Efficacy of Suvorexant to Improve Postoperative Sleep and Reduce Delirium Severity in Older Surgical Patients: A Double-blinded, Randomized, Placebo-controlled Trial
Phase: PHASE2
Conditions: Delirium in Old Age
Sponsor: Duke University

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PROTOCOL TITLE  
 
Efficacy of suvorexant to improve postoperative sleep and reduce 
delirium severity in older surgical patients: A double-blinded, 
randomized, placebo-controlled trial  
 
Short Title: REPOSE Study: Reducing Delirium by Enhancing 
Postoperative Sleep with Suvorexant 
 
 
 
 
 
Protocol Number 
PRO 00111869 
 
IND Number: 
163490 
 
NCT05733286 
 
Version 1.0 
 
 
Date 
21 NOV 2022 
 
 
 
 
 
 
 
 
 
 
 

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Sponsor-Investigator: 
Michael Devinney, MD, PhD 
Department of Anesthesiology 
40 Medicine Circle rm 4317, Orange Zone 
Duke Hospital South 
919-681-3579 
 
Funding Sponsor: 
Scientific Affairs Neuroscience 
Global Center for Scientific Affairs 
Merck Sharp & Dohme LLC 
351 N. Sumneytown Pike, UG-2CD30 
North Wales, PA 19454-2505 
Study Product: 
Suvorexant (Brand name: Belsomra) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
STUDY SUMMARY .................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................ 4 
1.1 
BACKGROUND .............................................................................................................................. 4 
1.2 
INVESTIGATIONAL AGENT .............................................................................................................. 5 
 1.3 
CLINICAL DATA TO DATE ............................................................................................................... 6 
1.4 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 7 
2 
STUDY OBJECTIVES........................................................................................................................ 8 
3 
STUDY DESIGN ................................................................................................................................ 9 
3.1 
GENERAL DESIGN ........................................................................................................................ 9 
3.2 
PRIMARY STUDY ENDPOINTS ...................................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................. 10 
3.4 
EXPLORATORY ENDPOINTS ......................................................................................................... 10 
4 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................ 11 
4.1 
INCLUSION CRITERIA .................................................................................................................. 11 
4.2 
EXCLUSION CRITERIA ................................................................................................................. 11 
4.3 
SUBJECT RECRUITMENT AND SCREENING .................................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................. 12 
4.4.1 
When and How to Withdraw Subjects ................................................................................. 12 
4.4.2 
When to Withhold Study Drug ............................................................................................. 12 
       4.4.3      Data Collection and Follow-up for Withdrawn Subjects………………………………………..13 
5 
STUDY DRUG .................................................................................................................................. 13 
5.1 
DESCRIPTION ............................................................................................................................. 13 
5.2 
TREATMENT REGIMEN ................................................................................................................ 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ...................................................... 14 
5.4 
SUBJECT COMPLIANCE MONITORING ........................................................................................... 14 
5.5 
PRIOR THERAPY ........................................................................................................................ 14 
5.6 
PACKAGING ............................................................................................................................... 16 
5.7 
BLINDING OF STUDY DRUG ......................................................................................................... 16 
5.8 
RECEIVING, STORAGE, DISPENSING AND RETURN ........................................................................ 16 
5.8.1 
Receipt of Drug Supplies ..................................................................................................... 16 
5.8.2 
Storage ................................................................................................................................ 16 
5.8.3 
Dispensing of Study Drug .................................................................................................... 16 
5.8.4 
Return or Destruction of Study Drug .................................................................................... 16 
6 
STUDY PROCEDURES ................................................................................................................... 17 
6.1 
VISIT 1 ...................................................................................................................................... 20 
6.2 
VISIT 2 ...................................................................................................................................... 21 
6.3 
VISIT 3. ..................................................................................................................................... 21 
    6.4        Visit 4 and 5 …...………………………………………………………………………………………21 
     6.5        Visit 6…………………………………………………………………………………………………...21 
     6.6        Visit 7 and 8……………………………………………………………………………………………22 
     6.7        Visit 9……………………………………………………………………………………………...……22 
7 
STATISTICAL PLAN ....................................................................................................................... 22 
7.1 
SAMPLE SIZE DETERMINATION .................................................................................................... 22 
7.2 
STATISTICAL METHODS .............................................................................................................. 22 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................. 23 

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8.1 
DEFINITIONS .............................................................................................................................. 23 
8.2 
RECORDING OF ADVERSE EVENTS .............................................................................................  26 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ................................................................................. 26 
8.3.1 
Study Sponsor Notification by Investigator .......................................................................... 26 
8.3.2 
EC/IRB Notification by Investigator ...................................................................................... 27 
8.3.3 
FDA Notification by Sponsor................................................................................................ 27 
8.4 
UNBLINDING PROCEDURES ......................................................................................................... 27 
8.5 
STOPPING RULES ....................................................................................................................... 27 
8.6 
MEDICAL MONITORING ............................................................................................................... 27 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................. 28 
9.1 
CONFIDENTIALITY ....................................................................................................................... 28 
9.2 
SOURCE DOCUMENTS ................................................................................................................ 28 
9.3 
CASE REPORT FORMS ................................................................................................................ 29 
9.4 
RECORDS RETENTION ................................................................................................................ 29 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................. 29 
10.1 
STUDY MONITORING PLAN .......................................................................................................... 29 
10.2 
AUDITING AND INSPECTING ......................................................................................................... 29 
11 
ETHICAL CONSIDERATIONS ........................................................................................................ 29 
12 
STUDY FINANCES .......................................................................................................................... 30 
12.1 
FUNDING SOURCE ...................................................................................................................... 30 
12.2 
CONFLICT OF INTEREST .............................................................................................................. 30 
13 
PUBLICATION PLAN ...................................................................................................................... 30 
14 
REFERENCES ................................................................................................................................. 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
List of Abbreviations 
 
Abbreviation 
Definition 
3D-CAM 
3-minute diagnostic interview for confusion assessment method 
AE 
Adverse Event 

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EEG 
Electroencephalography 
CAM-ICU 
Confusion Assessment Method for the ICU 
CQMP 
Clinical Quality Management Plan 
CRF 
Case Report Form 
CT 
Cat Scan 
CYP2A4 
Cytochrome P450 3A4 
DUMC 
Duke University Medical Center 
EC 
Ethics Committee 
EDTA 
Ethylenediaminetetraacetic Acid 
FDA 
Food and Drug Administration 
HIPPA 
Health Insurance and Portability and Accountability Act 
ICU 
Intensive Care Unit 
IDS 
Investigational Drug Services 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity index 
MOCA 
Montreal Cognitive Assessment 
NPO 
Nothing by Mouth 
OHRP 
Office for Human Research Protections 
PSQI 
Pittsburgh sleep quality inventory 
PHI 
Private Health Information 
PI 
Principal Investigator 
PVT 
Psychomotor Vigilance Task 
RASS 
Richmond-Agitation Sedation Scale 
RCSQ 
Richmond-Campbell Sleep Questionnaire 
RPM 
Revolutions Per Minute 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
TST 
Total Sleep Time 
 
 
 
 
 

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Study Summary 
Title 
Efficacy of suvorexant to improve postoperative sleep and 
reduce delirium severity in older surgical patients: A double-
blinded, randomized, placebo-controlled trial. 
Short Title 
REPOSE Study: Reducing Delirium by Enhancing Postoperative 
Sleep with Suvorexant. 
Protocol Version 
1.0 
Phase 
Phase 2 
Methodology 
Double-blinded, randomized, placebo-controlled trial 
Study Duration 
30 months 
Study Center(s) 
Single-center 
 
 
 
 
 

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Objectives 
Primary Objective:  
- 
To determine the effect of the postoperative administration of 
oral suvorexant (20 mg) on electrographic total sleep time on 
the first night after surgery that patient received study drug. 
 
