Suvorexant and Sleep/Delirium in ICU Patients

Insomnia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04092894
• Other study ID #: 2019P000759
• Status: Recruiting
• Phase: Phase 4
• Start date: February 28, 2020
• Est. completion date: July 1, 2025

Study information

• Verified date: November 2023
• Source: Beth Israel Deaconess Medical Center
• Contact: Balachundhar Subramaniam
• Phone: 617-632-7034
• Email: bsubrama[@]bidmc.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: July 1, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Delirium
• Emergence Delirium
• Insomnia
• Postoperative Delirium
• Sleep Deprivation
• Sleep Fragmentation
• Sleep Initiation and Maintenance Disorders

Intervention

Drug:
• Suvorexant 20 mg
Administration of oral Suvorexant 20 mg
• Placebo oral tablet
Administration of oral placebo (same non-identifiable form as active comparator)

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center/Albert Einstein college of Medicine	Bronx	New York

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

References & Publications (17)

Berry RB, Brooks R, Gamaldo C, Harding SM, Lloyd RM, Quan SF, Troester MT, Vaughn BV. AASM Scoring Manual Updates for 2017 (Version 2.4). J Clin Sleep Med. 2017 May 15;13(5):665-666. doi: 10.5664/jcsm.6576. No abstract available. — View Citation

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Dres M, Younes M, Rittayamai N, Kendzerska T, Telias I, Grieco DL, Pham T, Junhasavasdikul D, Chau E, Mehta S, Wilcox ME, Leung R, Drouot X, Brochard L. Sleep and Pathological Wakefulness at the Time of Liberation from Mechanical Ventilation (SLEEWE). A Prospective Multicenter Physiological Study. Am J Respir Crit Care Med. 2019 May 1;199(9):1106-1115. doi: 10.1164/rccm.201811-2119OC. — View Citation

Drouot X, Roche-Campo F, Thille AW, Cabello B, Galia F, Margarit L, d'Ortho MP, Brochard L. A new classification for sleep analysis in critically ill patients. Sleep Med. 2012 Jan;13(1):7-14. doi: 10.1016/j.sleep.2011.07.012. Epub 2011 Dec 6. — View Citation

Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753. — View Citation

Figueroa-Ramos MI, Arroyo-Novoa CM, Lee KA, Padilla G, Puntillo KA. Sleep and delirium in ICU patients: a review of mechanisms and manifestations. Intensive Care Med. 2009 May;35(5):781-95. doi: 10.1007/s00134-009-1397-4. Epub 2009 Jan 23. — View Citation

Hatta K, Kishi Y, Wada K, Takeuchi T, Ito S, Kurata A, Murakami K, Sugita M, Usui C, Nakamura H; DELIRIA-J Group. Preventive Effects of Suvorexant on Delirium: A Randomized Placebo-Controlled Trial. J Clin Psychiatry. 2017 Sep/Oct;78(8):e970-e979. doi: 10.4088/JCP.16m11194. — View Citation

Herring WJ, Connor KM, Snyder E, Snavely DB, Morin CM, Lines C, Michelson D. Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data. Sleep Med. 2019 Apr;56:219-223. doi: 10.1016/j.sleep.2018.09.010. Epub 2018 Oct 2. — View Citation

Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, Matzura-Wolfe D, Benca RM, Krystal AD, Walsh JK, Lines C, Roth T, Michelson D. Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials. Am J Geriatr Psychiatry. 2017 Jul;25(7):791-802. doi: 10.1016/j.jagp.2017.03.004. Epub 2017 Mar 8. — View Citation

Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T, Michelson D. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology. 2012 Dec 4;79(23):2265-74. doi: 10.1212/WNL.0b013e31827688ee. Epub 2012 Nov 28. — View Citation

Kamdar BB, Shah PA, King LM, Kho ME, Zhou X, Colantuoni E, Collop NA, Needham DM. Patient-nurse interrater reliability and agreement of the Richards-Campbell sleep questionnaire. Am J Crit Care. 2012 Jul;21(4):261-9. doi: 10.4037/ajcc2012111. — View Citation

Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 May;13(5):461-71. doi: 10.1016/S1474-4422(14)70053-5. Epub 2014 Mar 27. — View Citation

Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep. 2013 Feb 1;36(2):259-67. doi: 10.5665/sleep.2386. — View Citation

Tamura K, Maruyama T, Sakurai S. Preventive Effect of Suvorexant for Postoperative Delirium after Coronary Artery Bypass Grafting. Ann Thorac Cardiovasc Surg. 2019 Feb 20;25(1):26-31. doi: 10.5761/atcs.oa.18-00038. Epub 2018 Aug 9. — View Citation

Timm FP, Zaremba S, Grabitz SD, Farhan HN, Zaremba S, Siliski E, Shin CH, Muse S, Friedrich S, Mojica JE, Kurth T, Ramachandran SK, Eikermann M. Effects of Opioids Given to Facilitate Mechanical Ventilation on Sleep Apnea After Extubation in the Intensive Care Unit. Sleep. 2018 Jan 1;41(1). doi: 10.1093/sleep/zsx191. — View Citation

Vacas S, McInrue E, Gropper MA, Maze M, Zak R, Lim E, Leung JM. The Feasibility and Utility of Continuous Sleep Monitoring in Critically Ill Patients Using a Portable Electroencephalography Monitor. Anesth Analg. 2016 Jul;123(1):206-12. doi: 10.1213/ANE.0000000000001330. — View Citation

Younes M, Ostrowski M, Soiferman M, Younes H, Younes M, Raneri J, Hanly P. Odds ratio product of sleep EEG as a continuous measure of sleep state. Sleep. 2015 Apr 1;38(4):641-54. doi: 10.5665/sleep.4588. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	First night after extubation between 11:00pm and 6:00am
Other	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.	Up to 24 hours after initiation of sleep trial
Other	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.	Every morning from preoperative day 3 up to postoperative day 7
Other	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.	Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days
Other	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.	Every day from postoperative day 1 up to day of hospital discharge, an expected average of 21 days
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.	First night after extubation between 11:00pm and 6:00am
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.	First night after extubation between 11:00pm and 6:00am