Ramelteon for Treatment of Insomnia in Cirrhosis

To study the effect of ramelteon, a melatonin receptor agonist, on sleep quality, duration and cognitive function in cirrhotics with insomnia.

Patients with cirrhosis have difficulties with their sleep quality, which adversely affects their health-related quality of life. It is assumed the sleep disturbances are related to hepatic encephalopathy (HE) in these patients. However, several recent reports have indicated that this is not a perfect concordance and that cognition is not related to sleep disturbance. The mechanism for this change is not clear, although there is evidence of melatonin-delayed phase in these patients as well as difficulties with the excretion pattern of cortisol. Ghrelin is an orexigenic hormone produced by the stomach which stimulates the appetite and also has a profound effect on sleep. Our group has demonstrated a substantial alteration in ghrelin secretion in cirrhosis that correlates with poor slow-wave sleep. In healthy individuals, ghrelin injection encourages slow-wave sleep while sleep deprivation increases ghrelin levels. The role of ghrelin in the sleep disturbances of cirrhosis has not been determined. Prior studies have also lacked the use of overnight polysomnography as a tool and have relied on either actigraphy or questionnaires. There is a need for detailed mechanistic and therapeutic approaches to analyzing sleep disturbances in cirrhosis.

Also the therapy of sleep disturbance in cirrhosis is largely empirical. Prior studies have evaluated hydroxyzine which runs the risk of precipitating HE. Ramelteon is a melatonin analog that is FDA-approved for use in insomnia and will potentially be useful to restore the sleep-wake cycle in cirrhosis-associated sleep disturbance.

The investigators aim to study the impact of the FDA-approved ramelteon on the sleep quality (using questionnaires and sleep diaries) on these patients with cirrhosis.

Study Overview

• Status: Completed
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: Ramelteon Pill

Detailed Description

This study will be a prospective study of patients with compensated cirrhosis This study will be divided into screening and post-ramelteon visits.

For this study, subjects with cirrhosis will be recruited from the hepatology clinic.

Screening: All subjects will come for an initial screening visit to the CRSU at which point the following procedures will be performed:

1. Vitals, including BMI
2. Neck circumference
3. Skinfold thickness and waist-hip ratio
4. Beck Depression Inventory (BDI)
5. Sickness impact profile for overall HRQOL

Questionnaires regarding sleep:

1. Berlin questionnaire
2. STOP Bang questionnaire
3. Epworth sleepiness scale (ESS) and
4. Pittsburgh sleep quality index (PQSI)

Cirrhotic patients with either of the criteria below (a) neck circumference >17 inches for men and >16 inches for women (b) Positive Berlin questionnaire will be excluded because these are highly suggestive of sleep disturbances and OSA. The investigators will also exclude patients who have evidence of moderate to severe depression on Beck Depression Inventory (score ≥20) without the suicide question.

All enrolled study participants will perform 5 paper-pencil and two computerized tests of intelligence which will last approximately 35 minutes total.

RAMELTEON THERAPY:

The subjects' study chart, current medications, medical history and pregnancy testing will be assessed by sleep physicians at VCU, who will then decide if this patient would benefit from ramelteon.

The criteria used will be insomnia along with the absence of OSA by the questionnaires. Ramelteon is an FDA-approved selective melatonin receptor 1 and 2 analog indicated for use in insomnia. The dose used will be 8 mg, the lowest possible dose. If the sleep specialists believe that a particular cirrhotic patient is a candidate for this therapy, they will be clinically prescribed ramelteon after a detailed face to face visit explaining the risks and benefits. Ramelteon is not indicated in patients with severe hepatic impairment (defined as Child Class C), therefore, these patients will not be included in this study.

If the patient agrees to take the medicine, it will be dispensed through the investigational pharmacy, where it will be stored for this study. Patients will be asked to complete a medication and sleep diary for the duration of the drug therapy which will be a maximum of 15 days. Within 15 days of drug initiation, the patients will be asked to complete the sleep questionnaires again and cognitive testing similar to that described in visit 1.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Child class A cirrhosis proven by biopsy, radiology or endoscopic evidence of varices - Able to give informed consent

Exclusion Criteria:

• Patient unwilling to start therapy
• Allergic reactions to ramelteon in the past
• Obstructive sleep apnea
• Periodic limb movement disorder
• Moderate to severe depression
• Unable to give informed consent
• Night shift workers
• Inter-continental travel within the last 4 weeks
• Renal insufficiency on dialysis
• Current alcohol or illicit drug use
• Diabetes Mellitus using insulin therapy
• Use of chronic hypnotic medications more than once per week or more than 5-6 times per month

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ramelteon Pill; Patients given ramelteon and re-evaluated after 15 days of therapy	Drug: Ramelteon Pill; Patients with compensated cirrhosis and insomnia will be provided ramelteon; Other Names: Ramelteon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Quality Evaluation	Pittsburgh Sleep Quality Index (PSQI) is a 19 item survey measuring 7 components of sleep. Component scores are summed to yield a global PSQI score. Scores range from 0 to 21 with higher scores indicate worse sleep quality.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daytime Sleepiness Evaluation	Epworth Sleepiness Scale asks participants to rate (on a scale of 0 to 3) their likelihood of falling asleep during 8 daily activities. Scores range from 0 to 24 with lower scores indicating less sleepiness.	14 days
Sickness Impact Profile	Sickness Impact Profile is a 68 question assessment. Items are scored 0 (no) or 1 (yes). Scores range from 0 to 68 with higher numbers indicating worse quality of life.	14 days

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Jasmohan S Bajaj, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: March 16, 2017
• First Submitted That Met QC Criteria: March 21, 2017
• First Posted (Actual): March 27, 2017

Study Record Updates

• Last Update Posted (Actual): March 29, 2021
• Last Update Submitted That Met QC Criteria: March 25, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: sleep
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: HM13968; 5R01DK087913 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No