Protocol and design of the REPOSE study: a double-blinded, randomised, placebo-controlled trial to evaluate the efficacy of suvorexant to improve postoperative sleep and reduce delirium severity in older patients undergoing non-cardiac surgery

Abstract

Introduction
Postoperative delirium occurs in up to 40% of older surgical patients and has been associated with prolonged hospital stays, long-term cognitive impairment and increased 1-year postoperative mortality. Postoperative sleep disturbances may increase the risk of delirium, but studies investigating pharmacotherapies to improve postoperative sleep to prevent delirium remain limited. Suvorexant is a selective antagonist of orexin 1 and 2 receptors and is approved for insomnia pharmacotherapy by the Food and Drug Administration. It has the potential to improve postoperative sleep and reduce postoperative delirium rates, but randomised controlled trials (RCTs) are needed to determine the efficacy of postoperative suvorexant administration. The REPOSE study ( r educing delirium by e nhancing po stoperative s leep with suvor e xant) is a single-centre, randomised, double-blinded RCT that aims to evaluate the efficacy of suvorexant in increasing total sleep time (TST) and decreasing delirium severity in older patients undergoing non-cardiac surgery.

Methods and analysis
REPOSE will enroll 130 patients (aged ≥65 years) undergoing non-cardiac surgery with a planned postoperative inpatient stay. Participants will be randomised to receive 20 mg oral suvorexant or placebo nightly on postoperative nights 0, 1 and 2. The primary endpoint is TST on the first postoperative night, as measured using an electroencephalography headband. The secondary endpoint is peak postoperative delirium severity as measured by the 3-minute diagnostic interview for the confusion assessment method severity scores. Primary endpoint data will be analysed with a two-sample t-test using an intent-to-treat approach to compare TST on the first night that a patient received a study drug dose. Secondary and exploratory endpoint data will be analysed using two-sample t-tests between groups.

Ethics and dissemination
Ethical approval was obtained from the Duke Institutional Review Board (protocol #00111869). Results of the REPOSE study will be published in a peer-reviewed journal and presented at academic conferences. Trial data will be deposited in ClinicalTrials.gov.

Trial registration number
NCT05733286 .

Full text

1
FallonJM, etal. BMJ Open 2025;15:e091099. doi:10.1136/bmjopen-2024-091099
Open access
Protocol and design of the REPOSE
study: a double- blinded, randomised,
placebo- controlled trial to evaluate the
efcacy of suvorexant to improve
postoperative sleep and reduce delirium
severity in older patients undergoing
non- cardiac surgery
John Michael Fallon ,1 Mona Hashemaghaie,2 Christy E Peterson,2
Dieplinh Tran,3 Sophie R Wu,4 Jonathan M Valdes,1 Nicole M Pedicini,1
Melissa E Adams,2 Marjorie Soltis,5 Wissam Mansour,6 Mary Cooter Wright,2
Karthik Raghunathan,2 Miriam M Treggiari,2 Cina Sasannejad ,5
Michael J Devinney 2
To cite: FallonJM,
HashemaghaieM, PetersonCE,
etal. Protocol and design of
the REPOSE study: a double-
blinded, randomised, placebo-
controlled trial to evaluate
the efcacy of suvorexant to
improve postoperative sleep
and reduce delirium severity
in older patients undergoing
non- cardiac surgery. BMJ Open
2025;15:e091099. doi:10.1136/
bmjopen-2024-091099
►Prepublication history
and additional supplemental
material for this paper are
available online. To view these
les, please visit the journal
online (https://doi.org/10.1136/
bmjopen-2024-091099).
Received 12 July 2024
Accepted 14 February 2025
For numbered afliations see
end of article.
Correspondence to
Dr Michael J Devinney;
michael. devinney@ duke. edu
Protocol
© Author(s) (or their
employer(s)) 2025. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ Group.
ABSTRACT
Introduction Postoperative delirium occurs in up to 40%
of older surgical patients and has been associated with
prolonged hospital stays, long- term cognitive impairment
and increased 1- year postoperative mortality. Postoperative
sleep disturbances may increase the risk of delirium,
but studies investigating pharmacotherapies to improve
postoperative sleep to prevent delirium remain limited.
