Ramelteon in the Prevention of Post-operative Delirium (RECOVER)

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

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.

Study Overview

• Status: Completed
• Conditions: Delirium; Delayed Emergence From Anesthesia; Delirium, Dementia, Amnestic, Cognitive Disorders; Cognitive Disorders
• Intervention / Treatment: Drug: Ramelteon; Drug: Microcrystalline Cellulose; Drug: Riboflavin 100 mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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:

  1. ramelteon
  2. melatonin
  3. fluvoxamine
  4. rifampin
  5. ketoconazole
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only)	Drug: Ramelteon; 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered; Other Names: Rozerem; Drug: Microcrystalline Cellulose; Placebo Comparator; Drug: Riboflavin 100 mg; 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); Other Names: Adherence marker
Placebo Comparator: Placebo; Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient)	Drug: Microcrystalline Cellulose; Placebo Comparator; Drug: Riboflavin 100 mg; 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); Other Names: Adherence marker

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Karin J Neufeld, MD MPH, Professor - Department of Psychiatry and Behavioral Sciences

Publications and helpful links

General Publications

• Oh ES, Leoutsakos JM, Rosenberg PB, Pletnikova AM, Khanuja HS, Sterling RS, Oni JK, Sieber FE, Fedarko NS, Akhlaghi N, Neufeld KJ. Effects of Ramelteon on the Prevention of Postoperative Delirium in Older Patients Undergoing Orthopedic Surgery: The RECOVER Randomized Controlled Trial. Am J Geriatr Psychiatry. 2021 Jan;29(1):90-100. doi: 10.1016/j.jagp.2020.05.006. Epub 2020 May 16.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2017
• Primary Completion (Actual): June 26, 2019
• Study Completion (Actual): June 26, 2019

Study Registration Dates

• First Submitted: December 15, 2014
• First Submitted That Met QC Criteria: December 18, 2014
• First Posted (Estimate): December 24, 2014

Study Record Updates

• Last Update Posted (Actual): June 30, 2020
• Last Update Submitted That Met QC Criteria: June 16, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Post-operative Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Delirium; Disease; Cognition Disorders; Delayed Emergence from Anesthesia; Neurocognitive Disorders; Physiological Effects of Drugs; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Vitamins; Vitamin B Complex; Riboflavin
• Other Study ID Numbers: IRB00097232; 1R21AG050850-01A1 (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
• product manufactured in and exported from the U.S.: No