Hepatic EncephalopathySNORE-HENCT07046429
Affect of Melatonin on Sleep and Cognition in Cirrhosis
A study testing Melatonin tablet 3 mg once daily and Thiamine in people with Hepatic Encephalopathy and Covert Hepatic Encephalopathy, run by Weill Medical College of Cornell University at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatic Encephalopathy, Covert Hepatic Encephalopathy, Cirrhosis
- What is being tested?
- Melatonin tablet 3 mg once daily and Thiamine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Aug 2025to 31 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Cirrhosis with clinically significant portal hypertension or decompensation defined by Baveno VII criteria [de Franchis R et al 2022]
- Adults over age 18
- CHE (defined by PHES≤ -4) or previously diagnosed HE
- Disturbed sleep, with Pittsburgh Sleep Quality Index (PSQI) ≥5
- Possession of a "smart phone" with Bluetooth capability and ability to download the Oura application (Apple iOS version 14.0 or greater or Android version 8.0 or higher)
Who cannot join
- Use of melatonin regularly (3x per week) if unable/unwilling to discontinue for the study
- Inability provide informed consent
- Heavy current alcohol use (>7 drinks weekly for women and 14 drinks weekly for men)'
- -- Body mass index >40
- Known prior sleep disorder including obstructive sleep apnea
- Use of other prescription neuromodulating sleep aides
- Self-reported pregnancy during study screening, as sleep physiology is different in this population
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
NewYork-Presbyterian/Weill Cornell Medical Center
New York, New York, 10021
Adam P Buckholz, MD MS, 646-962-5483, apb9012@med.cornell.edu
Cecilia Mero, cmm2002@med.cornell.edu
About this study
Official title: Effect of Supplemental Nightly Melatonin On REM and Cognition in Hepatic Encephalopathy (SNORE-HE) Trial
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:
- Does taking melatonin increase REM sleep, an important part of healthy sleep that is reduced in cirrhosis?
- Does taking melatonin improve cognitive function and reported QoL?
Read more
This is a pilot study, where participants will:
- take one month of melatonin, followed by one month of thiamine, which is another supplement but is not suspected to impact sleep significantly.
- Undergo cognitive testing and take surveys
- Wear a commercial wearable sleep tracker
- Have a formal sleep study and salivary melatonin collection at the end of taking each supplement at our sleep center Participants will be blinded, and neither they nor the researchers will know which supplement they are taking first and which they are taking second. They will also be randomized, with half starting with melatonin and the other half starting with thiamine.
Read the detailed description
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.
- Conditions
- Hepatic Encephalopathy, Covert Hepatic Encephalopathy, Cirrhosis, Sleep Disturbances and Insomnia
- Being tested
- Melatonin tablet 3 mg once daily, Thiamine
- Keywords
- cirrhosis, hepatic encephalopathy, covert hepatic encephalopathy, portal hypertension, sleep disturbances, insomnia, sleep problems, wearable technology
- Medical subject headings
- Hepatic Encephalopathy, Fibrosis, Parasomnias, Sleep Initiation and Maintenance Disorders, Hypertension, Portal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Melatonin tablet 3 mg once dailyDietary supplement
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.
ThiamineDietary supplement
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.
| Study group | Role | What they receive |
|---|---|---|
| Melatonin then Thiamine | Experimental | 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. Receives: Dietary Supplement: Melatonin tablet 3 mg once daily; Dietary Supplement: Thiamine |
| Thiamine then melatonin | Experimental | 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. Receives: Dietary Supplement: Melatonin tablet 3 mg once daily; Dietary Supplement: Thiamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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..
Measured: Approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment.