Secondary Objectives: 
- 
To determine the effect of the nightly administration of 
postoperative suvorexant or placebo on peak postoperative 
delirium severity scores up through postoperative day 5 or 
discharge, whichever occurs first.  
 
Exploratory Objectives: 
Objective sleep measures 
- 
To determine the impact of the daily administration of 
postoperative suvorexant or placebo on 3-night average 
electrographic total sleep time over nights of postoperative 
day 0, 1, and 2.  
 
Subjective sleep measures: 
- 
To determine the effect of the daily administration of 
postoperative suvorexant or placebo on average 
postoperative Richards-Campbell subjective sleep quality 
scores over postoperative day 1, 2,3, 4 and 5. 
 
Other endpoints:  
- 
Additional study endpoints that will be compared between 
suvorexant and placebo groups include: 1. postoperative 
length of stay 2. postoperative pupil diameter fluctuations 
3. average response latency on postoperative 
psychomotor vigilance testing. 
 
Potential effect modifiers: 
- In exploratory analyses, we will determine if the effect of 
suvorexant on sleep characteristics and peak delirium 
severity is modified by specific patient baseline 
characteristics including: 1. Actigraphically measured long 
vs. short preoperative sleep duration 2. High vs. low 
resting preoperative pupil diameter fluctuations; and 3. 
Preoperative average response latency on psychomotor 
vigilance testing. 4. Insomnia severity index scores ≤7 vs 
≥8. 
 
 
 
 
 

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Number of 
Subjects 
130 
Diagnosis and 
Main Inclusion 
Criteria 
Patients ages 65 years old or older undergoing non-cardiac, non-
neurologic surgery who are scheduled to stay overnight in the 
hospital postoperatively 
Study Product, 
Dose, Route, 
Regimen 
Suvorexant (Belsomra®) 20 mg, administered as two 10 mg 
tablets by mouth nightly 
Duration of 
administration 
3 days or until hospital discharge, whichever occurs first. 
Reference 
therapy 
Placebo 
 
Statistical 
Methodology 
Total sleep time on the first postoperative night that study drug is 
received will be compared between treatment groups (placebo 
vs. suvorexant) using a two-sample t-test. Total sleep time on 
the night of postoperative day 1 will be compared between 
treatment groups (placebo vs. suvorexant) using a two-sample t-
test. Peak postoperative delirium severity scores between 
treatment groups will be compared using a two-sample t-test. A 
two-sided alpha level of 0.05 will be required for statistical 
significance.  
 
 
 
 
 
 
 
 
 

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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
1.1 Background 
Sleep deprivation is associated with immune dysfunction,1 disturbed metabolism,2 
cardiovascular disease,3 earlier onset of dementia,4 and increased mortality.5 Thus, there 
is increasing focus on improving sleep in vulnerable patient populations such as older 
surgical patients, because they are at increased risk for postoperative complications and 
prone to sleeping problems before and after surgery.6 Preoperative sleep problems are 
further exacerbated postoperatively in hospital settings due to frequent nursing 
assessments, noisy environments, postoperative pain, and administration of medications 
that disrupt normal sleep architecture.7 Although these postoperative sleep disruptions 
could increase risk for postoperative delirium,8 physical debility,9 and cognitive 
dysfunction,10 we seldom utilize FDA-approved medications that restore normal sleep 
architecture and prevent sleep deprivation in hospitalized older surgical patients because 
there are few studies testing effective sleep aids in this setting. Further, commonly used 
pharmacologic sleep aids such as benzodiazepines actually disrupt normal sleep 
architecture and promote complications such as falls and delirium. Thus, there is an 
urgent need to test therapies that normalize sleep in older surgical patients such as 
suvorexant to determine whether suvorexant improves postoperative sleep and 
decreases the incidence of postoperative delirium.  
 
Postoperative delirium is a fluctuating disturbance in attention and consciousness that 
occurs in up to the 40% of the >19 million older Americans who undergo surgery each 
year. Although postoperative delirium is associated with longer hospitalization, 
decreased quality of life,11 increased risk for Alzheimer’s disease,12, 13 and increased 1-
year mortality, there are few, if any, FDA-approved medications to prevent and/or treat 
delirium.14 To help find interventions to reduce postoperative delirium, our group is 
investigating the role of sleep disruptions in the development of postoperative delirium. 
We have generally found that ~25% of older adults develop postoperative delirium after 
non-cardiac, non-neurologic surgery (Figure 1). In our recently completed study: Sleep 
Apnea, Neuroinflammation, & cognitive Dysfunction Manifesting After Non-cardiac 
surgery (SANDMAN) we investigated the role of neuro-inflammation and disrupted 
sleep (due to sleep apnea) in postoperative delirium. Although we found that sleep 
apnea was not associated with postoperative delirium, preoperative excessive daytime 
sleepiness is associated with increased postoperative delirium severity (Figure 2), 
suggesting that perioperative sleep dysfunction contributes to postoperative delirium. 
Our next step is to measure perioperative sleep disruptions and test interventions to 
improve postoperative sleep, because few studies have determined whether improving 
postoperative sleep actually decreases delirium incidence and severity. Since delirium 
 
 

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is associated with higher hospitalization costs and mortality, there is a critical need to find 
an FDA-approved therapeutic to decrease delirium incidence and severity.  
 
There is also an unmet need for safe and effective sleep pharmacotherapy for older 
hospitalized patients. Commonly used hypnotic sleep aids such as benzodiazepines and 
non-benzodiazepines (z-drugs) are increasingly avoided in hospitalized patients because 
they increase delirium, but this leaves older hospitalized patients with few, if any, options 
for safe pharmacologic sleep aids. Medications that improve circadian alignment, such as 
ramelteon and melatonin are increasingly used but have mild, if any, effects on overall 
sleep time or delirium in hospitalized patients.15 In contrast, suvorexant is an effective 
sleep aid that can be used to treat insomnia and increase total sleep time in older 
dementia patients,16 suggesting that suvorexant has potential as an effective and safe in-
hospital pharmacologic sleep aid in older hospitalized patients. Instead of increasing risk 
for falls and delirium like benzodiazepines and other sleep aids,17 suvorexant might 
decrease delirium (as described above), since it has been found to decrease 
postoperative delirium in older surgical patients in randomized controlled trials in Japan.18, 
19 Thus, it is important that we study suvorexant in older American surgical patients, to 
determine if the Japanese findings are applicable to our population. Even if we find that 
suvorexant has no effect on postoperative delirium, our proposed study will be useful to 
demonstrate that suvorexant effectively improves postoperative sleep, in contrast to the 
benzodiazepines and non-benzodiazepines (z-drugs) that increase delirium and falls. 
These data could support the widespread use of suvorexant to improve postoperative 
sleep in older surgical patients.  
 
