Affect of Melatonin on Sleep and Cognition in Cirrhosis

NCT07046429 | Recruiting DMC

• 2 other identifiers: 25-01028397TRA25-218891
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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). 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.

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

Outcome Measures

Primary Outcomes (1)

• 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..

  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

  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

  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

  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

  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

  approximately 4 weeks and 9 weeks, at polysomnography which marks the end of each treatment (melatonin or thiamine) assignment

Study Arms (2)

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.

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.

Dietary Supplement: Melatonin tablet 3 mg once daily; Dietary Supplement: Thiamine

Interventions

Melatonin tablet 3 mg once daily DIETARY_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.

Melatonin then Thiamine; Thiamine then melatonin

Thiamine DIETARY_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.

Melatonin then Thiamine; Thiamine then melatonin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• American Association for the Study of Liver Diseases: collaborator

Study Sites (1)

NewYork-Presbyterian/Weill Cornell Medical Center

New York, New York, 10021, United States

RECRUITING

Related Publications (31)

• 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.

  PMID: 28323455 BACKGROUND

• Desai 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.

  PMID: 37222262 BACKGROUND

• Tapper 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.

  PMID: 37278246 BACKGROUND

• Wellek 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.

  PMID: 22567063 BACKGROUND

• Enezi 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.

  PMID: 28611264 BACKGROUND

• de 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.

  PMID: 35120736 BACKGROUND

• Weissenborn K. Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles. Drugs. 2019 Feb;79(Suppl 1):5-9. doi: 10.1007/s40265-018-1018-z.

  PMID: 30706420 BACKGROUND

• Ghabril 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.

  PMID: 28167158 BACKGROUND

• De 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.

  PMID: 32782966 BACKGROUND

• Almeida 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.

  PMID: 12790159 BACKGROUND

• Cajochen 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.

  PMID: 9140019 BACKGROUND

• Kunz 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.

  PMID: 14715839 BACKGROUND

• Montagnese 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.

  PMID: 19756996 BACKGROUND

• Boeve 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.

  PMID: 14592300 BACKGROUND

• Chinoy 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.

  PMID: 33378539 BACKGROUND

• Depner CM, Cheng PC, Devine JK, Khosla S, de Zambotti M, Robillard R, Vakulin A, Drummond SPA. Wearable technologies for developing sleep and circadian biomarkers: a summary of workshop discussions. Sleep. 2020 Feb 13;43(2):zsz254. doi: 10.1093/sleep/zsz254.

  PMID: 31641776 BACKGROUND

• Malhotra A, Younes M, Kuna ST, Benca R, Kushida CA, Walsh J, Hanlon A, Staley B, Pack AI, Pien GW. Performance of an automated polysomnography scoring system versus computer-assisted manual scoring. Sleep. 2013 Apr 1;36(4):573-82. doi: 10.5665/sleep.2548.

  PMID: 23565003 BACKGROUND

• Marjot T, Ray DW, Williams FR, Tomlinson JW, Armstrong MJ. Sleep and liver disease: a bidirectional relationship. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):850-863. doi: 10.1016/S2468-1253(21)00169-2. Epub 2021 Jul 15.

  PMID: 34273289 BACKGROUND

• Bajaj JS, Saeian K, Schubert CM, Franco R, Franco J, Heuman DM. Disruption of sleep architecture in minimal hepatic encephalopathy and ghrelin secretion. Aliment Pharmacol Ther. 2011 Jul;34(1):103-5. doi: 10.1111/j.1365-2036.2011.04681.x. No abstract available.

  PMID: 21631553 BACKGROUND

• Buckholz A, Clarke L, Paik P, Jesudian A, Schwartz R, Krieger A, Rosenblatt R, Brown RS Jr. Evaluating sleep in covert encephalopathy with wearable technology: results from the WATCHES study. Hepatol Commun. 2023 Feb 1;7(2):e0002. doi: 10.1097/HC9.0000000000000028. eCollection 2023 Feb 1.

  PMID: 36724117 BACKGROUND

• Liu C, Zhou J, Yang X, Lv J, Shi Y, Zeng X. Changes in sleep architecture and quality in minimal hepatic encephalopathy patients and relationship to psychological dysfunction. Int J Clin Exp Med. 2015 Nov 15;8(11):21541-8. eCollection 2015.