Secondary outcomes (23)
Mean change in total sleep time measured by polysomnography
The mean difference in individuals in total sleep duration after use of melatonin or thiamine
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2025
- Study start5 Aug 2025
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (31)Papers the sponsor has linked to this study.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Sleep is highly complex and individualized. Therefore, it is difficult to properly randomize participants in a small pilot study and then compare sleep physiology ex post facto. Therefore, the investigators will utilize a crossover technique to allow participants to serve as their own controls. Half of participants will be randomized to start with melatonin, and the other half with thiamine. There will be a two week lead in, and there will be a one week crossover washout period.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 18 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Collaborators
- American Association for the Study of Liver Diseases
- Responsible party
- Sponsor
- Investigators
- Adam Buckholz, MD MS, Principal investigator, NewYork-Presbyterian/Weill Cornell Medical College
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07046429
- Sponsor's protocol ID
- 25-01028397
- Other IDs
- TRA25-218891
- Acronym
- SNORE-HE
- Status last verified
- Jul 2026
- First submitted
- 23 Jun 2025
- Last updated
- 29 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: de-identified study data that underlie results in a publication.
Publications
de Zambotti M, Rosas L, Colrain IM, Baker FC. The Sleep of the Ring: Comparison of the OURA Sleep Tracker Against Polysomnography. Behav Sleep Med. 2019 Mar-Apr;17(2):124-136. doi: 10.1080/15402002.2017.1300587. Epub 2017 Mar 21.
PubMed 28323455Desai AP, Madathanapalli A, Tang Q, Orman ES, Lammert C, Patidar KR, Nephew LD, Ghabril M, Monahan PO, Chalasani N. PROMIS Profile-29 is a valid instrument with distinct advantages over legacy instruments for measuring the quality of life in chronic liver disease. Hepatology. 2023 Dec 1;78(6):1788-1799. doi: 10.1097/HEP.0000000000000480. Epub 2023 May 25.
PubMed 37222262Tapper EB, Lai JC. Time to embrace PROMIS-29 as the standard health-related quality of life instrument for patients with cirrhosis. Hepatology. 2023 Dec 1;78(6):1688-1691. doi: 10.1097/HEP.0000000000000508. Epub 2023 Jun 7. No abstract available.
PubMed 37278246Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2012 Apr;109(15):276-81. doi: 10.3238/arztebl.2012.0276. Epub 2012 Apr 13.
PubMed 22567063Enezi AAl, Al-Jahdali F, Ahmed AE, Shirbini N, Harbi AAl, Salim B, Ali YZ, Abdulrahman A, Khan M, Khaleid A, Hamdan AJ. Symptoms of Daytime Sleepiness and Sleep Apnea in Liver Cirrhosis Patients. Ann Hepatol. 2017 Jul-Aug;16(4):591-598. doi: 10.5604/01.3001.0010.0304.
PubMed 28611264de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30.
PubMed 35120736Weissenborn K. Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles. Drugs. 2019 Feb;79(Suppl 1):5-9. doi: 10.1007/s40265-018-1018-z.
PubMed 30706420Ghabril M, Jackson M, Gotur R, Weber R, Orman E, Vuppalanchi R, Chalasani N. Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1271-1278.e6. doi: 10.1016/j.cgh.2017.01.027. Epub 2017 Feb 3.
PubMed 28167158De Silva AP, Niriella MA, Ediriweera DS, De Alwis JP, Liyanage IK, Ettickan U, Liyanapathirana KV, Undugodage C, de Silva HA, de Silva HJ. Low-dose melatonin for sleep disturbances in early-stage cirrhosis: A randomized, placebo-controlled, cross-over trial. JGH Open. 2020 May 18;4(4):749-756. doi: 10.1002/jgh3.12356. eCollection 2020 Aug.
PubMed 32782966Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martin G. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003 May;28(3):191-6.
PubMed 12790159Cajochen C, Krauchi K, Mori D, Graw P, Wirz-Justice A. Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis. Am J Physiol. 1997 Apr;272(4 Pt 2):R1189-96. doi: 10.1152/ajpregu.1997.272.4.R1189.
PubMed 9140019Kunz D, Mahlberg R, Muller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. J Clin Endocrinol Metab. 2004 Jan;89(1):128-34. doi: 10.1210/jc.2002-021057.
PubMed 14715839Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY. Sleep and circadian abnormalities in patients with cirrhosis: features of delayed sleep phase syndrome? Metab Brain Dis. 2009 Sep;24(3):427-39. doi: 10.1007/s11011-009-9146-5.
PubMed 19756996Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med. 2003 Jul;4(4):281-4. doi: 10.1016/s1389-9457(03)00072-8.