Suvorexant is a selective antagonist of orexin 1 and 2
receptors and is approved for insomnia pharmacotherapy
by the Food and Drug Administration. It has the potential
to improve postoperative sleep and reduce postoperative
delirium rates, but randomised controlled trials (RCTs)
are needed to determine the efcacy of postoperative
suvorexant administration. The REPOSE study (reducing
delirium by enhancing postoperative sleep with suvorexant)
is a single- centre, randomised, double- blinded RCT that
aims to evaluate the efcacy of suvorexant in increasing
total sleep time (TST) and decreasing delirium severity in
older patients undergoing non- cardiac surgery.
Methods and analysis REPOSE will enroll 130 patients
(aged ≥65 years) undergoing non- cardiac surgery with
a planned postoperative inpatient stay. Participants
will be randomised to receive 20 mg oral suvorexant or
placebo nightly on postoperative nights 0, 1 and 2. The
primary endpoint is TST on the rst postoperative night,
as measured using an electroencephalography headband.
The secondary endpoint is peak postoperative delirium
severity as measured by the 3- minute diagnostic interview
for the confusion assessment method severity scores.
Primary endpoint data will be analysed with a two- sample
t- test using an intent- to- treat approach to compare TST
on the rst night that a patient received a study drug dose.
Secondary and exploratory endpoint data will be analysed
using two- sample t- tests between groups.
Ethics and dissemination Ethical approval was
obtained from the Duke Institutional Review Board
(protocol #00111869). Results of the REPOSE study will
be published in a peer- reviewed journal and presented
at academic conferences. Trial data will be deposited in
ClinicalTrials. gov.
Trial registration number NCT05733286.
INTRODUCTION
Postoperative delirium is a disorder charac-
terised by acute confusion, impaired atten-
tion, disorganised thinking and disturbances
in consciousness, and it typically occurs in
the first 3 days following surgery.1 Postop-
erative delirium affects up to 40% of older
STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒This study uses electroencephalography headbands
to determine whether postoperative suvorexant
administration increases postoperative total sleep
time.
⇒Trained staff members assess the secondary out-
come of delirium severity twice daily using the
3- minute diagnostic interview for the confusion as-
sessment method delirium assessment.
⇒This study will not provide information on whether
suvorexant improves sleep following hospital dis-
charge, because the drug and sleep measurements
are stopped upon hospital discharge.
⇒The single- centre setting limits the generalisability
to other populations due to potential site- specic
biases.
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patients undergoing surgery and is associated with
increased hospital length of stay, long- term cognitive
decline, Alzheimer’s disease and related dementias and
increased 1- year postoperative mortality.2–5 Although
delirium is associated with poor postoperative outcomes,
there are few interventions that prevent delirium, in part
due to the difficulty of addressing unmodifiable delirium
risk factors, such as older age and baseline cognitive
impairment.6
One potentially modifiable risk factor for delirium is
postoperative sleep disturbance.7–10 Sleep is a funda-
mental physiological process that influences cognition,
emotional well- being, immune function and homeo-
stasis.11–14 Following surgical procedures, patients
frequently experience sleep disruptions due to exces-
sive hospital noise and light, postoperative pain and the
effects of medications administered during the perioper-
ative period.15–17 Thus, strategies that mitigate postoper-
ative sleep disturbances and promote sleep hygiene may
decrease the risk of postoperative delirium.15 18 19 Addi-
tionally, the appropriate administration of pharmacolog-
ical sleep aids may help prevent postoperative delirium.
However, few studies have widely investigated pharmaco-
logical sleep aids for postoperative delirium prevention,
in part because some sedating pharmacological sleep aids
may increase the risk of delirium. For instance, benzodi-
azepines, often given for sedation in the intensive care
unit (ICU), exacerbate postoperative delirium in older
patients in the ICU.20–24 Consequently, recent guidelines
from the American Geriatric Society discourage the use
of benzodiazepines in older adults.25
Suvorexant is an emerging alternative pharmacotherapy
for treating sleep disturbances. Suvorexant received Food
and Drug Administration approval in 2014 for the treat-
ment of insomnia and acts by blocking orexin recep-
tors. Orexin is a wake- promoting neuropeptide pivotal
for sleep regulation.26 27 By blocking orexin receptors,
suvorexant improves both sleep onset latency and wake
after sleep onset. Interestingly, suvorexant administration
acutely reduces cerebrospinal fluid phosphorylated tau
levels, an Alzheimer’s disease biomarker, which suggests
that blocking the orexin pathway may affect Alzheimer’s
disease- related pathology.28–30 Additionally, suvorexant
increases total sleep time (TST) in older adults with prob-
able Alzheimer’s disease dementia. Thus, suvorexant may
be an ideal candidate for postoperative sleep pharmaco-
therapy in older patients undergoing surgery who are at
high risk for delirium.31
To evaluate suvorexant’s efficacy in increasing postoper-
ative sleep and reducing postoperative delirium severity,
we are conducting a single- centre, double- blinded,
placebo- controlled, randomised trial. Our primary
hypothesis is that postoperative suvorexant administra-
tion increases TST in older patients undergoing surgery.