  PMID: 26885103 BACKGROUND

• Labenz C, Baron JS, Toenges G, Schattenberg JM, Nagel M, Sprinzl MF, Nguyen-Tat M, Zimmermann T, Huber Y, Marquardt JU, Galle PR, Worns MA. Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients. Aliment Pharmacol Ther. 2018 Aug;48(3):313-321. doi: 10.1111/apt.14824. Epub 2018 Jun 4.

  PMID: 29863286 BACKGROUND

• Steindl PE, Finn B, Bendok B, Rothke S, Zee PC, Blei AT. Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med. 1995 Aug 15;123(4):274-7. doi: 10.7326/0003-4819-123-4-199508150-00005.

  PMID: 7611593 BACKGROUND

• Bersagliere A, Raduazzo ID, Nardi M, Schiff S, Gatta A, Amodio P, Achermann P, Montagnese S. Induced hyperammonemia may compromise the ability to generate restful sleep in patients with cirrhosis. Hepatology. 2012 Mar;55(3):869-78. doi: 10.1002/hep.24741. Epub 2012 Jan 19.

  PMID: 21994139 BACKGROUND

• SHERLOCK S, SUMMERSKILL WH, WHITE LP, PHEAR EA. Portal-systemic encephalopathy; neurological complications of liver disease. Lancet. 1954 Sep 4;267(6836):454-7. No abstract available.

  PMID: 13193045 BACKGROUND

• Tapper EB, Halbert B, Mellinger J. Rates of and Reasons for Hospital Readmissions in Patients With Cirrhosis: A Multistate Population-based Cohort Study. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1181-1188.e2. doi: 10.1016/j.cgh.2016.04.009. Epub 2016 Apr 13.

  PMID: 27085758 BACKGROUND

• Lauridsen MM, Bajaj JS. Hepatic encephalopathy treatment and its effect on driving abilities: A continental divide. J Hepatol. 2015 Jul;63(1):287-8. doi: 10.1016/j.jhep.2015.03.017. Epub 2015 Mar 18. No abstract available.

  PMID: 25796480 BACKGROUND

• Bajaj JS, Heuman DM, Sterling RK, Sanyal AJ, Siddiqui M, Matherly S, Luketic V, Stravitz RT, Fuchs M, Thacker LR, Gilles H, White MB, Unser A, Hovermale J, Gavis E, Noble NA, Wade JB. Validation of EncephalApp, Smartphone-Based Stroop Test, for the Diagnosis of Covert Hepatic Encephalopathy. Clin Gastroenterol Hepatol. 2015 Oct;13(10):1828-1835.e1. doi: 10.1016/j.cgh.2014.05.011. Epub 2014 May 17.

  PMID: 24846278 BACKGROUND

• European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatic encephalopathy. J Hepatol. 2022 Sep;77(3):807-824. doi: 10.1016/j.jhep.2022.06.001. Epub 2022 Jun 17.

  PMID: 35724930 BACKGROUND

• Hartmann IJ, Groeneweg M, Quero JC, Beijeman SJ, de Man RA, Hop WC, Schalm SW. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol. 2000 Aug;95(8):2029-34. doi: 10.1111/j.1572-0241.2000.02265.x.

  PMID: 10950053 BACKGROUND

• Ridola L, Cardinale V, Riggio O. The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. Ann Gastroenterol. 2018 Mar-Apr;31(2):151-164. doi: 10.20524/aog.2018.0232. Epub 2018 Feb 1.

  PMID: 29507462 BACKGROUND

MeSH Terms

Conditions

Hepatic Encephalopathy; Fibrosis; Parasomnias; Sleep Initiation and Maintenance Disorders; Hypertension, Portal

Interventions

Melatonin; Thiamine

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Sleep Wake Disorders; Mental Disorders; Sleep Disorders, Intrinsic; Dyssomnias

Intervention Hierarchy (Ancestors)

Tryptamines; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Pyrimidines

Study Officials

• Adam Buckholz, MD MS

  NewYork-Presbyterian/Weill Cornell Medical College

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adam Buckholz, MD MS

CONTACT

646-962-5483; apb9012@med.cornell.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 23, 2025
• First Posted: July 1, 2025
• Study Start: August 5, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: August 28, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (1)