PubMed 14592300Chinoy ED, Cuellar JA, Huwa KE, Jameson JT, Watson CH, Bessman SC, Hirsch DA, Cooper AD, Drummond SPA, Markwald RR. Performance of seven consumer sleep-tracking devices compared with polysomnography. Sleep. 2021 May 14;44(5):zsaa291. doi: 10.1093/sleep/zsaa291.
PubMed 33378539
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Supplemental Nightly Melatonin On REM and Cognition in Hepatic Encephalopathy (SNORE-HE) Trial
- ClinicalTrials.gov ID
- NCT07046429
- Acronym / sponsor ID
- SNORE-HE / 25-01028397
- Conditions
- Hepatic Encephalopathy, Covert Hepatic Encephalopathy, Cirrhosis, Sleep Disturbances and Insomnia
- Keywords
- cirrhosis, hepatic encephalopathy, covert hepatic encephalopathy, portal hypertension, sleep disturbances, insomnia, sleep problems, wearable technology
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 18 participants (estimated)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Collaborators
- American Association for the Study of Liver Diseases
- Study start
- 5 Aug 2025 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 1 Jul 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Does taking melatonin increase REM sleep, an important part of healthy sleep that is reduced in cirrhosis?
- Does taking melatonin improve cognitive function and reported QoL?
This is a pilot study, where participants will:
- take one month of melatonin, followed by one month of thiamine, which is another supplement but is not suspected to impact sleep significantly.
- Undergo cognitive testing and take surveys
- Wear a commercial wearable sleep tracker
- Have a formal sleep study and salivary melatonin collection at the end of taking each supplement at our sleep center Participants will be blinded, and neither they nor the researchers will know which supplement they are taking first and which they are taking second. They will also be randomized, with half starting with melatonin and the other half starting with thiamine.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Sleep is highly complex and individualized. Therefore, it is difficult to properly randomize participants in a small pilot study and then compare sleep physiology ex post facto. Therefore, the investigators will utilize a crossover technique to allow participants to serve as their own controls. Half of participants will be randomized to start with melatonin, and the other half with thiamine. There will be a two week lead in, and there will be a one week crossover washout period.
| Arm | Type | Receives |
|---|---|---|
| Melatonin then Thiamine | Experimental | Dietary Supplement: Melatonin tablet 3 mg once daily, Dietary Supplement: ThiamineThis 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. |
| Thiamine then melatonin | Experimental | Dietary Supplement: Melatonin tablet 3 mg once daily, Dietary Supplement: ThiamineThis 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Cirrhosis with clinically significant portal hypertension or decompensation defined by Baveno VII criteria [de Franchis R et al 2022]
- Adults over age 18
- CHE (defined by PHES≤ -4) or previously diagnosed HE
- Disturbed sleep, with Pittsburgh Sleep Quality Index (PSQI) ≥5
- Possession of a "smart phone" with Bluetooth capability and ability to download the Oura application (Apple iOS version 14.0 or greater or Android version 8.0 or higher)
Key exclusion criteria (7 listed)
- Use of melatonin regularly (3x per week) if unable/unwilling to discontinue for the study
- Inability provide informed consent
- Heavy current alcohol use (>7 drinks weekly for women and 14 drinks weekly for men)'
- -- Body mass index >40
- Known prior sleep disorder including obstructive sleep apnea
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Melatonin tablet 3 mg once dailyParticipants 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. | Dietary supplement | Melatonin then Thiamine, Thiamine then melatonin |
| ThiamineParticipants 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. | Dietary supplement | Melatonin then Thiamine, Thiamine then melatonin |
Primary outcome
Mean change in rapid eye movement (REM) sleep as a percentage of total sleep measured by polysomnography after melatonin vs thiamine
Time frame: Approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment.
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..
23 secondary outcomes
Mean change in total sleep time measured by polysomnography
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
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
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
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
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
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
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
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
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
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
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Variation in sleep midpoint as measured by Oura 3.0
Time frame: Entire duration of study period (visit 1-3). Approximately week 0-9
Variation in body temperature as measured by Oura 3.0
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
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)
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)
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
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
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
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
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
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
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
Time frame: Entire time of concomitant measurement with both devices (Oura/PSG), which is during each polysomnography, approximately weeks 4 and 9.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2026.
