQI score. Total scores range from 0 to 21. A score of 0 indicates no sleep difficulty, while 21 is severe sleep difficulty A score of 5 or greater will be used as a threshold to indicate poor sleep quality.
Time frame: At time of polysomnography (Approximately week 4 and week 9)
Mean difference in health related quality of life as measured by PROMIS-29 v2.0 PROPr
Change in PROMIS-29 v2.0 PROPr as assessed prior to polysomnography after treatment with melatonin or thiamine. The PROMIS-29 v2.0 (Patient-Reported Outcomes Measurement Information System 29-item profile, version 2.0) is a standardized health-related quality of life (HRQoL) instrument developed by the NIH. It assesses 7 domains: physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain interference, plus a single pain intensity item. The PROPr (Preference-Based Scoring System for PROMIS) is a utility score derived from PROMIS domain scores using societal preference weights. It produces a single summary measure of overall health utility suitable for economic evaluations such as quality-adjusted life years (QALYs). Total scores range from -0.022 to 1.0. A score of 1.0 represents full health. A score of 0 represents a health state equivalent to death. Scores below 0 (minimum -0.022) indicate health states con
Time frame: At time of polysomnography (Approximately week 4 and week 9)
Mean change in pre-bedtime to awake salivary melatonin levels in participants after 4 weeks of treatment with melatonin or thiamine as measured at time of polysomnography
We will collect night and morning salivary melatonin levels and assess the difference between the two levels after each treatment period. The mean change in melatonin levels will be compared between the two treatment assignments.
Time frame: At time of polysomnography (Approximately week 4 and week 9)
Correlation in measurement of deep sleep determination between polysomnography and Oura 3.0 ring
Both Oura and polysomnography assess sleep phases (awake, light sleep, deep sleep and REM sleep) on an epoch (5 minutes for Oura, one minute for polysomnography) level. We will assess intraclass coefficient and generate Bland-Altman plots for agreement between Oura and polysomnography on deep sleep stage
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Correlation in measurement of light sleep determination between polysomnography and Oura 3.0 ring
Both Oura and polysomnography assess sleep phases (awake, light sleep, deep sleep and REM sleep) on an epoch (5 minutes for Oura, one minute for polysomnography) level. We will assess intraclass coefficient and generate Bland-Altman plots for agreement between Oura and polysomnography on light sleep stage
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Correlation in measurement of rapid eye movement (REM) sleep determination between polysomnography and Oura 3.0 ring
Both Oura and polysomnography assess sleep phases (awake, light sleep, deep sleep and REM sleep) on an epoch (5 minutes for Oura, one minute for polysomnography) level. We will assess intraclass coefficient and generate Bland-Altman plots for agreement between Oura and polysomnography on REM sleep stage
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Correlation in measurement of awake/sleep determination between polysomnography and Oura 3.0 ring
Both Oura and polysomnography assess sleep phases (awake, light sleep, deep sleep and REM sleep) on an epoch (5 minutes for Oura, one minute for polysomnography) level. We will assess intraclass coefficient and generate Bland-Altman plots for agreement between Oura and polysomnography on sleep vs awake.
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Correlation in measurement of heart rate between polysomnography and Oura 3.0 ring
Both Oura and polysomnography assess mean heart rate on an epoch (60 second) level. We will assess intraclass coefficient and generate Bland-Altman plots for agreement between Oura and polysomnography on heart rate measurement
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Plan to share: Yes — de-identified study data that underlie results in a publication.
Supporting information: Study protocol, Statistical analysis plan, Analytic code
Time frame: Beginning 3 months and ending 5 years following article publication
Access criteria: Researchers who provide a methodologically sound proposal, to achieve aims in the approved proposal. Proposals should be directed to apb9012@med.cornell.edu. To gain access, data requestors will need to sign a data access agreement. Data will be available for 5 years after publication at a third party website.
Started Aug 2025 (actual). Primary completion is estimated for Dec 2026, 16 months after the start.
Of 25 interventional studies with no phase under Hepatic Encephalopathy, half reached primary completion within 32 months of starting (the median), counting those still running; a quarter within 15 and three quarters within 72. This study's planned 16 months is below that.
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Studies of the drugs tested here: Melatonin · Thiamine
Weill Medical College of Cornell University →