Clinical trial NCT06630390
Conditions: POSTOPERATIVE DELIRIUM POSTOPERATIVE COGNITIVE DECLINE
Keywords: delirium sleep cognitive decline Alzheimer disease and related dementias
Sponsor: University of Rochester
Start date: 2024-11-11; Completion date: 2025-02-16
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this phase 2 clinical trial is to demonstrate the feasibility of the current study methods and obtain preliminary data for an adequately powered trial of daridorexant with the aim of preventing delirium after heart surgery. The main aims this feasibility trial aims to answer are to demonstrate: (1) the feasibility of study recruitment; (2) the ability deliver study compounds to subjects according to the proposed methods; and (3) completeness of data capture; and (4) recording of potential adverse events.

Participants will: (1) complete a baseline visit; (2) take the study drug--either daridorexant or placebo--each of the first 3 nights after heart surgery; and (3) be evaluated for sleep and delirium each of the first three days after heart surgery.

Detailed description:

Arms: arm 1: Oral daridorexant 50 mg (or 25 mg, if taking a moderate 3A4 inhibitor) each of the first three nights after heart surgery. arm 2: Oral matching placebo each of the first three nights after heart surgery.
Interventions: intervention 1: Daridorexant 50 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Administered consistent with labeling from the US Food and Drug Administration. intervention 2: Identical appearing to daridorexant

Protocol documents:
Prot_000.pdf: 
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Randomized, double-blind trial of daridorexant to prevent delirium after heart surgery
PI: Mark Oldham, MD
1. PURPOSE OF THE STUDY
Purpose: This feasibility study is designed to inform and ultimately support a grant application for 
funding for an adequately powered randomized, clinical trial (RCT) of daridorexant to prevent 
postoperative delirium. In this phase 2 study, we will test the following specific aims:
Aim 1: To demonstrate that we can recruit subjects for a placebo-controlled RCT of daridorexant to 
prevent postoperative delirium.
Target: We will enroll up to 16 subjects. Our recruitment goal is four subjects per month, for a total of 
12 subjects completing the protocol.
Aim 2: To demonstrate that we can deliver study compounds to subjects per our proposed methods, 
including successful use of the OnCore Enterprise Clinical Trial Management System.
Target: All doses of study compound will be delivered successfully.
Aim 3: To demonstrate successful capture of preoperative, intraoperative, and postoperative data 
relevant for analyses during the conduct of this trial.
Target: We aim for 100% data capture, including subject retention through all doses of study 
compound.
Aim 4: To document all potential adverse events (AEs) and serious adverse events (SAEs).
Target: All subjects will be evaluated daily after receipt of study compound for AEs and SAEs.
2. BACKGROUND AND RATIONALE
A. Significance
A.1. Postoperative delirium is a serious, unmet public health need:
Delirium costs an estimated $38–$164 billion annually in the US and causes untold stress on patients, their 
families, and caregivers. It predicts greater risk of institutionalization, Alzheimer’s disease and related 
dementias (ADRD), and death.3-5 A third of all older adults have delirium during medical hospitalization. 
After cardiac surgery, 25–50% develop delirium.6 More than 75% of critically ill adults and up to 85% of 
palliative care patients at the end of life develop delirium.7 Despite its tremendous public health 
significance, most delirium is not preventable with current interventions,8 and no intervention decisively 
improves delirium or its outcomes, including ADRD.9 There is a dire need for efficacious, well tolerated 
interventions to prevent and treat delirium.
A.2. Delirium after heart surgery is especially important: 
Cardiac surgery is plagued with delirium: rigorous studies report 25–50% incidence.6 Post-cardiotomy 
delirium prevention has also often met with a sense of nihilism10 due to unique challenges relative to other 
surgical cohorts,11 only underscoring the need for efficacious delirium therapeutics in this population. 
Post-cardiotomy delirium is associated with nearly 3x higher mortality, 6x higher risk of 24h+ 
mechanical ventilation, and longer ICU and hospital duration.12