- Background: PubMed 28323455de Zambotti M, Rosas L, Colrain IM, Baker FC. The Sleep of the Ring: Comparison of the OURA Sleep Tracker Against Polysomnography. Behav Sleep Med. 2019 Mar-Apr;17(2):124-136. doi: 10.1080/15402002.2017.1300587. Epub 2017 Mar 21.
- Background: PubMed 37222262Desai AP, Madathanapalli A, Tang Q, Orman ES, Lammert C, Patidar KR, Nephew LD, Ghabril M, Monahan PO, Chalasani N. PROMIS Profile-29 is a valid instrument with distinct advantages over legacy instruments for measuring the quality of life in chronic liver disease. Hepatology. 2023 Dec 1;78(6):1788-1799. doi: 10.1097/HEP.0000000000000480. Epub 2023 May 25.
- Background: PubMed 37278246Tapper EB, Lai JC. Time to embrace PROMIS-29 as the standard health-related quality of life instrument for patients with cirrhosis. Hepatology. 2023 Dec 1;78(6):1688-1691. doi: 10.1097/HEP.0000000000000508. Epub 2023 Jun 7. No abstract available.
- Background: PubMed 22567063Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2012 Apr;109(15):276-81. doi: 10.3238/arztebl.2012.0276. Epub 2012 Apr 13.
- Background: PubMed 28611264Enezi AAl, Al-Jahdali F, Ahmed AE, Shirbini N, Harbi AAl, Salim B, Ali YZ, Abdulrahman A, Khan M, Khaleid A, Hamdan AJ. Symptoms of Daytime Sleepiness and Sleep Apnea in Liver Cirrhosis Patients. Ann Hepatol. 2017 Jul-Aug;16(4):591-598. doi: 10.5604/01.3001.0010.0304.
- Background: PubMed 35120736de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30.
- Background: PubMed 30706420Weissenborn K. Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles. Drugs. 2019 Feb;79(Suppl 1):5-9. doi: 10.1007/s40265-018-1018-z.
- Background: PubMed 28167158Ghabril M, Jackson M, Gotur R, Weber R, Orman E, Vuppalanchi R, Chalasani N. Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1271-1278.e6. doi: 10.1016/j.cgh.2017.01.027. Epub 2017 Feb 3.
- Background: PubMed 32782966De Silva AP, Niriella MA, Ediriweera DS, De Alwis JP, Liyanage IK, Ettickan U, Liyanapathirana KV, Undugodage C, de Silva HA, de Silva HJ. Low-dose melatonin for sleep disturbances in early-stage cirrhosis: A randomized, placebo-controlled, cross-over trial. JGH Open. 2020 May 18;4(4):749-756. doi: 10.1002/jgh3.12356. eCollection 2020 Aug.
- Background: PubMed 12790159Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martin G. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003 May;28(3):191-6.
- Background: PubMed 9140019Cajochen C, Krauchi K, Mori D, Graw P, Wirz-Justice A. Melatonin and S-20098 increase REM sleep and wake-up propensity without modifying NREM sleep homeostasis. Am J Physiol. 1997 Apr;272(4 Pt 2):R1189-96. doi: 10.1152/ajpregu.1997.272.4.R1189.
- Background: PubMed 14715839Kunz D, Mahlberg R, Muller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. J Clin Endocrinol Metab. 2004 Jan;89(1):128-34. doi: 10.1210/jc.2002-021057.
- Individual participant dataSharing planned: Yes. de-identified study data that underlie results in a publication.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Adam Buckholz, MD MS principal investigator
NewYork-Presbyterian/Weill Cornell Medical College
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Melatonin tablet 3 mg once daily and Thiamine in people with Hepatic Encephalopathy and Covert Hepatic Encephalopathy, run by Weill Medical College of Cornell University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Adam Buckholz, MD MS (646-962-5483, apb9012@med.cornell.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean change in rapid eye movement (REM) sleep as a percentage of total sleep measured by polysomnography after melatonin vs thiamine (time frame: Approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07046429, which also lists 31 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2026.