Secondarily, we hypothesise that suvorexant administra-
tion decreases postoperative delirium severity. Our study
aims to provide valuable insights into the potential thera-
peutic role of suvorexant to improve postoperative sleep
and reduce delirium severity in older patients under-
going surgery.
METHODS AND ANALYSIS
Study design
This randomised, double- blinded, placebo- controlled
trial will be conducted at a single centre at Duke Univer-
sity Medical Center in Durham, North Carolina, USA.
The trial began on 28 June 2024 and is estimated to finish
enrollment in late 2025. The study design schedule is
outlined in table 1 and is approved by the Duke Institu-
tional Review Board (IRB). Participants will be enrolled
and randomised to intervention until 130 participants
have completed the primary outcome data for analysis.
Study population
This study will enroll patients undergoing non- cardiac
surgery with a planned postoperative inpatient overnight
stay, who will undergo randomisation and receive at least
one dose of the study drug. Inclusion and exclusion
criteria are listed in table 2. Exclusion criteria include
factors that affect suvorexant administration safety, phar-
macokinetics or metabolism/excretion and the ability
to safely wear the electroencephalography (EEG) head-
band (eg, intracranial surgery). Given the complexity of
patient and surgical factors that could affect the safety of
suvorexant administration or study assessment, we will
also sparingly exclude some cases based on the principal
investigator’s judgement. The reasons for these principal
investigator determinations will be provided in the results
of the study.
Potential candidates will be identified and screened
for eligibility using the electronic health record. Eligible
participants will be contacted through either an auto-
mated MyChart message or a phone call by a designated
study team member using the IRB- approved phone script.
All subjects will be informed of the purpose, procedures
and intent of the study and be provided with a consent
form (see online supplemental file 1) prior to enroll-
ment. Informed written consent will be obtained before
the subject initiates any study activities or begins any
screening procedures that are not considered standard
patient care activities. All sexes, races and ethnicities will
be recruited.32
Intervention
At least 130 participants will be randomised to receive
suvorexant (20 mg) or a matched placebo for the first 3
postoperative nights while in the hospital. Patients will
be administered suvorexant or placebo orally unless
they are not able to take medications by mouth due to
difficulty swallowing, in which case the medication can
be administered via an indwelling nasogastric or gastros-
tomy tube if one is already present and is usable. Patients
will be assigned to blinded treatment groups through
stratified permuted block randomisation in a 1:1 ratio
for suvorexant or placebo. Stratification will be based
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on age (≥70 years and <70 years of age) and sex (male vs
female) to ensure balanced age and sex between study
groups. The administration will occur starting on postop-
erative day 0 through postoperative day 2, between 20:00
and 22:00. After an order for the study drug is placed,
the investigational drug pharmacy will be responsible for
randomising, barcoding and labelling the study drug.
The study team will then deliver the study drug to the
bedside nurse, who will scan the study drug into the elec-
tronic medical record after administration in order to
accurately track the study drug administration for each
participant. The study team and participants will remain
blinded to treatment allocation throughout this process.
Because suvorexant is primarily metabolised by CYP3A,
the primary clinical team for enrolled subjects will be
advised to avoid ordering moderate or strong CYP3A
inhibitors.33 If recent exposure (<12 hours) to a moderate
CYP3A inhibitor is noted in the electronic health record,
the study drug dose will be halved, and if the subject is
exposed to a strong inhibitor (within 12 hours of study
drug administration), the study drug will not be adminis-
tered. However, eligibility for future doses on subsequent
postoperative nights is retained if criteria are met. Non-
sedating sleep aids like melatonin are allowed anytime,
while sedating sleep aids (table 3) are generally restricted
on nights of the study drug. To allow for the standard
of care treatment of in- hospital insomnia, patients are
permitted sedating sleep aids for persistent sleeplessness
1 hour after study drug administration, up until midnight.
