Suvorexant and Sleep/Delirium in ICU Patients

Sponsor

Beth Israel Deaconess Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04092894

Collaborator

Merck Sharp & Dohme LLC (Industry)

120

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Insomnia Sleep Fragmentation Sleep Initiation and Maintenance Disorders Postoperative Delirium	Drug: Suvorexant 20 mg Drug: Placebo oral tablet	Phase 4

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomization in a 1:1 ratio (suvorexant 20 mg versus placebo) will be stratified by duration of perioperative anesthesia and sedation.Randomization in a 1:1 ratio (suvorexant 20 mg versus placebo) will be stratified by duration of perioperative anesthesia and sedation.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Effects of the Orexin Receptor Antagonist Suvorexant on Sleep Architecture and Delirium in the Intensive Care Unit: A Multi-Centric Randomized Controlled Trial

Actual Study Start Date :

Feb 28, 2020

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Suvorexant 20 mg Administration of oral Suvorexant 20 mg Other Names: Belsomra
Placebo Comparator: 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.	Drug: Placebo oral tablet Administration of oral placebo (same non-identifiable form as active comparator) Other Names: Placebo

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Suvorexant 20 mg

Administration of oral Suvorexant 20 mg

Other Names:

Belsomra

Placebo Comparator: 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.

Drug: Placebo oral tablet

Administration of oral placebo (same non-identifiable form as active comparator)

Other Names:

Placebo

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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 Outcome Measures

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.
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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Age 60 years or older
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:

Preoperative left ventricular ejection fraction of less than 30%
Renal failure (creatinine >2 mg/dl or dialysis dependence)
Liver failure (CHILD-Pugh>4)
Coma (RASS<-1)
Signs and symptoms of delirium and agitation at time of enrollment (CAM-ICU positive)
Montreal Cognitive Assessment (MoCA) below 23 at time of consent
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)
Severe sleep apnea requiring home continuous positive airway pressure treatment
Morbid obesity (BMI >40)
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).
Patients with known hypersensitivity to study medications
English language limitations (Sleep assessment and delirium assessment tools are only validated in English)
Patients enrolled in other interventional studies which could confound the primary endpoint.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
2	Montefiore Medical Center/Albert Einstein college of Medicine	Bronx	New York	United States	10467

Sponsors and Collaborators

Beth Israel Deaconess Medical Center
Merck Sharp & Dohme LLC

Investigators

Principal Investigator: Matthias Eikermann, Montefiore Medical Center/Albert Einstein College of Medicine
Principal Investigator: Balachundhar Subramaniam, Beths Israel Deaconess Medical Center