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A.3. Sleep/wake disturbance (SWD) confer vulnerability to delirium9,13-15:
SWD is a core feature of delirium,16-20 with research diagnostic criteria for delirium including SWD as one 
of delirium’s three core domains.20,21 Although whether SWD directly cause delirium has yet to be 
established,22,23 there is strong evidence for the physiological link between SWD and delirium. Sleep is 
governed by the diencephalon (i.e., hypothalamus and thalamus).24 The anterior hypothalamus contains the 
sleep/wake “switch,” which coordinates transitions between sleep and wake via dense reciprocal 
connections with all major sleep/wake centers in the brain.25 The thalamus controls slow waves,26 sleep 
spindles (linked with attentional disorders),27 and sensory gating.28 Each of these sleep/wake processes 
regulated by the diencephalon is disrupted in delirium,29-32 strongly suggesting that maintaining or restoring 
sleep/wake integrity could combat delirium. Given that SWD are modifiable, they are an obvious and 
promising target for innovative pharmacological trials to prevent delirium.9,13-15
A.4. Prior “sleep” trials for delirium are methodologically limited33:
 Most prior trials have studied circadian interventions and conflate the two related but dissociable 
processes of sleep/wake—process S (sleep propensity) and process C (endogenous circadian rhythm).34 
Melatonin/melatonin agonists influence circadian rhythms but have very limited effects on sleep quality.35 
Most prior circadian trials, which have yielded negative results,36-47 have used circadian interventions 
with the goal of improving sleep, rather than studying them according to circadian principles, such as 
evaluating premorbid circadian phase to inform timing or evaluating circadian rhythmicity.48 Sleep 
studies need to consider the specific effects of an intervention on sleep architecture (e.g., REM sleep, N2 
transients, N3), which is different from circadian studies that should evaluate effects on circadian rhythm 
(e.g., 24-hr amplitude, dim-light melatonin onset).49
A.5. Orexin stabilizes sleep and wake states: 
Orexin, also called hypocretin, is secreted by the tuberal hypothalamus and stabilizes sleep and wake 
states. Central orexin deficiency is the underlying cause of type 1 narcolepsy, which presents with 
excessive daytime sleepiness accompanied by either an irrepressible need to sleep or frank lapses into 
sleep.50 The densest orexin projections are to the noradrenergic locus coeruleus with other projections to 
the cholinergic basal forebrain and serotonergic raphe nuclei.50 Orexin receptor (OX1R/OX2R) 
antagonism inhibits noradrenergic activity, thereby facilitating sleep onset.51 In humans, orexin 
antagonism increases total sleep time, reduces sleep latency, and reduces wake after sleep onset.52 
A.6. Application of dual orexin receptor antagonists (DORAs) to neurodegenerative disorders: 
Many reasons encourage studying DORAs in relation to delirium. DORAs (1) are efficacious in older 
adults;52,53 (2) have good tolerability in older adults, including at the highest approved doses;52,53 (3) do 
not suppress N2 transients, N3 sleep, or REM sleep;54 (4) lack GABA-ergic activity;55 (5) lack clinically 
significant anticholinergic effects;56-58 (6) do not prolong the QTc to a clinically relevant degree;56-58; (7) 
have very limited abuse liability;59 (8) do not cause rebound insomnia or withdrawal;60 (9) improve total 
sleep time in obstructive sleep apnea;60 (10) do not worsen obstructive sleep apnea at therapeutic doses;61 
(11) reduce stress-induced insomnia62 and exert anxiolytic effects63 in rodent models; and (12) appear to 
improve CSF clearance of Alzheimer disease biomarkers even after a single nightly dose.64 Their effects 
on postural stability65 and reaction time66 are limited, and less than those of GABA-ergic agents like 
benzodiazepines. The three FDA-approved DORAs are similar pharmacologically; however, 
daridorexant has the shortest half-life and negligible next-morning effects in clinical trials (Table 
1).52,67,68 Given that cognitive performance is worst in the morning, especially attention69 (n.b., inattention 
is delirium’s hallmark feature), and that delirium assessments often occur in the morning, the ideal DORA 
for delirium prevention should have negligible morning cognitive effects. Thus, daridorexant is the most 
promising DORA for delirium prevention. 


