Clinical trial NCT03091738
Conditions: Cirrhosis
Keywords: sleep
Sponsor: Virginia Commonwealth University
Start date: 2017-02-01; Completion date: 2018-10-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

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.

Arms: arm 1: Patients given ramelteon and re-evaluated after 15 days of therapy
Interventions: intervention 1: Ramelteon Pill
Intervention descriptions: intervention 1: Patients with compensated cirrhosis and insomnia will be provided ramelteon

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Title: Study of Sleep in Cirrhosis 
 
NCT #: NCT03091738 
 
Document date: 09/04/2013 
 
Document Type: Study Protocol and Statistical Analysis Plan 
 
 
 














 
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Employee V#
3. If "Other Unique Identifier" was selected above, describe the identifiers  
4. * Will participants be able to withdraw their data (paper, electronic, or specimens) from the study if they no
longer wish to participate  
  Yes
No
5. If yes above, describe how participants will be able to withdraw their data  
they can contact the PI in writing as indicated in the consent form for withdrawal of all their data including genetic data.
  














 
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Individuals with limited English proficiency
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Active military personnel

Student populations in K-12 educational settings or other learning environments
7. * Does this study obtaining data in, or from, the European Economic Area? (see Help Text for list of countries
included in the EEA) 
  Yes No
8. Justify the inclusion and exclusion criteria if necessary. If you are either targeting, or excluding, a particular
segment of the population / community, provide a description of the group/organization/community and
provide a rationale  
The PI only sees adults in his practice, pregnancy can cause increase in reflux symptoms that can worsen sleep
regardless of cirrhosis, and we cannot ensure that prisoners can take the medications as needed for this study.
9. * Select the age range(s) of the participants who may be involved in this study  
 

< 1 Year

1 - 6 Years

7 - 12 Years

13 - 17 Years
18 - 20 Years
21 - 65 Years
> 65 Years
  














unnecessary treatments and can in turn worsen their quality of life. A study with treatment with an FDA-approved
medication, will be able to identify and possibly correct the underlying sleep disturbances both pathophysiologically as
well as therapeutically. 
The minor risk to confidentiality and privacy and adverse effects of ramelteon are low compared to the potential
benefits of elucidating the mechanism and treatment options for these patients and potentially improve their QOL.
13. * Describe the scientific benefit or importance of the knowledge to be gained  
Sleep quality is a major concern in patients with cirrhosis and this impacts their quality of life immensely. Patients with
sleep problems are not able to function normally and this is often mistaken for hepatic encephalopathy. This leads to
unnecessary treatments and can in turn worsen their quality of life. A study with treatment with an FDA-approved
medication, will be able to identify and possibly correct the underlying sleep disturbances both pathophysiologically as
well as therapeutically. 
The minor risk to confidentiality and privacy and adverse effects of ramelteon are low compared to the potential
benefits of elucidating the mechanism and treatment options for these patients and potentially improve their QOL.
14. If applicable, describe alternatives (research or non-research) that are available to potential participants if they
choose not to participate in this study  
15. * Indicate if this study will have a Data Safety Monitoring Board (DSMB) or a Data Safety Monitoring Plan
(DSMP)  [Required for all greater than minimal risk studies] 
 

DSMB

DSMP
No DSMB/DSMP [Note  This response is not applicable for greater than minimal risk studies]