Ramelteon in the Prevention of Post-operative Delirium

Study Overview
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Brief Summary
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This trial focuses on a Phase II randomized masked clinical trial testing the effectiveness and safety of peri-operative administration of ramelteon, a melatonin agonist in the prevention of postoperative delirium.

Detailed Description
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This trial will randomize older aged patients undergoing general or regional anesthesia for orthopedic surgical procedures to three perioperative doses of a melatonin agonist, ramelteon, and placebo in a masked double blind fashion. The primary outcomes are 1) the incidence of post-operative delirium in the recovery period in the Postoperative Anesthesia Care Unit and on post-operative days 1 and 2 following surgery, and 2) the safety of ramelteon as documented by the presence of adverse events in the follow-up period.

Official Title
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A Randomized Double Blind Placebo Controlled Trial of Ramelteon in the Prevention of Post-operative Delirium in Older Patients Undergoing Orthopedic Surgery

Conditions
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Delirium, Delirium, Dementia, Amnestic, Cognitive Disorders, Delayed Emergence From Anesthesia, Cognitive Disorders

Intervention / Treatment
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* Drug: Ramelteon
* Drug: Microcrystalline Cellulose
* Drug: Riboflavin 100 mg


Participation Criteria
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Eligibility Criteria
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Planned orthopedic surgery under general or regional anesthesia and post-operative inpatient stay 65 years of age or older Mini-mental Status Exam (MMSE) score of 15 or greater prior to surgery; Ability to understand, speak, read and write English. Exclusion Criteria: Delirium diagnosis on the Confusion Assessment Method instrument at baseline Is unable to give informed consent due to cognitive impairment and a suitable legally authorized representative (LAR) cannot be identified Declines participation Current medications that include: ramelteon melatonin fluvoxamine rifampin ketoconazole fluconazole History of ramelteon or riboflavin intolerance Heavy daily alcohol intake by medical record or history Current moderate to severe liver failure (as defined by Charlson criteria Evidence of Systemic Inflammatory Response Syndrome (SIRS) as measured by > 2 criteria8) Presence of a condition that in the opinion of the PI compromises patient safety or data quality if enrolled in the study.

Ages Eligible for Study
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Minimum Age: 65 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) | Drug: Ramelteon<br>* 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered<br>* Other names: Rozerem;Drug: Microcrystalline Cellulose<br>* Placebo Comparator<br>Drug: Riboflavin 100 mg<br>* Riboflavin will be added to both placebo and active intervention capsules in order to track adherence to dose while taken as an outpatient (i.e. only the first preoperative dose)<br>* Other names: Adherence marker;|
| Placebo Comparator: Placebo<br>Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) | Drug: Microcrystalline Cellulose<br>* Placebo Comparator<br>Drug: Riboflavin 100 mg<br>* Riboflavin will be added to both placebo and active intervention capsules in order to track adherence to dose while taken as an outpatient (i.e. only the first preoperative dose)<br>* Other names: Adherence marker;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Delirium During Two Days Following Surgery | Delirium DSM 5 based criteria informed by standardized history gathering, examination, cognitive evaluation using cognitive tests, informant interview, and medical record review) measured during Post-operative Day 1 and/or Day 2 | Up to Post Operative Day 2 | 
| Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU) | Delirium (DSM 5 based criteria informed by standardized history gathering, examination, cognitive evaluation using cognitive tests, informant interview, and medical record review) measured once recovered from anesthesia. | Post Operative Day 0: Post Anesthesia Care Unit Following Recovery from Anesthesia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients | Measure Description: Delirium Rating Scale-Revised-98 (Severity items are rated on a scale of 0-3 and diagnostic items are rated on a scale of 0-2 or 0-3. The minimum score is 0. The maximum possible score for severity items is 39, while the maximum total score is 46. Higher scores indicate more severe delirium; score of 0 indicates no delirium.) Means and Standard Deviations were calculated from the maximum DRS-R98 score documented on Postoperative Day 1 and Day 2 for each participant who became delirious within each treatment arm. | Postoperative Day 1 and Day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-operative Delirium