The Effect of Ramelteon on Delirium and Sleep in Patients Admitted to the ICU

Study Overview
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Brief Summary
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Delirium is a disturbance in attention and awareness that occurs over a short period of time. Delirium is common in critically ill patients, and poor sleep quality in the intensive care unit (ICU) often worsens delirium. We aim to lower delirium in the intensive care unit (ICU) by using ramelteon, which is a drug used to improve sleep at night.

Detailed Description
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Rationale: Many pharmacologic agents have been studied to reduce delirium in high risk patients, but the data has not shown significant or clinically important outcomes. These agents also have more side effect profiles such as arrhythmia and QT prolongation. Ramelteon is an effective drug to improve sleep quality and has a low side effect profile. Improved sleep quality and reduced delirium in ICU population will lead to improved acute and long-term outcomes of the patients and lower delirium-related healthcare cost. Study Hypothesis: It is hypothesized that those receiving ramelteon will have a higher rate of delirium- and coma-free days, on average, than those receiving placebo. We also hypothesize that those receiving ramelteon will have lower Confusion Assessment Method for Intensive Care Unit-7 (CAM-ICU-7) scores than those receiving placebo, and that the reduction from baseline will be greater for those receiving ramelteon than those receiving placebo. In addition, those receiving ramelteon will be in the medical intensive care unit (MICU) and hospital fewer days than those receiving placebo. Those receiving ramelteon will have more sleep-time and fewer awakenings than those receiving placebo (as defined by the actigraph device). In addition, those receiving ramelteon will have higher subjective quality of sleep than those receiving placebo on patient-reported sleep evaluation questionnaire. Lastly, those receiving ramelteon will suffer less from post-intensive care syndrome compared to those receiving placebo. Study Procedure: Every day, investigator(s) will identify patients who meet criteria on chart review and these patients will be approached for consent. Consent will be obtained by patient or surrogate decision maker as appropriate. After consent is obtained, investigator will call pharmacy investigational service to provide patient information/patient study ID for randomization and medication allotment. Pharmacy investigational services will be informed whether the patient is mechanically ventilated or not (this is a subgroup that will require randomization in the urn randomization design). Patient's data will be recorded on REDcap including patient ID and delirium assessment. A sign will be placed at the door of the patient's room to identify patient as a study subject and to notify that the study subject should not be given ramelteon, melatonin, or fluvoxamine by the primary medical team. Upon enrollment, patients in Ramelteon group will receive 8 mg of Ramelteon capsule nightly at 9 pm and placebo group will receive the placebo capsule. Ramelteon and Placebo capsules will be indistinguishable from each other, even when opened to be administered via nasograstric or orogastric tubes. Medication administration will continue throughout the hospital stay, with maximum of 30 days, every night until death or discharge from the hospital. If a patient's code status changes to comfort measures only, study drug administration will be discontinued. An actigraph unit will be placed on patient's wrist for continuous non-invasive measurement of rest and activity to estimate sleep measures. The actigraph unit will be removed from the patient when the patient is discharged from the ICU. The data from the actigraph will then be extracted and analyzed by Action W software. Patients will be assessed by investigator daily for delirium using the Confusion Method Assessment for the ICU-7 (CAM-ICU-7). For patients who are on mechanical ventilation or on sedatives, all sedative medications will be held if the primary medical team approves. CAM-ICU-7 will be performed for each patient at the time of maximal awakening and after sedation (continuous infusion and as needed doses) is held for at least 30 to 60 minutes. For those patients that are able to participate, they will complete Richmond-Campbell Sleep Questionnaire (RCSQ), which is a two minute questionnaire, to assess their previous night's sleep. The CAM-ICU-7 and RCSQ assessments will continue throughout the hospitalization after ICU discharge, until discharge from the hospital or up to 30 days. Patients will not be monitored upon discharge from the hospital (ie. discharged to nursing home, skilled nursing facility, home). Patients will be contacted via telephone to conduct two surveys to assess post-intensive care quality of life at 1-, 3-, and 6-months after ICU discharge. Telephone Interview for Cognitive Status (TICS) will be used to assess for cognitive impairment, and EuroQol-5Dimensions (EQ-5D) will be used to assess for health quality including mobility, self-care, activity level, pain/discomfort, and anxiety/depression. Data Safety Monitoring Plan: We will have two faculty membersfrom the Division of Pulmonary, Critical Care and Sleep Medicine at the Warren Alpert Medical School of Brown University as data safety monitoring members for this study in the event a study-related adverse event occurs.