The use of rescue sedating sleep aids for sleeplessness will
be reported between placebo and suvorexant. Patients
who receive rescue sedating sleep aids will not be excluded
from the primary analysis.
Several strategies will be used to promote retention and
completeness of follow- up data. First, in the case that the
study drug is discontinued for any reason after randomi-
sation, participants will still be encouraged to remain in
the study to continue the other study- related assessments.
Second, if the participant is withdrawn from the study
for any reason, every effort will be made to continue
collecting data from the electronic medical record.
In the case that three unexpected, related serious
adverse events are reported in this study, the enrollment
of new participants will be halted, and an unblinded staff
statistician will perform analyses to determine whether
these related serious adverse events are associated with
the suvorexant or placebo group. This information will
then be used by the designated medical monitor to decide
whether to continue the study.
Study outcomes and assessment
Primary endpoint
The primary endpoint is TST, which is defined as the
amount of time spent sleeping during the lights- out
period (21:00–6:00) on the first night after surgery
that the patient receives the study drug. TST will
be assessed using EEG during postoperative nights
0 through 2 or until hospital discharge, whichever
occurs first. A headband with frontal electrodes,
along with a 3D accelerometer, will be used to record
EEG data, and the data will be saved for later analysis
to determine sleep stage and TST (figure 1).34 This
sleep EEG will allow for the determination of TST
Table 1 Schedule of study events
Before
Surgery
Postoperative
day 0
Postoperative
day 1
Postoperative
day 2
Postoperative
day 3
Postoperative
day 4
Postoperative
day 5
Questionnaires
Montreal Cognitive Assessment X
Athens Insomnia Scale X
Insomnia Severity Risk Index X
Epworth Sleepiness Scale X
Delirium Assessment X X* X*† X*† X*† X*† X*†
Modied Richards- Campbell Sleep
Quality
X* X* X* X* X*
Medications
Suvorexant versus placebo X* X* X*
Procedures
Nightly EEG X* X* X*
Wrist actigraphy X‡
Psychomotor vigilance task X X* X* X*
Pupillometry X X* X* X* X*
*These activities will not be performed after hospital discharge.
†Performed two times per day.
‡Activity is optional, must be worn for at least 3 days prior to surgery.
EEG, electroencephalography.
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despite the frequent interruptions of sleep that occur
postoperatively in the hospital wards. The headband
is designed to be less invasive than standard poly-
somnography so that study subject sleep is minimally
impacted by EEG monitoring, and EEG recording
adherence is optimised.
Sleep scoring of the EEG will be performed by
trained sleep technologists overseen by sleep medicine
physicians. Each 30 s epoch will be scored according
to the American Academy of Sleep Medicine Manual
for sleep stage and associated events.35 In epochs with
poor EEG quality, where sleep stage is indeterminate,
Table 2 Inclusion and exclusion criteria of the REPOSE study with rationale
Inclusion criteria Rationale
Aged 65 years and older Older patients undergoing surgery have higher insomnia symptom burden,
shorter total sleep times and higher risk of delirium compared with younger
patients.
Undergoing non- cardiac, non- intracranial surgery, any surgical procedure not
involving the skull, brain and cerebrovascular structures
Patients undergoing cardiac surgery are often exposed to sedatives
postoperatively in the ICU, and patients undergoing intracranial surgery
may have increased sensitivity to suvorexant, possibly increasing the risk of
adverse events.
Scheduled postoperative inpatient overnight stay Study drug administration and assessments must occur while in the
hospital as they are not feasible in the outpatient setting in this study.
Able to give informed consent or has a legally authorised representative who is able to
give informed consent on their behalf
Required to maintain ethical standards.
English speakers Delirium assessment and sleep questionnaires are only available in English,
and non- English speakers face a barrier to informed consent.
Exclusion criteria
Inmate of a correctional facility Inmates are considered a vulnerable population that require additional
protections and limitations in our health system, which are not feasible in
this study.
Body mass index >40 Patients with obesity may have altered pharmacokinetics of suvorexant,
leading to decreased drug effect.
Legal blindness Vision is required to complete study assessments.