Decreased preoperative sleep and circadian rhythm disruptions could increase risk for 
postoperative sleep disruptions and postoperative delirium, but few studies have 
thoroughly evaluated preoperative sleep and circadian rhythms. Wrist-watch actigraphy 
that measure movement using accelerometry can quantify sleep time and sleep onset 
time using well-studied algorithms, allowing for determination of total sleep time and 
circadian patterns. Sleep deprivation and excessive sleepiness is also associated with 
decreased fluctuations in resting pupil diameter. Thus, decreased fluctuation in resting 
pupil diameter could indicate sleep deficits and increased preoperative delirium risk but 
no studies have investigated this. Importantly, these preoperative sleep indicators could 
shed insight into patients who are most likely to benefit from interventions to improve 
postoperative sleep.  
 
Here, we propose a double-blinded, randomized placebo-controlled trial to determine 
whether postoperative suvorexant administration improves objective and subjective 
measures of sleep and reduces postoperative delirium severity in older non-cardiac, 
non-neurologic surgery patients. 
1.2 Investigational Agent 
Belsomra tablets contain suvorexant, an orexin receptor antagonist. Suvorexant is used 
in older adults with insomnia characterized by difficulties with sleep onset and/or 
maintenance. Each film coated table contains 10 mg of suvorexant. Suvorexant is 
administered orally and exhibits similar pharmacokinetics and bioavailability in healthy 

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subjects and patients with insomnia. Suvorexant is primarily metabolized by CYP3A, 
and thus dosage is recommended to be lower in patients receiving moderate CYP3A4 
inhibitors and is not recommended for use with strong CYP3A4 inhibitors.  
 
Each Belsomra tablet contains, suvorexant is a white powder that is insoluble in water in 
addition to the inactive ingredients: croscarmellose sodium, lactose monohydrate, 
magnesium stearate, microcrystalline cellulose, and polyvinylpyrrolidone/vinyl acetate 
copolymer (copovidone). In addition, the film coating contains the following inactive 
ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The film 
coating for the 10 mg tablets also contains FD&C Blue #1/Brilliant Blue FCF Aluminum 
Lake and iron oxide yellow. 
1.3 Clinical Data to Date 
Suvorexant has been previously studied in older adults with mild to moderate 
Alzheimer’s disease for the treatment of insomnia symptoms and was found to 
significantly increase total sleep time and decrease wake after sleep onset time 
compared to those treated with placebo.16 The FDA approved for this data to be 
included in its label packaging insert.  
 
In a small randomized controlled trial in Japan,18 suvorexant significantly improved 
subjective sleep quality and decreased postoperative delirium incidence, suggesting 
that proactive treatment of common postoperative sleep problems in older surgical 
patients could reduce the incidence of delirium.  
 
In our previous studies, we found that delirium occurs in ~20% of older (age≥65) non-
cardiac, non-neurologic surgery patients (Figure 1A) and has a wide range of severity 
(Figure 1B). We have also found that increased preoperative daytime sleepiness was 
associated with increased postoperative delirium severity (Figure 2), suggesting that 
poor sleep could contribute to delirium pathogenesis.  
 
 
  
 

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Figure 2. Older surgical patients with preoperative excessive daytime sleepiness (Epworth Sleepiness 
Scale score ≥13) experienced increased postoperative delirium severity (adjusted odds ratio 3.95, p= 
0.035).  
1.4 Dose Rationale and Risk/Benefits 
We choose to administer 20 mg suvorexant by mouth each night for the first 3 nights 
postoperatively because 1) this dosage has the greatest effect on increasing total sleep 
time in previous clinical trials,20  2) it is unlikely that lower doses of suvorexant would be 
effective in keeping patients asleep because sleep is frequently disrupted in hospital 
settings, and 3) this dosage is being studied to improve postoperative sleep in a 
separate study of older cardiac surgery patients.21 Using the same dose will allow for 
future combined analyses comparing its potential effects across surgical groups on 
postoperative sleep that has potential to help clinicians decide what postoperative 
pharmacologic sleep aid to use. Patients will receive nightly (between 9 and 10PM) oral 
suvorexant, which is the standard administration route and typical time of suvorexant 
administration. Patients will receive suvorexant for up to three nights, starting with the 
night of postoperative day 0, because sleep is most disrupted in this immediate 
postoperative period.22 Patients will not receive any study medication after discharge 
from the hospital because sleep disruptions are less frequent at home. 
 
Known potential risks of suvorexant: 
Most common side effects of suvorexant include: 
1. Headache (7%) 
2. Diarrhea (2%) 
3. Xerostomia (2%) 
4. Cough (2%) 
5. Abnormal dreams (2%) 
6. Dizziness (3%) 
7. Drowsiness (3%) 

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8. Daytime tiredness (4%) 
 
Less common side effects of suvorexant include 
1. Sleep paralysis 
2. Sleep-walking 
3. Itchiness 
4. Nausea 
5. Vomiting 
6. Palpitations 
7. Daytime sedation 
8. Worsening of depression and suicidal Ideation 
 
Known potential benefits of suvorexant: 
There are currently no known benefits of suvorexant administration in older adults after 
surgery. Since suvorexant has been shown to decrease time to sleep onset and 
improve sleep maintenance in outpatients with insomnia, suvorexant has the potential to 
improve postoperative sleep, which could improve patient satisfaction and postoperative 
cognition as well as prevent the development of postoperative delirium.  
2 Study Objectives 
Primary Objective:  
- 
To determine the effect of the postoperative administration of oral suvorexant (20 
mg) on electrographic total sleep time on the first night after surgery that patient 
received study drug. 
 
Secondary Objectives: 
- 
To determine the effect of the nightly administration of postoperative suvorexant 
or placebo on peak postoperative delirium severity scores up through 
postoperative day 5 or discharge, whichever occurs first.  
 
Exploratory Objectives: 
Objective sleep measures 
- 
To determine the impact of the daily administration of postoperative suvorexant 
or placebo on 3-day average electrographic total sleep time over nights of 
postoperative day 0, 1, and 2.  
 
Subjective sleep measures: 
- 
To determine the effect of the daily administration of postoperative suvorexant or 
placebo on average postoperative Richards-Campbell subjective sleep quality 
scores over postoperative day 1, 2,3, 4 and 5. 
 
Other endpoints:  
- 
Additional study endpoints that will be compared between suvorexant and 
placebo groups include: 1. postoperative length of stay 2. postoperative pupil 
diameter fluctuations 3. average response latency on postoperative psychomotor 
vigilance testing. 

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Potential effect modifiers: 
- In exploratory analyses, we will determine if the effect of suvorexant on sleep 
characteristics and peak delirium severity is modified by specific patient baseline 
characteristics including: 1. Actigraphically measured long vs. short preoperative 
sleep duration 2. High vs. low resting preoperative pupil diameter fluctuations; and 
3. Preoperative average response latency on psychomotor vigilance testing. 4. 
Insomnia severity index scores ≤7 vs ≥8. 
3 Study Design 
3.1 General Design 
This randomized, double-blind, placebo-controlled phase II trial will be conducted at 
Duke University Medical Center. A total of 130 subjects, age ≥ 65 undergoing non-
cardiac, non-intracranial surgery with planned inpatient stay ≥ 24 hours will be 
randomized 1:1 to receive nightly oral suvorexant 20 mg vs. placebo on the nights of 
postoperative day 0, 1, and 2. 
 