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Table 1 - Comparison of DORAs approved by the US FDA for insomnia 
Daridorexant
Suvorexant
Lemborexant
OX1R binding affinity (Ki)
0.47 nM
0.55 nM
6.1 nM
OX2R binding affinity (Ki)
0.93 nM
0.35 nM
2.6 nM
Major metabolite
None
None
M10
Effects on QTc
Not clinically relevant
Not clinically relevant
Not clinically 
relevant
Mean Tmax
1-2 hours
2 hours
1-3 hours
Volume of distribution
31 L
49 L
1970 L
Terminal t1/2
8 hours
12 hours
17 hours
Metabolism
CYP3A4 (89%)
CYP3A > CYP2C19
CYP3A4 > CYP3A5
Severe liver impairment
“Not recommended”
“Not recommended”
“Not recommended”
Severe renal impairment
50% higher Cmax
No dose adjustment
50% higher Cmax
A.7. A new program of sleep-delirium trials:
 This proposed trial is the first in an anticipated research program that aims to combat delirium with sleep 
interventions. This project builds on the PI’s K23 work investigating SWD in relation to delirium 
and will serve as a transition into translational research to develop sleep-focused delirium 
therapeutics. 
A.8. Whether sleep-focused interventions combat delirium, thus improving long-term cognitive 
outcomes, is unproven:
 SWD are also closely associated with the permanent, progressive conditions of AD and CVD, which cause 
dementia, and considered a potential mechanism causing or accelerating these conditions,14,70-73 perhaps by 
way of disrupted glymphatic clearance.74 If (a) delirium mediates the relationship between SWD and 
AD/CVD and (b) preserving healthy sleep/wake prevents delirium,64,75-77 then preventing delirium could 
prevent subsequent AD/CVD.73 What the field needs are conclusive data linking discrete sleep/wake 
interventions with the prevention of delirium and its dire cognitive and functional outcomes, 
including ADRD. This project is aligned with the ADRD Milestones as it investigates targets of delirium 
vulnerability along with longer-term outcomes9 by examining the mechanisms that link delirium physiology 
with its sequelae.78
A.9. Summary of significance: 
Although delirium is an acute event, it often has permanent effects on patients’ cognition and function. To 
date, no medication is FDA-approved to prevent or treat delirium, along with its terrible costs to 
patients, their families, and health systems.
B. Innovation
B.1. The orexin system invites delirium-related investigation:
Orexin is a promising alternative target to GABA for sleep pharmacology, especially in older adults. Early 
evidence suggests that DORAs may have a role in relation to delirium.75,76,79-83 Both published RCTs of the 
DORA suvorexant to prevent delirium were positive but have methodological limitations, including that 
neither was double-blind. The first, from 2017, randomized 72 ICU and medical unit patients (mean age 
78) to suvorexant or placebo in a “rater blind” manner and found a lower delirium incidence with 
suvorexant: 0 (0%) vs 6 (17%), p = 0.025.75 The second, from 2018, randomized ICU patients to placebo 
or standard care and found a longer time to delirium with suvorexant (6.3d vs 5.7d, log–rank test p < 0.05);84 
however, 80% of comparison arm subjects arm received as-needed trazodone 25 mg qhs, confounding 