Unable to complete study- related questionnaires and assessments Study- related questionnaires and assessments are required for data
analysis.
Use of outpatient sedating sleep aids (see table2) more than two times per any week
in the 1 month preceding the day of surgery
To avoid concomitant administration of other sedating sleep aids with
suvorexant, which has not been well- studied and may lead to increased
adverse events.
History of psychotic disorders, including schizophrenia, schizoaffective disorder,
schizophreniform disorder or brief psychotic disorder
These psychotic disorders may increase the risk of adverse events, since
suvorexant may cause increased suicidal ideation.
History of liver failure with a documented international normalised ratio>1.2 or with a
history of hepatic encephalopathy
Liver disease may decrease suvorexant metabolism and clearance,
increasing the risk of adverse events.
History of severe sleep apnoea or obesity hypoventilation syndrome requiring home
bilevel positive airway pressure therapy, home ventilator or other forms of non-
invasive ventilation
Clinically signicant respiratory depression effects of suvorexant in patients
with severe central sleep apnoea have not been ruled out in other studies.
Chronic lung disease requiring home oxygen therapy Mild respiratory depression effects of suvorexant may increase the risk of
adverse events in this patient population.
History of narcolepsy Suvorexant is contraindicated in narcolepsy.
Use of systemic (oral, intravenous, intramuscular and subcutaneous) moderate or
strong CYP3A inhibitors within 1 week prior to surgery
Because CYP3A enzymes metabolise suvorexant, moderate or strong
CYP3A inhibitors may decrease suvorexant metabolism and increase risk
for advere events.
Use of systemic (oral, intravenous, intramuscular, subcutaneous) moderate or strong
CYP3A inducers within 1 week prior to surgery
Because CYP3A enzymes metabolise suvorexant, moderate or strong
CYP3A inducers may increase suvorexant metabolism and decrease the
efcacy of suvorexant.
Current or planned administration of digoxin or is currently experiencing digoxin
toxicity
Potential drug interactions; suvorexant administration results in decreased
digoxin metabolism.
Undergoing surgery that will result in the inability to take medications by mouth,
including laryngectomy, tracheostomy and oral resection/reconstructive surgery
Study drug requires oral administration or durable enteral access such as
large- bore feeding tube, which is not typically placed after these surgeries.
Undergoing surgery that will require postoperative strict bowel rest, including
gastrectomy, oesophagectomy and pancreaticoduodenectomy
Patients on strict bowel rest cannot take enteral medications and thus have
no route to receive suvorexant.
Undergoing surgery in an area that will make it unsafe to wear a headband, such as
scalp or forehead procedures
An EEG headband is required for the measurement of total sleep time and
sleep architecture.
Inappropriate for study inclusion based on the judgement of the principal investigator Individuals may have unique risk factors that make them unsuitable to
receive suvorexant per clinical judgement.
EEG, electroencephalography; ICU, intensive care unit; REPOSE, reducing delirium by enhancing postoperative sleep with suvorexant.
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sleep presence will be imputed based on adjacent
epoch staging. In epochs where the adjacent epoch
staging is also indeterminate, the accelerometer data
will be used to estimate whether the patient was asleep
or awake.
Secondary endpoint
The secondary endpoint is peak postoperative delirium
severity scores up through postoperative day 5 or
discharge. The 3- minute diagnostic interview for the
confusion assessment method (3D- CAM) will be used to
assess delirium in patients who are able to communicate
verbally.36–38 The 3D- CAM measures delirium severity
through attention and cognitive assessments, including
orientation items, short- term recall and digit span tasks.
It then scores the presence of key delirium features, such
as acute or fluctuating course, inattention, disorganised
thinking and altered level of consciousness.38 In non-
verbal or intubated patients, the confusion assessment
method for the ICU (CAM- ICU) will be used instead.39
Assessment will first occur in the afternoon, prior to 21:00,
on postoperative day 0. Subsequently, from postoperative
days 1 to 5, assessments will be systematically documented
two times per day until the conclusion of postoperative
day 5 or hospital discharge, whichever occurs first. The
first assessment will be administered prior to 12:00, and
the second assessment will be administered between
12:00 and 21:00.