Prior to surgery, participants will be assessed with structured sleep questionnaires, 
pupillometry, and a sustained attention test known as the psychomotor vigilance task 
(PVT). When there is enough time prior to surgery, wrist-watch actigraphy to measure 
sleep patterns and duration will be attempted for ≥ 3 nights prior to surgery, up to 6 
weeks prior to surgery. Study drug (placebo vs suvorexant 20 mg) will be administered 
once nightly between 21:00 and 22:00 (+- 30 min) on postoperative day 0, 1, and 2 or 
until hospital discharge, whichever occurs first. Postoperative sleep will be measured 
with electroencephalography (EEG) collected with the easy-to-wear Dreem headband 3 
on postoperative nights 0, 1, and 2 or until hospital discharge, whichever occurs first. 
Delirium will be assessed twice daily with the 3D-CAM (or CAM-ICU if non-verbal) up 
until postoperative day 5 or discharge, whichever occurs first.  Subjects will be 
contacted for an adverse event assessment at 4 weeks (+/-2 weeks) after surgery. 

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Table 1: Study Synopsis 
              3.2 Primary Study Endpoints 
Total sleep time (TST) on the first postoperative night that study medication is 
received, as measured by electroencephalography (EEG) with the Dreem 3 
headband. Total sleep time includes amount of time in sleep during the lights out 
period (defined between 21:00 and 06:00). 
3.3 Secondary Study Endpoints 
Peak 3D-CAM postoperative delirium severity scores up through postoperative 
day 5 or discharge, whichever occurs first, in patients receiving suvorexant vs 
placebo 
3.4 Exploratory endpoints 
Objective sleep measures 
- 
Average total sleep time over nights of postoperative day 0, 1, and 2 as 
measured by EEG in patients receiving suvorexant vs placebo. 
 
Subjective sleep measures: 
- 
Average postoperative Richards-Campbell subjective sleep quality scores over 
postoperative days 1,2,3,4 and 5 in patients receiving suvorexant vs placebo 
 
Other endpoints:  
1. Overall postoperative length of stay in patients receiving suvorexant vs. placebo. 
2. Average postoperative resting pupil diameter fluctuations in patients receiving 
suvorexant vs. placebo. 
3. Average response latency on psychomotor vigilance testing postoperatively in 
patients receiving suvorexant vs. placebo 
 

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Potential effect modifiers: 
1. Long (>8 hours average) vs. short (< 6 hours average) sleep preoperative sleep 
duration as measured with wrist-watch actigraphy for at least 3 nights and up to 6 
weeks before surgery 
2. High (upper quartile) vs. low (lower quartile) preoperative resting pupil diameter 
fluctuations as measured with pupillometer before surgery 
3. High (upper quartile) vs. low (lower quartile) average response latency on 
psychomotor vigilance testing preoperatively 
4. Low (≤7) vs. high (≥8) insominia severity index scores measured before surgery 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Age 65 and older 
2. Undergoing non-cardiac, non-intracranial surgery, any surgical procedure not 
involving the skull, brain, cerebrovascular structures  
3. Scheduled postoperative inpatient overnight stay 
4. Able to give informed consent or has legally authorized representative able to 
give informed consent on their behalf 
5. English-speaking 
4.2 Exclusion Criteria 
1. Inmate of correctional facility 
2. Body mass index> 40 
3. Legal blindness 
4. Unable to perform study related questionnaires and assessments 
5. Use of outpatient sedating sleep aids > 2 times per any week in 1 month 
preceding day of surgery. Sedating sleep aids, listed in section 5.5.   
6. History of psychotic disorder, including schizophrenia, schizoaffective disorder, 
schizophreniform or brief psychotic disorder. 
7. History of liver failure with documented international normalized ratio (INR) of 
>1.2 or with history of hepatic encephalopathy 
8. History of severe sleep apnea or obesity hypoventilation syndrome requiring 
home bilevel positive airway pressure therapy or home ventilator or other forms 
of noninvasive ventilation 
9. Chronic lung disease requiring home oxygen therapy 
10. History of narcolepsy 
11. Use of systemic (oral, intravenous, intramuscular, subcutaneous) moderate or 
strong CYP3A inhibitors within 1 week prior to surgery, listed in section 5.5. 
12. Current or planned administration of digoxin, or is currently experiencing digoxin 
toxicity 
13. Undergoing surgery that will result in inability to take medications by mouth 
including laryngectomy, tracheostomy, and oral resection/reconstructive surgery 
14. Undergoing surgery that will require postoperative strict bowel rest, including 
gastrectomy, esophagectomy, and pancreaticoduodenectomy  

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15. Undergoing surgery in an area that will make it unsafe to wear a headband, such 
as scalp or forehead procedures. 
16. Inappropriate for study inclusion based on the judgement of the principal 
investigator. 
4.3 Subject Recruitment and Screening 
Potentially eligible patients will be identified in the electronic medical record by a report, 
and those patients will be sent an automated message through Duke’s MyChart 
application briefly describing the study and including a link to contact the study team if 
they are interested in participating.  Patients will be consented before study activities 
begin. 
 
If the surgical patient is admitted prior to surgery, the patient or their LAR will be 
approached and ask whether they are interested in hearing about the study. If the 
patient is not admitted before surgery, the patient or LAR will be approached in one of 
the preoperative screening clinics, or approached via a phone call by a member of the 
study team using an IRB approved phone script. If the subject or LAR is interested in 
participating in the study, a study team member will explain the purpose, procedures, 
and intent of the study to each potential study subjects or LAR. Written informed 
consent must be obtained before the subject can begin any screening procedures that 
are not considered standard patient care 
 
We will enroll participants of both sexes and all ethnicities and racial groups.  
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
At any time, a subject may be withdrawn from the study at the discretion of the PI.  
 
In the case that study drug is discontinued for any reason after randomization, 
participants will still be encouraged to remain in the study to continue the other study-
related assessments 
 
If the patient withdraws consent to participate in the study, the subject will be withdrawn 
from the study. Consent to obtain data from the electronic medical record will be 
attempted per section 4.4.3.  
 4.4.2 When to Withhold Study Drug 
The study drug will be withheld in the following circumstances:  
1. If the subject has received a strong CYP3A inhibitor (see Section 5.5 for a 
complete list of CYP3A) within 12 hours prior to scheduled study drug 
administration time. 
2. If the subject is scheduled to receive digoxin within 24 hours after administration 
of study drug or is currently experiencing digoxin toxicity. 

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3. If the subject is receiving 8 liters or greater of oxygen via nasal cannula at the 
time of study drug administration. 
4. The subject cannot receive medications by mouth or enteric feeding tube at the 
time of study drug administration. 
5. If at any time during the dose period, participant safety is considered at risk due 
to study drug-related adverse events per the judgement of the PI 
 
Study drug will be administered at half dose in patients who have received a moderate 
CYP3A inhibitor within the past 12 hours from study drug administration.  
 