Official Title
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The Effect of Ramelteon on Delirium and Sleep in Patients Admitted to the ICU

Conditions
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Delirium

Intervention / Treatment
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* Drug: Ramelteon
* Drug: Placebo - Cap


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years of age newly admitted to ICU and expected to stay in ICU for at least three days as determined by study personnel. Able to take medicine via enteral access. Exclusion Criteria: Taking ramelteon or fluvoxamine Expected life expectancy of less than 48 hours. Pre-existing dementia Alcohol withdrawal admission diagnosis Acute neurological condition (brain abscess/tumor, head bleed, stroke, seizure) Known allergy/intolerance to ramelteon Severe liver dysfunction: Hepatic encephalopathy, cirrhosis (Child-Pugh class C or greater) Suicide attempt, admission for acute psychiatric illness GI bleed or other inability to use enteral nutrition Pregnant patient Incarcerated Prior enrollment into the study On paralytics at the time of admission Unable to get enteral feeds/meds

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramelteon<br>Patients assigned to Ramelteon group will receive 8mg of Ramelteon every night throughout the hospitalization or up to 30 days, whichever is sooner. | Drug: Ramelteon<br>* Nightly administration of Ramelteon 8 mg<br>* Other names: Rozerem;|
| Placebo Comparator: Placebo<br>Patients assigned to Placebo group will receive placebo pill that is indistinguishable from Ramelteon, every night throughout the hospitalization or up to 30 days, whichever is sooner. | Drug: Placebo - Cap<br>* Nightly administration of Placebo capsule, which is indistinguishable from Ramelteon<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium- and coma-free days | The average number of delirium- and coma-free days as defined by Richmond Agitation-Sedation Scale (RASS) greater than -4 (RASS score is a range from -5 to +4, the lower score indicates comatose state, the higher score indicates more awakeness/agitation) and Confusion Assessment Method in the Intensive Care Unit (CAM-ICU-7) score greater than 3 (CAM-ICU-7 score ranges from 0 to 7, the higher score indicates more severe delirium). | Until discharge or up to 30 days of hospitalization, whichever is sooner. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium assessment score (CAM-ICU-7) in Ramelteon group compared to the placebo group. | Confusion Assessment Method in the Intensive Care Unit (CAM-ICU-7) score will be measured to assess delirium. Score ranges from 0 to 7, and higher score indicates more severe delirium. | Until discharge or up to 30 days of hospitalization, whichever is sooner. | 
| Change in the delirium assessment scores (CAM-ICU-7) from baseline score on day one of enrolment in ramelteon group compared to the placebo group. | Confusion Assessment Method in the Intensive Care Unit (CAM-ICU-7) score will be measured to assess delirium. Score ranges from 0 to 7, and higher score indicates more severe delirium. | Until discharge or up to 30 days of hospitalization, whichever is sooner. | 
| Number of ICU and hospital days. | The average length of stay in the ICU and hospital, in days. | Until discharge or up to 30 days of hospitalization, whichever is sooner. | 
| Hours of total sleep, nighttime sleep and number of awakenings in ramelteon group compared to the placebo group. | The average number of hours of sleep, and the number of awakenings as measured by actigraphy, which is a wearable accelerometer that is validated to assess sleep quality. | During the entire ICU stay upon enrollment up to 30 days. | 
| Richards-Campbell Sleep Questionnaire (RCSQ) scores in ramelteon group compared to the placebo group. | RCSQ is a validated sleep survey using visual analog scale (VAS) filled out by the subject, which comprises of 5 questions with scores ranging from 0-100, and higher score indicates worse sleep quality. | Until discharge or up to 30 days of hospitalization, whichever is sooner. | 
| Telephone Interview for Cognitive Status (TICS) scores at 1-, 3-, and 6-month post ICU discharge in ramelteon group compared to the placebo group. | TICS is a validated phone-based assessment of cognitive status. The score ranges from 0 to 40, lower score indicates worse degree of cognitive impairment. | At one, three, and six month post ICU discharge. | 
| EQ-5D (EuroQol-5Dimensions) scores at 1-, 3-, and 6-month post ICU discharge in ramelteon group compared to the placebo group. | EQ-5D is a health related quality of life questionnaire that is telephone-based. It is comprised of 5 health related quality of life questions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), and each question is in multiple-choice format. The score ranges from 5 to 25, with the higher scores indicating worse health-related quality of life assessment. | At one, three, and six month post ICU discharge. |