Exploratory endpoints
Sleep architecture and other sleep features
Using the EEG headband data, differences in postopera-
tive sleep architecture (including stages 2 and 3 Non- REM
sleep and REM sleep) will be compared in patients who
received suvorexant compared with those who received
placebo using two- sample t- tests. No multiple comparison
correction for multiple sleep stages is planned because
these are exploratory analyses. The average TST over all
nights that subjects receive the study drug will also be
compared using two- sample t- tests.
Subjective sleep quality
To assess subjective sleep quality, the Richards- Campbell
Subjective Sleep Quality Questionnaire will be admin-
istered daily from postoperative day 1 until postopera-
tive day 5 or hospital discharge, whichever occurs first.
The total subjective sleep quality score will be compared
between placebo and suvorexant groups using a two-
sample t- test.
Sleep-related impairment in sustained attention
Sleep deprivation results in a decreased ability to sustain
attention, which can be measured with the 5 min psycho-
motor vigilance task (PVT).40 The PVT measures simple
reaction times to a visual stimulus over 5 minutes to assess
for slowed responses and lapses (ie, failed response to
visual stimuli).40 41 Response times, speed and lapses will
Table 3 Sedating sleep aids restricted in the REPOSE study
Sedating sleep aid Common name
Mirtazapine Remeron
Trazodone Desyrel, Oleptro
Flurazepam Dalmane
Temazepam Restoril
Triazolam Halcion
Estazolam Prosom
Quazepam Doral
Clonazepam Klonopin
Lorazepam Ativan
Midazolam Versed
Alprazolam Xanax
Diazepam Valium
Zolpidem Ambien
Zaleplon Sonata
Eszopiclone Lunesta
Diphenhydramine Benadryl
Doxylamine Unisom
Hydroxyzine Atarax, Vistaril
Suvorexant Belsomra
Doxepin Silenor
REPOSE, reducing delirium by enhancing postoperative sleep with suvorexant.
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be compared between suvorexant- treated and placebo-
treated groups to see if postoperative nightly suvorexant
has an effect on these sustained attention measures.
Using the NASA PVT+ application on an Apple iPad, the
PVT will be collected before surgery and daily on post-
operative day 1 and ending on postoperative day 3 or
hospital discharge, whichever occurs first. Analyses will
also examine preoperative- to- postoperative change in
sustained attention measures to adjust for preoperative
performance variability between subjects.
Delirium incidence and duration
The incidence and duration of postoperative delirium
in treatment groups will also be reported. Although this
study does not have adequate power to detect differences
in delirium incidence, these data could be useful to guide
future larger studies or in a meta- analysis of all studies of
suvorexant and delirium.
Pupillary unrest in ambient light
Pupillary unrest under ambient light is an index of spon-
taneous pupil fluctuations that occur secondary to the
activity of the locus coeruleus, an important brainstem
nucleus involved in the maintenance of wakefulness and
attentional control.42 43 Decreased wakefulness has been
associated with decreased pupillary unrest under ambient
light, suggesting that pupillary unrest in ambient light is
a marker of sleep deprivation- related alterations in wake-
fulness and attention. Here, infrared pupillometry will
be used to measure pupil diameter fluctuations under
ambient light conditions both before surgery and daily
up through postoperative day 3.44 We will compare post-
operative changes in pupillary unrest under ambient light
in both suvorexant- treated and placebo- treated groups
using a two- sided t- test.
Effect modication factors
Suvorexant effect modification by baseline cognitive
status, insomnia symptoms, excessive sleepiness and sleep
habits will be assessed by preoperatively administering
the Montreal Cognitive Assessment (MOCA), Insomnia
Severity Index, Epworth Sleepiness Scale (ESS) and the
Athens Insomnia Scale (AIS), respectively (table 4).
Study participants will also be offered a wrist actigraph
to wear before surgery to quantitatively measure preop-
erative sleep duration and sleep habits. This will be done
as an optional substudy and when feasible. Participants
will be asked to wear the wrist actigraph for at least 3
nights so that circadian rhythms and average TST can
be determined.45 Effect modification by these baseline
factors will be assessed by comparing point estimate
Figure 1 Electroencephalography (EEG) recordings of relatively acceptable sleep architecture (A and B) and relatively
disturbed sleep architecture (C and D). (A) Sleep architecture is preserved in one night of interrupted sleep, with sleep stages N2
and N3 observed alongside short periods of Rapid Eye Movement sleep (REM) in a hypnogram constructed from EEG data. (B)
N3 sleep is captured in a 60 s interval across ve channels, derived from pairings of the four electrodes (F7, F8, O1 and O2). (C)
Sleep architecture is disturbed in one night of interrupted sleep, as suggested by observation of N2 sleep without N3 or REM
stages. (D) N2 sleep is recorded across the ve channels in a 60 s period of irregular sleep.