In the case that study drug is withheld for any reason on any given day after 
randomization, participants will be assessed for study drug eligibility on subsequent 
administration times and will continue the other study-related assessments, pending the 
discretion of the study PI.  
4.4.3 Data Collection and Follow-up for Withdrawn Subjects 
If study drug is discontinued after randomization, the subject will be asked for 
permission to record data and other study-related assessment until the end of the 
follow-up period, because important information about sleep and study outcomes can 
be ascertained from study-related assessments. These assessments include the nightly 
EEG, twice daily delirium assessments, psychomotor vigilance task, pupillometry, and 
questionnaires. Additionally, if a subject no longer wishes to participate in particular 
study activities, those activities will not be performed, but the subject will be asked 
permission to continue other study-related assessments until the end of the follow-up 
period, because important information about sleep and study outcomes can be 
ascertained from study-related assessments. 
 
The study subject can opt out of any assessments at their discretion and remain in the 
study. Additionally, early withdrawal could be related to the study drug and it is 
important to understand factors related to withdrawal from the study and study drug 
administration. If the subject wishes to opt entirely out of the study, the subject will be 
asked permission to record data from the electronic medical record so that 
hospitalization and recovery factors related to study drug administration can be 
ascertained.  
 
5 Study Drug  
5.1 Description 
Suvorexant 10 mg green tablets and matching placebo will supplied by Merck. The 
medication will be stored at 20-25 degrees Celsius. Dosing labels will be attached to 
each study drug dose and include pre-printed fields with  
 Protocol number 
 Personal ID number 
 Participant initials 
 Date 
 Time 

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5.2 Treatment Regimen 
Eligibility to receive study drug will be determined by clinical research staff based on 
study inclusion and exclusion criteria. Study drug (i.e., 2 tablets of suvorexant 10 mg vs 
two tablets of placebo) will be given via mouth or via feeding tube nightly between 21:00 
and 22:00 (±30 min) for the first 3 postoperative nights or until hospital discharge, 
whichever occurs first.  In the case that participants are not able to take medications by 
mouth due to difficulty swallowing, the medication can be administered via an indwelling 
nasogastric or gastrostomy tube, if one is already present and is usable. In the case that 
the patient cannot receive enteric medications (i.e., strict NPO) by study drug 
administration time, then the study drug will not be administered. 
 
• If the patient has received a moderate CYP3A inhibitor within the last 12 hours, 
the study drug dose will be halved by the investigational drug services (i.e., one 
tablet of suvorexant 10 mg vs. placebo will be provided and administered). 
 
• If the patient has received a strong CYP3A inhibitor within 12 hours prior to study 
drug administration, the study drug will not be given to the subject.  
5.3 Method for Assigning Subjects to Treatment Groups 
Stratified permuted block randomization 1:1 to suvorexant vs placebo will be performed 
to assign patients to blinded treatment groups. The randomization will be stratified by 
age and sex. The randomization to study drug will be performed by our investigational 
pharmacy using age by sex strata tables provided by our study statistician, and the 
study team will be blinded to treatment allocation. Randomization will occur on the day 
of surgery.  
5.4 Subject Compliance Monitoring 
The patient care nurse will administer the study drug and document the time of 
administration in the electronic medical record. 
 
Compliance with nightly EEG will be monitored daily via interrogation of the Dreem 
Headband 3 data.   
5.5 Prior Therapy 
Prior Therapy: 
Preoperative medication use will be gathered from the electronic medical record. Prior 
to consent, potential subjects will be asked whether they are taking any of the strong or 
moderate CYP3A inhibitors, digoxin or CYP3A inducers. If they are currently taking 
these medications, then they are not eligible for the study. Additionally, patients will be 
asked whether they are taking medications to help them sleep, and how often that they 
take that medicine. If they have required any sedating sleep medicines greater than 2 
times per week within the last month, they are not eligible for the study.  
 

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Moderate CYP3A inhibitors: Amprenavir, Aprepitant, Atazanavir, Ciprofloxacin, 
Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Imatinib, Verapamil.  
 
Strong CYP3A inhibitors: Ketoconazole, Itraconazole, Posaconazole, Clarithromycin, 
Ritonavir, Saquinavir, Nelfinavir, Indinavir, Boceprevir, Telprevir, Telithromycin, 
Conivaptan 
 
 
Moderate/Strong CYP3A inhibitors: Apalutamide, Carbamazepine, Enzalutamide, 
Ivosidenib, lumacaftor, Mitotane, Phenytoin, Rifampin, St. John’s wort, Bosentan, 
Cenobamate, Dabrafenib, Efavirenz, Etravirine, Lorlatinib, Pexidartinib, Phenobarbital, 
Primidone, Sotorasib. 
 
Sedating sleep aids: Mirtazapine, Trazodone, Flurazepam, Temazepam, Triazolam, 
Estazolam, Quazepam, Clonazepam, Lorazepam, Midazolam, Alprazolam, Diazepam, 
Zolpidem, Zaleplon, Eszopiclone, Diphenhydramine, Doxylamine, Hydroxyzine, 
Suvorexant, Doxepin 
 
Concomitant Therapy: 
For enrolled subjects, the primary clinical team (anesthesia and surgical teams) will be 
instructed to avoid administration of moderate or strong CYP3A4 inhibitors unless there 
is no equivalent alternative therapy. During the study period, the electronic medical 
record will be checked in the evening up to 4 hours prior to release of the study drug to 
assess whether the patient had received any moderate or strong CYP3A inhibitors 
within 12 hours prior to study drug administration time.  
 
• If the patient has received a moderate CYP3A inhibitor within the last 12 hours, 
the study drug dose will be halved by the investigational drug services.  
 
• If the patient has received a strong CYP3A inhibitor within 12 hours prior to study 
drug administration, the study drug will not be given to the subject.  
 
The subject will still be eligible to receive future drug doses on subsequent 
postoperative nights until postoperative night 3, as long as they meet criteria listed 
above (e.g., no strong CYP3A inhibitor within last 12 hours from study drug 
administration time). 
 
Non-sedating concomitant pharmacologic sleep aids such as melatonin and ramelteon 
are permitted at any time during the study. Sedating sleep aids are not permitted 
postoperatively during nights that study drug will be administered unless the patient 
exhibits sleeplessness and is requesting additional pharmacologic sleep aids. In this 
case, additional sleep aid is permitted starting 1 hour after the study drug has been 
delivered up until midnight. After midnight, no further administration of sedating sleep 
aids (for sleeplessness) are permitted. Administration of sedating sleep aids for other 
medical indications are permitted at any time (e.g., administration of midazolam for 
seizures, diphenhydramine for itching, etc.). 

