Trial Outcomes & Findings for Ramelteon in the Prevention of Post-operative Delirium (NCT NCT02324153)

Last Updated: 2020-06-30

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

80 participants

Primary outcome timeframe

Up to Post Operative Day 2

Results posted on

2020-06-30

Participant Flow

Participant milestones

Participant milestones
Measure	Treatment 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)	Placebo 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)
Overall Study STARTED	41	39
Overall Study COMPLETED	33	38
Overall Study NOT COMPLETED	8	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment 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)	Placebo 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)
Overall Study Withdrawal by Subject	4	1
Overall Study Surgery postponed after randomization	3	0
Overall Study Developed delirium preoperatively	1	0

Baseline Characteristics

Ramelteon in the Prevention of Post-operative Delirium

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment n=33 Participants 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)	Placebo n=38 Participants 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 n=71 Participants Total of all reporting groups
Age, Continuous	74.3 years STANDARD_DEVIATION 5.5 • n=5 Participants	75.4 years STANDARD_DEVIATION 5.0 • n=7 Participants	74.9 years STANDARD_DEVIATION 5.2 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	24 Participants n=7 Participants	43 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	14 Participants n=7 Participants	28 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	32 Participants n=7 Participants	59 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	33 participants n=5 Participants	38 participants n=7 Participants	71 participants n=5 Participants
DRS-R98 Total	2.2 units on a scale STANDARD_DEVIATION 2.6 • n=5 Participants	2.6 units on a scale STANDARD_DEVIATION 3.0 • n=7 Participants	2.4 units on a scale STANDARD_DEVIATION 2.8 • n=5 Participants

PRIMARY outcome

Timeframe: Up to Post Operative Day 2

Outcome measures

Outcome measures
Measure	Treatment n=33 Participants 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)	Placebo n=38 Participants 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)
Number of Participants With Delirium During Two Days Following Surgery	3 Participants	2 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Treatment n=33 Participants 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)	Placebo n=38 Participants 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)
Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU)	7 Participants	3 Participants

SECONDARY outcome

Timeframe: Postoperative Day 1 and Day 2

Population: Participants With Delirium

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.

Outcome measures

Outcome measures
Measure	Treatment n=3 Participants 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)	Placebo n=2 Participants 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)
Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients	19.7 score on a scale Standard Deviation 8.0	19.0 score on a scale Standard Deviation 11.3

Adverse Events

Treatment

Serious events: 3 serious events

Other events: 13 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Treatment n=41 participants at risk 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)	Placebo n=39 participants at risk 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)
Cardiac disorders Bigeminy	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Injury, poisoning and procedural complications Fall	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Cardiac disorders Hypotension	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).

Other adverse events

Additional Information

Karin Neufeld MD MPH: PI of Trial

Johns Hopkins University School of Medicine

Phone: 410-550-0197

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Treatment n=41 participants at risk 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)	Placebo n=39 participants at risk 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)
Skin and subcutaneous tissue disorders Flushing	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 2 • 30-day follow-up after surgery 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).
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Cardiac disorders Fainting	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Cardiac disorders Hypotension	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Blood and lymphatic system disorders Reactive leukocytosis	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Cardiac disorders Sinus bradycardia	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Cardiac disorders Syncope	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Renal and urinary disorders Hematuria	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Renal and urinary disorders Urinary incontinence	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Renal and urinary disorders Urinary retention	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Gastrointestinal disorders Diarrhea	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Gastrointestinal disorders Nausea	12.2% 5/41 • Number of events 5 • 30-day follow-up after surgery 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).	5.1% 2/39 • Number of events 2 • 30-day follow-up after surgery 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).
Gastrointestinal disorders Sore throat	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Gastrointestinal disorders Vomiting	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Ear and labyrinth disorders Dizziness	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	5.1% 2/39 • Number of events 2 • 30-day follow-up after surgery 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).
Blood and lymphatic system disorders Edema in limbs	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Eye disorders Eye disorders and eye pain	4.9% 2/41 • Number of events 2 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Surgical and medical procedures Foot pain	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Nervous system disorders Hyperalertness	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Nervous system disorders Restlessness	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).
Musculoskeletal and connective tissue disorders Muscle cramps	2.4% 1/41 • Number of events 1 • 30-day follow-up after surgery 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).	0.00% 0/39 • 30-day follow-up after surgery 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).
Musculoskeletal and connective tissue disorders Surgical procedure - other	0.00% 0/41 • 30-day follow-up after surgery 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).	2.6% 1/39 • Number of events 1 • 30-day follow-up after surgery 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).