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FallonJM, etal. BMJ Open 2025;15:e091099. doi:10.1136/bmjopen-2024-091099
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outcome effect sizes in subgroups (baseline cognitive
impairment vs normal cognition, excessive sleepiness
presence, insomnia symptom presence and preoperative
short versus long sleep). These results will be considered
hypothesis- generating for future study designs on postop-
erative sleep pharmacotherapy.
Data management and monitoring
All participants will be assigned a subject study number
so that their data will be de- identified. EEG data will be
accessed through a secure cloud- based platform and
backed up in secure local drive, while pupillometry and
PVT data will be stored on a secure local drive. All other
data will be stored on the secure web- based REDCap
software. Technical appendix, statistical code and the
relevant dataset will be available from the Vivli Clinical
Research Data Repository (https://vivli.org/). This study
will be monitored according to the Duke Clinical Quality
Management Plan, which includes biannual indepen-
dent reviews of all study- related documents and facilities.
The principal investigator will also permit study- related
monitoring, audits and inspections of all study- related
documents and facilities by the IRB, sponsor, government
regulatory bodies and university compliance and quality
assurance groups.
Adverse events and safety
Adverse events will be assessed daily by study staff. The
principal investigator will determine whether the adverse
event was unrelated, unlikely related, possibly related,
probably related or definitely related to study drug
treatment. Any symptom, sign, illness or experience
that develops or worsens in severity will be identified as
an adverse event and reported to the sponsor and IRB,
if necessary. All adverse events occurring during the
study period will be recorded in the source document
and case report form. The most common side effects of
suvorexant include headache, diarrhoea, xerostomia,
cough, abnormal dreams, dizziness, drowsiness and
daytime tiredness. Minor side effects include sleep paral-
ysis, sleepwalking, itchiness, nausea, vomiting, palpita-
tions, daytime sedation and worsening of depression and
suicidal ideation.46 47 Study drug- related adverse events
will be reported for placebo versus suvorexant groups in
the manuscript results. Study subjects may be withdrawn
from the study at any time by the principal investigator.
In the case that three unexpected, related serious
adverse events are reported in this study, an unblinded
staff statistician will perform analyses to determine
whether these related serious adverse events are associ-
ated with the suvorexant or placebo group. This informa-
tion will then be used by a designated medical monitor, an
appointed physician not involved in the study, to decide
whether to continue the study.
Statistical analysis
Since some patients may miss a study drug dose on the
first postoperative night, the primary analysis will be
conducted on a modified intent- to- treat basis comparing
TST on the first night that a patient received a study
drug dose with a two- sample t- test. Secondary analysis
will compare peak postoperative delirium severity scores
between suvorexant and placebo groups with a two-
sample t-test. This modified intent- to- treat analysis will
only include those patients who received the study drug
dose. Based on the American Academy of Sleep Medicine
Insomnia Clinical Practice Guidelines, we will consider a
20 min difference in TST a clinically meaningful differ-
ence.48 We expect that a sample size of 130 subjects
Table 4 Summary of study questionnaires and assessments
Questionnaires Assesses Tasks
Montreal Cognitive Assessment Cognition Tasks such as trail- making, drawing, naming objects, memory recall, attention span, verbal
uency, abstraction, delayed recall and orientation
3- minute Diagnostic Interview for
Confusion Assessment Method
Delirium Structured interview with observer ratings to assess delirium symptoms such as orientation,
memory, attention, hallucinations and level of consciousness. Subsequent observer ratings
determine sleepiness, stupor, hypervigilance, clarity of ideas, speech, attention uctuation,
distraction, consciousness uctuation and potential acute changes
Insomnia Severity Risk Index Insomnia Scaled responses (0–4) regarding severity of insomnia problems, satisfaction with sleep
patterns and sleep interference with daily functioning
Athens Insomnia Scale Insomnia Scaled responses (0–3) regarding sleep latency, awakenings, total sleep duration, sleepiness
and overall sleep quality
Epworth Sleepiness Scale Daytime sleepiness Scaled responses (0–3) regarding the likelihood of sleeping in various daytime situations
Assessments
EEG Sleep patterns Dry electrodes within the headband that non- invasively record brainwaves while sleeping
Wrist actigraphy Sleep patterns Wrist- worn device with 3- axis accelerometers and lux metre
Psychomotor Vigilance Task Attention Randomly displayed stimuli on a tablet to which the participants respond by tapping on the
screen; records their reaction times, lapses and errors
Pupillometry Cognition Evaluation of pupil diameter uctuations under ambient light conditions through an infrared
camera
EEG, electroencephalography.