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 5.6 Packaging 
Suvorexant 10 mg tablets and matching placebo will supplied by Merck in bottles. The 
bottles will be labeled with a unique ID.  
5.7 Blinding of Study Drug 
Dosing labels will be attached to each study drug dose and include pre-printed fields 
with  
 Protocol number 
 Personal ID number 
 Participant initials 
 Date 
 Time 
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
Upon receipt of the study drug from Merck, an inventory will be performed by 
Investigational Drug Services (IDS) Pharmacy and a drug receipt log will be 
completed and signed by the personnel receiving the shipment. The counts of 
placebo and suvorexant tablets will be recorded. Damaged and unusable study drug 
in a given shipment will be documented in study files. Merck will be notified of any 
damaged or unusable study treatments that were supplied.  
5.8.2 Storage 
The study drug will be stored in IDS pharmacy at controlled room temperature 
between 20°C to 25°C in the storage area of the investigational site pharmacy, which 
is a secure, temperature controlled, locked environment with restricted access.  
Temperature excursions permitted to 15°C to 30°C, in the original package until use 
to protect from light and moisture. There are no special handling requirements.  
5.8.3 Dispensing of Study Drug 
IDS pharmacy will maintain a Study Drug Dispensing Log. The following information 
will be recorded: 
• Total amount of study drug dispensed (quantity of tablets dispensed) 
• Identification (study number and initials) of the patient to whom the study drug was 
dispensed; 
• Initials of the person who dispensed the study drug; 
• Initials of the person who received the study drug for administration to the patient 
5.8.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, 

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resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. 
6 
Study Procedures 
Table 2: Schedule of Events: 
 
Consent 
Preop 
Postop 
 day 0 
Postop 
day 1 
Postop 
day 2 
Postop 
day 3 
Postop 
day 4 
Postop 
day 5 
Postop 
week 4 
Visit 1 
Visit 22 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Enrollment 
  
  
  
  
  
  
  
  
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics & 
History 
X 
 
 
 
 
 
 
 
 
Confirm 
Inclusion/Exclusion 
X 
X3 
 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
 
 
 
 
Montreal Cognitive 
Assessment (MOCA) 
 
X3 
 
 
 
 
 
 
 
Pittsburgh Sleep 
Quality Index (PSQI) 
X 
 
 
 
 
 
 
 
 
Insomnia Severity 
Risk Index 
X 
 
 
 
 
 
 
 
 
Epworth Sleepiness 
Scale 
X 
 
 
 
 
 
 
 
 
Delirium Assessment 
X 
 
X4 
X4,5 
X4,5 
X4,5 
X4,5 
X4,5 
 
Modified Richards-
Campbell Sleep 
Quality  
 
 
 
X4 
X4 
X4 
X4 
X4 
 
Medications 
 
 
 
 
 
 
 
 
 
Suvorexant vs. 
placebo 
 
 
X4 
X4 
X4 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
Nightly EEG 
 
 
X4 
X4 
X4 
 
 
 
 
 
Wrist actigraphy 
X1,2 
 
 
 
 
 
 
 
 
 
Psychomotor 
vigilance task (PVT) 
 
X3 
 
X4 
X4 
 
 
 
 
Pupillometry 
 
X3 
X4 
X4 
X4 
 
 
 
 
Blood sampling 
 
X3 
 
X4 
X4 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
Adverse Event 
review 
 
X 
X 
X 
X 
X 
X 
X 
X6 
 
Medication Review 
X 
X3 
X 
X 
X 
X 
X 
X 
 
Notes 
  
  
  
  
  
  
  
  
 
1Will be performed if adequate time before surgery 
2Visit 1 and 2 activities may be performed at same time 
3These activities may be performed during visit 1 or anytime between visit 1 and surgery start. 
4These activities will not be performed after hospital discharge  
5Performed twice daily 
6To occur 4 weeks ± 2 weeks after surgery via phone call   
 

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Questionnaires: 
1) Montreal Cognitive Assessment (MOCA): used to measure baseline cognitive 
performance and screen for cognitive impairment. If this assessment is unable to 
be done in a study visit or over web-conferencing, then the MOCA questionnaire 
will be at later time after consent prior to surgery, such as on the day of surgery 
in preoperative holding.  
2) Pittsburgh Sleep Quality Index (PSQI): a questionnaire that assesses sleep 
quality and disturbances over a 1-month time interval, including subjective sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleeping medication, and daytime dysfunction 
3) Insomnia Severity Index (ISI): Assesses the nature, severity, and impact of 
insomnia 
4) Epworth Sleepiness Scale: a questionnaire that assesses excessive daytime 
sleepiness 
5) Delirium will be assessed with the 3-minute diagnostic interview for confusion 
assessment method (3D-CAM) in patients who are able to communicate verbally. 
In non-verbal or intubated patients, the confusion assessment method for the 
intensive care unit (CAM-ICU) will be used in place of the 3D-CAM instrument. 
Delirium will be assessed between once daily prior to 21:00 starting on 
postoperative day#0 and will continue twice daily in the morning (prior to noon) 
and then in the afternoon sometime before 21:00 until the end of postoperative 
day #5, or hospital discharge, whichever occurs first. 
6) Modified Richards-Campbell sleep quality: self-report questionnaire that 
assesses perceived sleep depth, sleep latency, number of awakenings, sleep 
efficiency, quality in addition to the number of hours of daytime napping the day 
prior. This questionnaire will be administered until the end of postoperative day 
#5, or hospital discharge, whichever occurs first. 
 
Relevant tests listed above may be recorded using a digital voice recorder for quality 
assurance purposes. Quality assurance activities will include reviewing of testing audio 
files, generating performance review documents, and providing feedback on accuracy 
and completeness. There is no risk to the trial participants since participant identifiers 
will not be provided. Trial participants will not be identified by name on the recording. 
Only the trial number, test date, and initials of the tester will be provided on the digital 
file label. The link between trial number and participant identifiers will be maintained. 
These files will be stored on locked computers within locked offices to which only 
authorized research personnel will have access.  
 
Nightly EEG:  
After surgery, nightly EEG will be collected using the Dreem Headband 3 (Figure 3) 
approximately between 9PM-6AM on the nights of postoperative day 0, 1, and 2, or until 
hospital discharge, whichever occurs first.   The Dreem headband 3 includes dry frontal 
and occipital EEG electrodes in addition to head accelerometry to determine sleep 
stage and total sleep time. These devices will be cleaned with isopropyl alcohol 
between assessments.  
 

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Figure 3: Dreem Headband 
 
 
Wrist Actigraphy: 
When there is enough time prior to surgery, wrist-watch actigraphy with the Actigraph 
wGT3X-BT will be attempted for ≥ 3 nights prior to surgery up to 6 weeks prior to 
surgery to measure sleep patterns and duration. By measuring motion with the 
actigraph (wrist-watch accelerometer), patterns of inactivity that reflect periods of sleep 
are quantified. This enables quantification of sleep during any period throughout the 
day/night, permitting a comprehensive understanding of sleep timing and patterns (i.e., 
circadian rhythms). The device will be collected when the patient presents for their 
surgery. Preoperative actigraphy will be performed for up to 6 weeks prior to surgery to 
provide information on preoperative total sleep duration. If the participant is unwilling, or 
the equipment is unavailable, the wrist actigraphy will not be performed.  
 
