Insomnia, Postoperative Delirium, Sleep Fragmentation, Sleep Initiation and Maintenance Disorders
Conditions
Keywords
Suvorexant, Sleep architecture, Delirium, Intensive care unit
Brief summary
Investigators will evaluate the efficacy of postoperative oral suvorexant treatment on nighttime wakefulness after persistent sleep onset (WASO) among adult cardiac surgical patients recovering in the cardiac intensive care unit (ICU). The study include patients ≥ 60 years old undergoing coronary artery bypass graft surgery (CABG), with or without valve surgery (aortic or mitral). Patients will receive either oral suvorexant or placebo for 7 nights starting the night after extubation. The primary hypothesis is that suvorexant compared with placebo decreases WASO, as measured by a specialized electroencephalogram (EEG), the SedLine monitor, during the first night in the cardiac ICU. Investigators will also assess total sleep time (TST), time to sleep onset (TSO), and postoperative delirium and delirium-free days.
Detailed description
This is a prospective, randomized, placebo-controlled, blinded study. Participants will be enrolled preoperatively. After postoperative extubation, eligible patients will be randomly allocated in a 1:1 ratio to receive either suvorexant 20 mg or placebo. Study procedures will start on preoperative night 3 when the patient is first asked to report information about their sleep using the Richards-Campbell Sleep Questionnaire (RCSQ). Patients will complete the RCSQ every morning during the 3 days prior to surgery. The intervention (study drug) will be applied for 7 nights starting the night after postoperative extubation in the ICU. Primary and secondary outcomes will be assessed once during the night of the sleep trial in the ICU. The sleep trial will take place during the first night after extubation if the patient has been extubated before 7pm. Exploratory outcomes will be assessed from day of extubation until hospital discharge. Suvorexant 20 mg or placebo will be administered p.o. once a day between 9:00pm and 10:00pm for a maximum of 7 days starting the night after extubation in the ICU. The study drug will be discontinued after 7 consecutive doses following extubation; or at hospital discharge (if less than 7 days after extubation); or at ICU discharge, if patient showed signs of airway obstruction during sleep or when strong inhibitors of CYP3A are co-administered; or in the event of early termination, subject withdrawal of consent, investigator withdrawal for toxicity or other reasons. If deemed necessary by the treating clinicians, melatonin or benzodiazepine may be added for treatment of insomnia. All patients will receive usual supportive care as per the treating physicians and standard practice. Duration of nighttime wakefulness after persistent sleep onset (WASO), total sleep time (TST), time to sleep onset (TSO) will be measured by electroencephalogram (EEG) using a Next Generation SedLine® Brain Function Monitor during the night of the sleep trial. Incidence of postoperative in-hospital delirium and increases delirium free days will be assessed using Confusion Assessment Method (CAM).
Interventions
DRUGSuvorexant 20 mg
Administration of oral Suvorexant 20 mg
DRUGPlacebo oral tablet
Administration of oral placebo (same non-identifiable form as active comparator)
Sponsors
Merck Sharp & Dohme LLC
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomization in a 1:1 ratio (suvorexant 20 mg versus placebo) will be stratified by duration of perioperative anesthesia and sedation.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 60 years or older 2. Undergoing elective coronary artery bypass graft surgery with or without aortic and/or mitral valve replacement, who are expected to be transferred to the ICU postoperatively
Exclusion criteria
1. Preoperative left ventricular ejection fraction of less than 30% 2. Renal failure (creatinine \>2 mg/dl or dialysis dependence) 3. Liver failure (CHILD-Pugh\>4) 4. Coma (RASS\<-1) 5. Signs and symptoms of delirium and agitation at time of enrollment (CAM-ICU positive) 6. Montreal Cognitive Assessment (MoCA) below 23 at time of consent 7. Psychiatric or neurologic diseases (including chronic benzodiazepine use, bipolar disorder, psychotic disorder, posttraumatic stress disorder, requirement of prophylactic psychiatric medication, evidence of acute depression on screening visit, preexisting cognitive impairment, Alzheimer disease, Parkinson's disease, medications for cognitive decline, history of recent seizures (within 1 year prior visit), alcoholism or documented history of alcohol abuse, and narcolepsy) 8. Severe sleep apnea requiring home continuous positive airway pressure treatment 9. Morbid obesity (BMI \>40) 10. Known or suspected pregnancy (there are no adequate and well-controlled studies of suvorexant in pregnant women. Based on animal data, Suvorexant may cause fetal harm). 11. Patients with known hypersensitivity to study medications 12. English language limitations (Sleep assessment and delirium assessment tools are only validated in English) 13. Patients enrolled in other interventional studies which could confound the primary endpoint.