RECOVER: Ramelteon in the Prevention of Post-operative Delirium

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02324153
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 80
• Location: 1
• Arms: 2
• Actual Duration (Months): 27.1
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Delirium; Delirium, Dementia, Amnestic, Cognitive Disorders; Delayed Emergence From Anesthesia; Cognitive Disorders	Drug: Ramelteon; Drug: Microcrystalline Cellulose; Drug: Riboflavin 100 mg	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized Double Blind Placebo Controlled Trial of Ramelteon in the Prevention of Post-operative Delirium in Older Patients Undergoing Orthopedic Surgery
• Actual Study Start Date: Mar 24, 2017
• Actual Primary Completion Date: Jun 26, 2019
• Actual Study Completion Date: Jun 26, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Delirium During Two Days Following Surgery [Up to Post Operative Day 2]

   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

2. Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU) [Post Operative Day 0: Post Anesthesia Care Unit Following Recovery from Anesthesia]

   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.

Secondary Outcome Measures

1. Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients [Postoperative Day 1 and Day 2]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Bayview Medical Center	Baltimore	Maryland	United States	21224

Sponsors and Collaborators

• Johns Hopkins University
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Karin J Neufeld, MD MPH, Professor - Department of Psychiatry and Behavioral Sciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 12, 2019
• Informed Consent Form - Jul 12, 2019

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02324153
• Other Study ID Numbers: IRB00097232; 1R21AG050850-01A1
• First Posted: Dec 24, 2014
• Last Update Posted: Jun 30, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Johns Hopkins University: Post-operative Delirium
• Additional relevant MeSH terms: Delirium; Disease; Delayed Emergence from Anesthesia; Cognition Disorders; Neurocognitive Disorders; Riboflavin

Study Results

Participant Flow

Arm/Group Title	Treatment	Placebo
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)	Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)
Period Title: Overall Study
STARTED	41	39
COMPLETED	33	38
NOT COMPLETED	8	1

Baseline Characteristics

Arm/Group Title	Treatment	Placebo	Total
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)	Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)	Total of all reporting groups
Overall Participants	33	38	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.3 (5.5)	75.4 (5.0)	74.9 (5.2)
Sex: Female, Male (Count of Participants)
Female	19 57.6%	24 63.2%	43 60.6%
Male	14 42.4%	14 36.8%	28 39.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 18.2%	6 15.8%	12 16.9%
White	27 81.8%	32 84.2%	59 83.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	33 100%	38 100%	71 100%
DRS-R98 Total (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.2 (2.6)	2.6 (3.0)	2.4 (2.8)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Delirium During Two Days Following Surgery
Description	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
Time Frame	Up to Post Operative Day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)	Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)
Measure Participants	33	38
Count of Participants [Participants]	3 9.1%	2 5.3%

2. Primary Outcome

Title	Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU)
Description	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.
Time Frame	Post Operative Day 0: Post Anesthesia Care Unit Following Recovery from Anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)	Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)
Measure Participants	33	38
Count of Participants [Participants]	7 21.2%	3 7.9%

3. Secondary Outcome

Title	Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients
Description	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.
Time Frame	Postoperative Day 1 and Day 2

Outcome Measure Data

Analysis Population Description

Participants With Delirium

Arm/Group Title	Treatment	Placebo
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)	Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)
Measure Participants	3	2
Mean (Standard Deviation) [score on a scale]	19.7 (8.0)	19.0 (11.3)

Adverse Events

Time Frame	30-day follow-up after surgery
Adverse Event Reporting Description	All adverse events (AE and SAE) were collected from the medical record and daily patient assessment using a customized instrument ("Health Questionnaire") which systematically probed for known side effects (fatigue, headache and next day somnolence).
Arm/Group Title	Treatment		Placebo
Arm/Group Description	Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) Ramelteon: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered Microcrystalline Cellulose: Placebo Comparator 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)		Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient) Microcrystalline Cellulose: Placebo Comparator 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)
All Cause Mortality
	Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/39 (0%)
Serious Adverse Events
	Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/41 (7.3%)		0/39 (0%)
Cardiac disorders
Bigeminy	1/41 (2.4%)	1	0/39 (0%)	0
Hypotension	1/41 (2.4%)	1	0/39 (0%)	0
Injury, poisoning and procedural complications
Fall	1/41 (2.4%)	1	0/39 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/41 (31.7%)		13/39 (33.3%)
Blood and lymphatic system disorders
Reactive leukocytosis	0/41 (0%)	0	1/39 (2.6%)	1
Edema in limbs	0/41 (0%)	0	1/39 (2.6%)	1
Cardiac disorders
Fainting	1/41 (2.4%)	1	0/39 (0%)	0
Hypotension	1/41 (2.4%)	1	1/39 (2.6%)	1
Sinus bradycardia	1/41 (2.4%)	1	0/39 (0%)	0
Syncope	1/41 (2.4%)	1	1/39 (2.6%)	1
Ear and labyrinth disorders
Dizziness	1/41 (2.4%)	1	2/39 (5.1%)	2
Eye disorders
Eye disorders and eye pain	2/41 (4.9%)	2	0/39 (0%)	0
Gastrointestinal disorders
Diarrhea	0/41 (0%)	0	1/39 (2.6%)	1
Nausea	5/41 (12.2%)	5	2/39 (5.1%)	2
Sore throat	1/41 (2.4%)	1	0/39 (0%)	0
Vomiting	1/41 (2.4%)	1	1/39 (2.6%)	1
Musculoskeletal and connective tissue disorders
Muscle cramps	1/41 (2.4%)	1	0/39 (0%)	0
Surgical procedure - other	0/41 (0%)	0	1/39 (2.6%)	1
Nervous system disorders
Hyperalertness	0/41 (0%)	0	1/39 (2.6%)	1
Restlessness	0/41 (0%)	0	1/39 (2.6%)	1
Renal and urinary disorders
Hematuria	0/41 (0%)	0	1/39 (2.6%)	1
Urinary incontinence	1/41 (2.4%)	1	0/39 (0%)	0
Urinary retention	1/41 (2.4%)	1	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Flushing	0/41 (0%)	0	1/39 (2.6%)	2
Pruritus	0/41 (0%)	0	1/39 (2.6%)	1
Surgical and medical procedures
Foot pain	1/41 (2.4%)	1	0/39 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.