Psychomotor Vigilance Task (PVT):  
The 5-minute psychomotor vigilance task (PVT) is a measure of alertness and 
sustained attention that will be obtained using an electronic device that displays a 
stimulus image at random times, such as a shape on the screen. The participant is 
instructed to press a button as soon as they see the stimulus (i.e., shape on screen). 
Reaction times to the stimulus, lapses (missed stimuli), and errors are recorded 
electronically throughout the 5-minute test, which will be performed in a quiet room 
without interruptions. The data recordings will be recorded in a file that is labeled with 
the patient study number and date but no identifying information on the electronic tablet 

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computer, and the file will be transferred to a secure server after the test. The PVT will 
be performed in the morning sometime before 12:00. If the participant is unwilling, or the 
equipment are unavailable, the psychomotor vigilance task will not be performed. 
 
Pupillometry: 
Pupillometry measurements will also be obtained at the preoperative study visit or 
alternatively on day of surgery, if the equipment is available. Pupil measurements will be 
performed using the NeuroLight infrared pupillometer sold by IDMed. This device is 
510K exempt by the FDA and is already being commercialized in the United States for 
pupil measurements in the intensive care unit setting. Up to three measurements of 
pupil diameter fluctuations at ambient light will be performed in each eye during each 
measurement. Subsequently, pupillary constriction to light will be assessed with the 
device. We expect these measurements to take about 5 minutes on average and no 
longer than 10 minutes. Patients who are blind or cannot tolerate pupil measurements 
will be excluded from these assessments but not from the study. Inability to undergo 
pupil measurements will not prohibit the subject from participating in any other study-
related activity. If the participant is unwilling, or the equipment is unavailable, 
pupillometry will not be performed. 
 
Blood Sampling: 
Blood samples will be used for metabolic/inflammatory marker assays. Whole-blood  
(10mls at each time point) will be collected on the day of surgery before incision, and on 
the mornings of postoperative day 1 and 2, between 8AM and noon.  A total of 30mls of 
blood will be collected for this study. Blood samples will be collected either from an 
arterial or IV catheter, or from sterile venipuncture, into a purple top EDTA tube. After 
collection, the sample will be placed on ice, and then spun in a centrifuge at 4°C at 3500 
RPM for 15 minutes. Samples will be aliquoted intro cryovials and placed into -80°C 
freezer. All assay measurements will be performed at DUMC or in the accredited 
laboratory of a collaborator. All blood samples will be held in freezers in the Department 
of Anesthesiology and/or DUMC research facilities. 
6.1 
Visit 1 – Consent 
During this visit, the study will be explained in detail to the patient, or a legally 
authorized representative, and informed consent will be obtained. This visit can occur in 
person, via secure video web conferencing, or over the telephone.  
 
• Verify eligibility based on inclusion/exclusion criteria 
• Obtain voluntarily given, written informed consent from subject or LAR 
• Record demographics, medical history, and current medication list 
• MOCA 
• PSQI 
• Insomnia Severity Index 
• Epworth Sleepiness Scale 
• Delirium assessment 
• Wrist actigraphy if sufficient time prior to surgery 
• Psychomotor vigilance task 

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• Pupillometry 
• Medication review 
6.2 
Visit 2 – Preoperative  
• Confirm inclusion/exclusion criteria 
• MOCA, if not completed at consent visit 
• Randomization 
• Psychomotor vigilance task, if not completed at consent visit 
• Pupillometry, if not completed at consent visit 
• Blood sampling 
• Adverse event review 
• Medication review 
6.3 
Visit 3 – Postoperative Day of Surgery 
• Delirium assessment 
• Confirm eligibility to receive study drug 
• Study drug administration (between 21:00-22:00 ± 30 min) 
• Nightly EEG 
• Pupillometry 
• Adverse event review 
• Medication review 
 
If the patient is discharged at this time, the study drug will not be administered 
and no further assessments will be completed until the 4-week visit.  
6.4 
Visit 4 and 5 Postoperative days 1-2 
• Delirium assessment (twice daily) 
• Richards-Campbell Subjective Sleep Quality assessment (in morning) 
• Confirm eligibility to receive study drug 
• Study drug administration (between 21:00-22:00 ± 30 min) 
• Nightly EEG 
• Psychomotor vigilance task 
• Pupillometry 
• Blood sampling 
• Adverse event review 
• Medication review 
 
If the patient is discharged at this time, the study drug will not be administered and no 
further assessments will be completed until the 4-week visit.  
6.5 
Visit 6 Postoperative day 3 
• Delirium assessment (twice daily) 
• Richards-Campbell Subjective Sleep Quality assessment (in morning) 
• Blood sampling 

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• Psychomotor vigilance task 
• Pupillometry 
• Adverse event review 
• Medication review 
 
If the patient is discharged at the time of assessment, no further assessments will be 
completed until the 4-week visit.  
6.6 
Visit 7 and 8 – Postoperative Days 4 and 5  
• Delirium assessment (twice daily) 
• Richards-Campbell Subjective Sleep Quality assessment (in morning) 
• Adverse event review 
• Medication review 
 
If the patient is discharged at the time of assessment, no further assessments will be 
completed until the 4-week visit.  
6.7 
Visit 9 – 4-week (+/- 2 week) telephone call 
Study patients will be contacted over the phone to assess for adverse events since  
discharge from the hospital. 
7 Statistical Plan 
7.1 Sample Size Determination 
Based on American Academy of Sleep Medicine insomnia clinical practice guidelines, 
we will consider a 20 minute difference in TST a clinically meaningful difference.25 Given 
a standard deviation (SD) of approximately 35 min for TST in healthy adults,26 a sample 
size of 58 subjects per group will provide 86% power to detect a 20 minute difference in 
TST between treatment groups using a two-sample t-test with a two-sided alpha= 0.05. 
Although few older surgical patients have dementia (<5% in our prior studies), it is still 
possible that the TST SD will be greater than 35 min in our older cohort. Even if our 
measured TST SD approaches 57 min, approximating the SD of TST found in dementia  
patients,16 we would have 80% power to detect a 30 min difference in TST in our study. 
A 30 min difference in TST is a clinically meaningful effect, as it was recently shown in a 
study of older dementia patients treated with suvorexant.16 
7.2 Statistical Methods 
Our primary analysis of sleep will be conducted on a modified intent to treat basis using 
data collected on the first postoperative night that the participant received a dose of 
study drug. The total sleep time and the peak postoperative delirium severity score will 
be compared between suvorexant and placebo groups using a two-sample t-test, and 
subsequent multivariable linear regression. Sensitivity analyses will be performed on the 
full intent-to-treat population, on the per-protocol cohort, and restricted to those who did 

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not receive any additional pharmacologic sleep aid and/or sedatives during the first 3 
postoperative nights.  
 
Covariates chosen for the multivariable modeling will explore potential effect modifiers 
and include insomnia severity index score as the main variable of interest. Further 
precision variables including preoperative performance on the MOCA, excessive 
daytime sleepiness measured with Epworth sleepiness scale, and poor preoperative 
sleep habits measured with the Pittsburgh sleep quality index will also be considered.  
 
Exploratory analysis of the effect of suvorexant administration on postoperative delirium 
incidence will be performed by chi-squared tests and logistic regression.  Mixed model 
regression analyses will be used to explore the effect of suvorexant administration on 1) 
subjective sleep quality as measured with average postoperative Richards-Campbell 
sleep quality scores 2) postoperative pupil diameter fluctuations 3) average response 
latency on postoperative psychomotor vigilance testing and 4) total average 
electrographic sleep time over nights of postoperative day 0, 1, and 2. 
 