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nighttime Wakefulness After Persistent Sleep Onset (WASO) | First night after extubation between 11:00pm and 6:00am | Nighttime wakefulness after persistent sleep onset (WASO) will be measured using a SedLine® Brain Function Monitor. WASO will be defined as the duration of wakefulness after the onset of persistent sleep in the observation period between 11:00pm (Lights-Off) to 6:00am (Lights-On) in minutes. Onset of persistent sleep will be defined as the first epoch of 10 consecutive minutes of sleep (REM or non-REM Stages 1, 2, 3 or 4) after Lights-Off. Wakefulness will be defined as any epoch of Stage 0. Sleep staging will be performed according to Rechtschaffen & Kales criteria and in accordance with AASM guidelines. The SedLine® monitor uses a symmetrical bilateral array of sensors that provides four-channel data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Sleep Time (TST) | First night after extubation between 11:00pm and 6:00am | Total sleep time will be measured by electroencephalogram (EEG) using a Next Generation SedLine® Brain Function Monitor during the night of the sleep trial in analogy to the primary outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Duration of Sleep During the Day | Up to 24 hours after initiation of sleep trial | Continuous EEG-monitoring throughout the day following the sleep trial will be performed until no more than 24 hours after initiation of the sleep trial, or until the patient is discharged from the ICU, whichever occurs first. Duration of sleep during the day will be assessed. |
| Subjective Sleep Quality: Richards-Campbell Sleep Questionnaire (RCSQ) | Every morning from preoperative day 3 up to postoperative day 7 | Subjective sleep quality will be assessed by applying the Richards-Campbell Sleep Questionnaire (RCSQ). The RCSQ is a validated survey instrument for assessing sleep quality in critically ill patients based on a five-item, visual analogue scale (each from 0 \[worst value\] to 100 \[best value\]). The scale evaluates perceptions of depth of sleep, sleep onset latency, number of awakenings, time spent awake, and overall sleep quality. |
| Delirium-free Days | Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days | Incidence of postoperative delirium will be measured daily by the Confusion Assessment Method (CAM) and CAM-ICU. The CAM is a standardized screening tool used for identification of delirium symptoms through a diagnostic algorithm based on 4 cardinal features of delirium, namely acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. The CAM-ICU, which is routinely performed in the ICU, includes both brief cognitive testing and the CAM algorithm to screen for delirium. For CAM-positive patients, the Delirium Symptom Interview, a standard cognitive assessment consisting of tests of attention, orientation, and memory will be performed by a research team members trained in the survey administration methodology and blinded to treatment assignment to verify the CAM screening results. |
| Postoperative Delirium | Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days | Incidence of postoperative delirium will be measured daily by the Confusion Assessment Method (CAM) and CAM-ICU. The CAM is a standardized screening tool used for identification of delirium symptoms through a diagnostic algorithm based on 4 cardinal features of delirium, namely acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. The CAM-ICU, which is routinely performed in the ICU, includes both brief cognitive testing and the CAM algorithm to screen for delirium. For CAM-positive patients, the Delirium Symptom Interview, a standard cognitive assessment consisting of tests of attention, orientation, and memory will be performed by a research team members trained in the survey administration methodology and blinded to treatment assignment to verify the CAM screening results. |
| Time to Sleep Onset (TSO) | First night after extubation between 11:00pm and 6:00am | Sleep onset latency will be measured by electroencephalogram (EEG) using a Next Generation SedLine® Brain Function Monitor during the night of the sleep trial in analogy to the primary outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Suvorexant Suvorexant 20 mg will be administered p.o. once a day between 9:00pm and 10:00pm for 7 days starting the night after extubation in the ICU. | 49 |
| Placebo Placebo will be administered p.o. once a day between 9:00pm and 10:00pm for 7 days starting the night after extubation in the ICU. | 51 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued EEG after randomization | 10 | 6 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Suvorexant | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 68 years | 70 years | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 8 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 34 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 9 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 5 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 | 12 Participants | 17 Participants | 29 Participants |
| Race (NIH/OMB) White | 29 Participants | 25 Participants | 54 Participants |
| Sex: Female, Male Female | 12 Participants | 12 Participants | 24 Participants |
| Sex: Female, Male Male | 37 Participants | 39 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 51 |
| other Total, other adverse events | 4 / 49 | 1 / 51 |
| serious Total, serious adverse events | 0 / 49 | 0 / 51 |
Outcome results
Primary
Nighttime Wakefulness After Persistent Sleep Onset (WASO)
Nighttime wakefulness after persistent sleep onset (WASO) will be measured using a SedLine® Brain Function Monitor. WASO will be defined as the duration of wakefulness after the onset of persistent sleep in the observation period between 11:00pm (Lights-Off) to 6:00am (Lights-On) in minutes. Onset of persistent sleep will be defined as the first epoch of 10 consecutive minutes of sleep (REM or non-REM Stages 1, 2, 3 or 4) after Lights-Off. Wakefulness will be defined as any epoch of Stage 0. Sleep staging will be performed according to Rechtschaffen & Kales criteria and in accordance with AASM guidelines. The SedLine® monitor uses a symmetrical bilateral array of sensors that provides four-channel data.
