Ramelteon for Treatment of Insomnia in Cirrhosis
Condition: Cirrhosis
MeSH terms: Liver Cirrhosis; Fibrosis
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Ramelteon Pill
Intervention type(s): Drug
Intervention description(s): Patients with compensated cirrhosis and insomnia will be provided ramelteon
Other intervention name(s): Ramelteon
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: sleep