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8FallonJM, etal. BMJ Open 2025;15:e091099. doi:10.1136/bmjopen-2024-091099
Open access
will yield a total of 116 subjects with complete primary
and secondary endpoint data. Given an SD of approxi-
mately 35 min for TST in healthy adults, a sample size of
58 subjects per group will provide 86% power to detect
a 20 min difference in TST between treatment groups
using a two- sample t- test with a two- sided alpha of 0.05.31
Prrior to unblinding and analysis, additional patients may
be recruited until a total of 116 subjects have complete
primary and secondary endpoint data.
For the secondary endpoint, we will consider a 50%
reduction in peak postoperative delirium severity scores
to be a clinically meaningful difference. A 50% reduction
in delirium severity is reasonable, as another study that
included non- pharmacological sleep promotion found a
reduction in delirium incidence by approximately 50%.49
Given a delirium severity SD of 1.8 and a mean peak
3D- CAM delirium severity score of 1.9 in the placebo
group, a sample size of 58 patients per group will provide
80% power to detect a 0.95- point difference between treat-
ment groups using a two- sided t- test with an alpha of 0.05.
In order to control for preoperative delirium status, as
well as other potential confounders, we will subsequently
use multivariable linear regression to assess the presence
of treatment effect. Delirium incidence and duration, two
exploratory outcomes, will be assessed via logistic regres-
sion, time- to- event and zero- inflated log- linear modelling.
Exploratory endpoint analysis will compare the effects
on subjective sleep quality, postoperative pupil diameter
fluctuations, average response latency in psychomotor
vigilance testing and total average electrographic sleep
time over postoperative days 0, 1 and 2, if applicable,
between suvorexant and placebo groups.
Precision variables include preoperative measures,
including the score on the MOCA, excessive daytime
sleepiness measured with the Epworth Sleepiness Scale,
and poor preoperative sleep reported with the Athens
Insomnia Scale.50–52
Author afliations
1Duke University, Trinity College of Arts and Sciences, Durham, North Carolina, USA
2Department of Anesthesiology, Duke University School of Medicine, Durham, North
Carolina, USA
3Louisiana State University School of Medicine, New Orleans, Louisiana, USA
4Duke University Pratt School of Engineering, Durham, North Carolina, USA
5Department of Neurology, Duke University School of Medicine, Durham, North
Carolina, USA
6Department of Medicine, Duke University School of Medicine, Durham, North
Carolina, USA
Acknowledgements We thank all subjects who participate in the REPOSE study.
Contributors MD conceptualised the study. MD, JMF, MH, CEP, MCW, JMV, NMP,
MEA, MS, WM, KR, MT and CS contributed to the study design. JMF, DT, SRW and
MD contributed to drafting the test and preparing gures and tables. All authors
critically reviewed and edited the nal draft. MD is the guarantor.
Funding Supported in part by a research grant from the Investigator- Initiated
Studies Program of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,
Rahway, New Jersey, USA. The opinions expressed here are those of the authors
and do not necessarily represent those of Merck Sharp & Dohme LLC, a subsidiary
of Merck & Co., Inc., Rahway, New Jersey, USA.
Competing interests Support for this study is provided by Merck Sharp &
Dohme LLC, a subsidiary of Merck & Co. (to MJD). MJD acknowledges additional
support from NIA R01AG073598, K23AG084898, and P30AG072958 grants. MT
acknowledges a clinical trial grant from Edwards Life Sciences Corporation.
Patient and public involvement Patients and/or the public were not involved in
the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs
John MichaelFallon http://orcid.org/0009-0006-4378-4644
CinaSasannejad http://orcid.org/0000-0001-6617-567X
Michael JDevinney http://orcid.org/0000-0003-3906-6421
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