Cognitive Disorders, Delayed Emergence From Anesthesia, Delirium, Delirium, Dementia, Amnestic, Cognitive Disorders
Conditions
Keywords
Post-operative Delirium
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.
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.
Interventions
DRUGRamelteon
1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered
DRUGMicrocrystalline Cellulose
Placebo Comparator
DRUGRiboflavin 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)
Sponsors
National Institute on Aging (NIA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) | 33 |
| 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) | 38 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Developed delirium preoperatively | 1 | 0 |
| Overall Study | Surgery postponed after randomization | 3 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Treatment | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 74.3 years STANDARD_DEVIATION 5.5 | 75.4 years STANDARD_DEVIATION 5 | 74.9 years STANDARD_DEVIATION 5.2 |
| DRS-R98 Total | 2.2 units on a scale STANDARD_DEVIATION 2.6 | 2.6 units on a scale STANDARD_DEVIATION 3 | 2.4 units on a scale STANDARD_DEVIATION 2.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 32 Participants | 59 Participants |
| Region of Enrollment United States | 33 participants | 38 participants | 71 participants |
| Sex: Female, Male Female | 19 Participants | 24 Participants | 43 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 39 |
| other Total, other adverse events | 13 / 41 | 13 / 39 |
| serious Total, serious adverse events | 3 / 41 | 0 / 39 |
Outcome results
Primary
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
Time frame: Up to Post Operative Day 2
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Delirium During Two Days Following Surgery | 3 Participants |
| Placebo | Number of Participants With Delirium During Two Days Following Surgery | 2 Participants |
Primary
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.
Time frame: Post Operative Day 0: Post Anesthesia Care Unit Following Recovery from Anesthesia
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU) | 7 Participants |
| Placebo | Number of Participants With Delirium in the Post Anesthesia Care Unit (PACU) | 3 Participants |
Secondary
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.
Time frame: Postoperative Day 1 and Day 2
Population: Participants With Delirium
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients | 19.7 score on a scale | Standard Deviation 8 |
| Placebo | Delirium Rating Scale - Revised- 98 (DRS-R98) in Delirious Patients | 19.0 score on a scale | Standard Deviation 11.3 |