Time frame: First night after extubation between 11:00pm and 6:00am
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Nighttime Wakefulness After Persistent Sleep Onset (WASO) | 200.7 minutes |
| Placebo | Nighttime Wakefulness After Persistent Sleep Onset (WASO) | 184.2 minutes |
Secondary
Total Sleep Time (TST)
Total sleep time will be measured by electroencephalogram (EEG) using a Next Generation SedLine® Brain Function Monitor during the night of the sleep trial in analogy to the primary outcome.
Time frame: First night after extubation between 11:00pm and 6:00am
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Total Sleep Time (TST) | 224 minuts |
| Placebo | Total Sleep Time (TST) | 253 minuts |
Other Pre-specified
Delirium-free Days
Incidence of postoperative delirium will be measured daily by the Confusion Assessment Method (CAM) and CAM-ICU. The CAM is a standardized screening tool used for identification of delirium symptoms through a diagnostic algorithm based on 4 cardinal features of delirium, namely acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. The CAM-ICU, which is routinely performed in the ICU, includes both brief cognitive testing and the CAM algorithm to screen for delirium. For CAM-positive patients, the Delirium Symptom Interview, a standard cognitive assessment consisting of tests of attention, orientation, and memory will be performed by a research team members trained in the survey administration methodology and blinded to treatment assignment to verify the CAM screening results.
Time frame: Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Delirium-free Days | 7 days |
| Placebo | Delirium-free Days | 7 days |
Other Pre-specified
Duration of Sleep During the Day
Continuous EEG-monitoring throughout the day following the sleep trial will be performed until no more than 24 hours after initiation of the sleep trial, or until the patient is discharged from the ICU, whichever occurs first. Duration of sleep during the day will be assessed.
Time frame: Up to 24 hours after initiation of sleep trial
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Duration of Sleep During the Day | 553 minutes |
| Placebo | Duration of Sleep During the Day | 565.5 minutes |
Other Pre-specified
Postoperative Delirium
Incidence of postoperative delirium will be measured daily by the Confusion Assessment Method (CAM) and CAM-ICU. The CAM is a standardized screening tool used for identification of delirium symptoms through a diagnostic algorithm based on 4 cardinal features of delirium, namely acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. The CAM-ICU, which is routinely performed in the ICU, includes both brief cognitive testing and the CAM algorithm to screen for delirium. For CAM-positive patients, the Delirium Symptom Interview, a standard cognitive assessment consisting of tests of attention, orientation, and memory will be performed by a research team members trained in the survey administration methodology and blinded to treatment assignment to verify the CAM screening results.
Time frame: Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Suvorexant | Postoperative Delirium | 10 Participants |
| Placebo | Postoperative Delirium | 11 Participants |
Other Pre-specified
Subjective Sleep Quality: Richards-Campbell Sleep Questionnaire (RCSQ)
Subjective sleep quality will be assessed by applying the Richards-Campbell Sleep Questionnaire (RCSQ). The RCSQ is a validated survey instrument for assessing sleep quality in critically ill patients based on a five-item, visual analogue scale (each from 0 \[worst value\] to 100 \[best value\]). The scale evaluates perceptions of depth of sleep, sleep onset latency, number of awakenings, time spent awake, and overall sleep quality.
Time frame: Every morning from preoperative day 3 up to postoperative day 7
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Subjective Sleep Quality: Richards-Campbell Sleep Questionnaire (RCSQ) | 35.47 points |
| Placebo | Subjective Sleep Quality: Richards-Campbell Sleep Questionnaire (RCSQ) | 34.42 points |
Other Pre-specified
Time to Sleep Onset (TSO)
Sleep onset latency will be measured by electroencephalogram (EEG) using a Next Generation SedLine® Brain Function Monitor during the night of the sleep trial in analogy to the primary outcome.
Time frame: First night after extubation between 11:00pm and 6:00am
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant | Time to Sleep Onset (TSO) | 30.5 miniutes |
| Placebo | Time to Sleep Onset (TSO) | 16.6 miniutes |