8 Safety and Adverse Events 
8.1 Definitions  
Adverse Event 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries 
should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
AE Classification   The following definitions were based on guidelines provided by the 
Office for Human Research Protections (OHRP). The following URL provides useful 
examples to help clarify classification of adverse events 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-
problems/index.html 
 
An AE is deemed an unanticipated problem if it is not expected given (a) the known or 
foreseeable risk of the study procedures that are described in the informed consent 
document or study protocol, (b) the characteristics of the population being studied, (c) 
related or possibly related to participation in the study, and (d) suggests the research 
places subjects are greater risk of harm than previously known. 
 

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The following adverse events are expected in this study population: nausea, vomiting, 
increased incisional pain, wound hernia, wound dehiscence, abscess formation, 
pressure sores, muscular pain, sore throat, endobronchial aspiration, hoarseness, teeth 
trauma, ulceration of lips/mouth/pharynx, vocal cord paralysis, trauma to 
lips/mouth/pharynx, dry mouth, eye trauma, corneal abrasion, blood loss anemia, 
wound infection, acute respiratory failure requiring prolonged mechanical ventilation, 
sepsis, fever, septic shock, perforation of intra-abdominal viscus, peritonitis, diarrhea, 
nerve injury, ileus, mechanical bowel obstruction, dysphagia, deep vein thrombosis, 
pulmonary embolism, pneumonia, respiratory depression, acute hypercapnic respiratory 
failure, acute hypoxic respiratory failure pulmonary atelectasis, urinary retention, urinary 
tract infection, sleeplessness, allergic reaction to medication, lower extremity edema, 
hypotension, supraventricular tachycardia, ventricular tachycardia, myocardial 
infarction, acute renal failure, stroke, acute confusion, delirium, somnolence, agitation, 
and malnutrition due to protein-calorie intake deficiency. 
 
Adverse reactions potentially associated with suvorexant use include: 
- 
worsening of suicidal ideation 
- 
complex sleep behaviors including sleep-walking 
- 
sleep paralysis and cataplexy-like symptoms 
- 
central nervous system depression and daytime impairment 
 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is 
any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 
follow-up.  For this study, the study treatment follow-up is defined as 4 weeks (+/- 2 
weeks) following the last administration of study treatment.  

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Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as 
an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time 
after a subject has discontinued or terminated study participation that may reasonably 
be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one 
of the following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management, e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical                
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 

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 Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator 
      8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the study period must be followed up 
to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
     8.3 Reporting of Serious Adverse Events 
      8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to Merck within 24 hours of the event.  A 
Serious Adverse Event (SAE) form must be completed by the investigator and faxed to 
the Merck within 24 hours.  The investigator will keep a copy of this SAE form on file at 
the study site.  Report serious adverse events by facsimile to: 215-661-6229 or toll-free 
fax 1-800-547-5552. Merck will confirm receipt of the report within one business day. 
 
 
At the time of the initial report, the following information should be provided: 
 Study identifier 
 Study Center 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study treatment was 
discontinued 
 The reason why the event is 
classified as serious 
 Investigator assessment of the 
association between the event 
and study treatment 
Within the following 48 hours, the investigator must provide further information on the 
serious adverse event in the form of a written narrative.  This should include a copy of the 
completed Serious Adverse Event form, and any other diagnostic information that will 
assist the understanding of the event.  Significant new information on ongoing serious 
adverse events should be provided promptly to the study sponsor 

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         8.3.2 IRB Notification by Investigator 
Reports of serious adverse events that are unexpected and related to study drug must 
be submitted to the IRB and Sponsor within 24 hours. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Clinical Investigator’s 
binder. 
         8.3.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA of any unexpected fatal or life-threatening 
experience causally associated with the use of the drug as soon as possible but no later 
than 7 calendar days from the sponsor’s original receipt of the information. Other 
serious, unexpected adverse events associated with the use of study drug shall be 
reported to the FDA no later than 15 calendar days from the sponsors’ original receipt of 
the information. SAEs that are expected and/or unrelated to study drug will be reported 
annually.  
 
If a previous adverse event that was not initially deemed reportable is later found to fit 
the criteria for reporting, the study sponsor will submit the adverse event in a written 
report to the FDA as soon as possible, but no later than 15 calendar days from the time 
the determination is made. 
      8.4 Unblinding Procedures 
In the case that three unexpected, related SAEs are reported in this study, the 
enrollment of new participants will be halted and the unblinded staff statistician can 
perform analyses to determine whether these related SAEs are associated with 
suvorexant vs. placebo. This information then can be used by the medical monitor to 
decide whether to continue the study or halt it.  
      8.5 Stopping Rules  
There are no predetermined stopping rules for efficacy. A staff statistician that will not 
perform analyses related to this study will be unblinded to treatment assignment. 
Additionally, a staff pharmacist at the investigational drug pharmacy will be unblinded to 
treatment assignment. None of these staff members will participate in study-related 
assessments or analyses. We will monitor closely for SAEs. In the case that three 
unexpected, related SAEs are reported in this study, the unblinded staff statistician will 
perform analyses to determine whether these related SAEs are associated with 
suvorexant vs. placebo. This information then will then be used by the medical monitor 
to decide whether to continue the study. 
      8.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. 
This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site 
data and safety-monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  
Medical monitoring will include a regular assessment of the number and type of serious 

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adverse events. A medical monitor will be designated to review unexpected severe 
adverse events to determine if they are related or unrelated to the study drug. This 
study will be subject to Duke Clinical Quality Management (CQM) policy and will have 
designated review.   
9 Data Handling and Record Keeping 
      9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a authorization signed by subject informing the 
subject of the following:  
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.   
      9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, electronic medical record, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, 
and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
      9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  
If a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write 
“N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO 
NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 

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      9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period if 
required by an agreement with the sponsor.  In such an instance, it is the responsibility 
of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
      10.1 Study Monitoring Plan 
This study will be monitored according to the Duke Clinical Quality Management Plan 
(CQMP).  The investigator will allocate adequate time for such monitoring activities. The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all the above noted study-related documents and study related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct 
the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.  The decision of 
the EC/IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before 

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commencement of this study.  The investigator should provide a list of EC/IRB members 
and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for 
review and approval by the EC/IRB for the study.  The formal consent of a subject, 
using the EC/IRB-approved consent form, must be obtained before that subject is 
submitted to any study procedure.  This consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
12 Study Finances       
12.1 Funding Source 
This study is financed through an investigator-initiated grant from Merck. Merck will 
provide Suvorexant to subjects free of charge. 
       12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study.  All investigators will 
follow the University conflict of interest policy. 
13 Publication Plan 
The intent is to publish our data in per-reviewed scientific literature.  Affiliations and 
inclusion of study support will be transparent.  Neither the complete nor any part of the 
results of the study carried out under this protocol, nor any of the information provided 
by the sponsor for the purposes of performing the study, will be published or passed on 
to any third party without the consent of the study sponsor.  Any investigator involved 
with this study is obligated to provide the sponsor with complete test results and all data 
derived from the study. 
 
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