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clinical interpretation. Critical readers are skeptical about these data, as with any delirium study that finds 
a 0% delirium incidence in any study arm. Further, rigorous delirium trials have often failed to replicate 
early delirium studies: for instance, despite a promising 2014 ramelteon trial85 (n.b., from the authors of the 
2017 suvorexant trial above) have not held up, as shown in a 2023 meta-analysis.86 Moreover, compelling 
data will be needed to overcome a general apprehension re the use of sleep aids in older adults and the 
prevailing convention that they be used only as a “last resort.”87 The field awaits the first double-blind 
RCT to prevent postop delirium and the first delirium prevention RCT of daridorexant.
B.2. This study employs methodologically rigorous trial design using a true sleep aid:
 As above, most prior “sleep” studies for delirium have investigated circadian interventions rather than 
interventions that improve sleep quality. This study aims to overcome the limitations of these prior trials 
by using an agent demonstrated to improve sleep quality and shorten wake bout duration using rigorous 
trial design (Error! Reference source not found.).
B.3. This project represents a transition from observational to interventional research for the PI:
This trial represents the first of an anticipated program of sleep-focused clinical trials to prevent as well as 
treat delirium. The delirium field is replete with observational research in delirium predictors and 
outcomes.88,89 However, there is far less translational inquiry, and precious little evidence of efficacious 
interventions.90 A new generation of double-blind, placebo-controlled trials is urgently needed in the 
delirium field.
B.4. Summary of innovation: 
This daridorexant trial studies a highly promising, novel intervention to prevent postop delirium in older 
adults, a condition for which there is no approved medication and little translational inquiry. Preventing 
delirium would improve postop recovery and well-being and might even reduce the neuropathological 
progression of AD. This is the first trial to study daridorexant to prevent delirium in any context. 
Establishing that daridorexant prevents delirium could have immediate, transformative value for clinical 
practice.
3. ADMINISTRATIVE ORGANIZATION
This single-site trial represents a collaboration among the Department of Psychiatry, Department of 
Anesthesiology, and the Department of Surgery, Division of Cardiac Surgery. Randomization with a 
block size of six and drug dispensing will occur through Investigational Drug Services (IDS) at Strong 
Memorial Hospital (SMH). Prospective subjects may be identified in the hospital while awaiting surgery, 
at the time of outpatient evaluation by a cardiac surgeon, or in conjunction with anesthesiology during 
pre-surgical history and physical, typically performed at the Center for Perioperative Medicine.
Table 2 - Considerations in sleep-delirium trials
Methodological consideration
Limitations of prior trials
The agent should enhance sleep.
Agents that entrain circadian phase.
The sleep aid should be taken each night before delirium 
assessments.
Several trials with non-nightly 
dosing.39,40,42,46,47
Sleep should be evaluated across subjects as a measure 
of primary effect
Most have neglected to assess sleep.39-
41,43,44,47
Baseline sleep health should be evaluated.
Very rare in prior studies (e.g.46).
Accounting for in-hospital sleep disruptions.
Done in only three (i.e., 36,37,45).
Measure of ADRD biomarkers
Not done previously.


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4. STUDY DESIGN
This double-blind, parallel-group trial will randomize patients having cardiac surgery—either surgical 
aortic valve replacement (SAVR) or coronary artery bypass graft (CABG) surgery—to oral daridorexant 
50 mg or identical-appearing placebo. The primary outcomes are feasibility and safety. Study subjects 
will provide written informed consent after receiving a complete description of the study. See Figure 1 
below for a timeline of study assessments (not to scale).
Figure 1 – Timeline of Study Assessments
Abbreviations: 3D-CAM, 3-minute Diagnostic interview for the Confusion Assessment Method; CAGE-
AID, CAGE [an acronym for “Cut down, Annoyed, Guilty, Eye-opener”] Adapted to Include Drugs; 
POD, postoperative day; PON, postoperative night; TICS, Telephone Interview for Cognitive Status
*25 mg for subjects on a moderate 3A4 inhibitor (see 4.2 STUDY INTERVENTION below for details)
4.1 SUBJECT POPULATION
We will enroll 16 persons scheduled to have SAVR or CABG at SMH, with the goal of having 12 
subjects complete the protocol.
Choice of study population: 
We propose a cardiac surgery cohort for several reasons. (1) Surgery provides a convenient model for 
understanding delirium pathophysiology and interventions as it allows for describing the sample at 
baseline and prospectively evaluating a cohort at elevated risk of delirium. (2) Cardiac surgery is 
associated with a 25–50% delirium incidence6, due in large part to the older mean age of this population. 
As noted above, we have found 30% delirium incidence after SAVR at our institution. (3) We select a 
cardiac surgery cohort over a hip repair cohort as the pain associated with hip pathology and the postop 
surgical site affects sleep positions before and after surgery, which contributes to SWD, thereby 
introducing a potential confound.
The subjects in this trial do not qualify as vulnerable populations.
4.2 STUDY INTERVENTION
We will administer enteral daridorexant 50 mg each evening before bedtime, from 8 to 10 PM. Per the 
package insert,58 subjects taking a moderate inhibitor of CYP 3A4 (per searchable FDA site92) will 
receive a reduced dose of 25 mg. Moderate inhibitors of 3A4 include: aprepitant, ciprofloxacin, 
conivaptan, crizotinib, diltiazem, dronedarone, erythromycin, fluconazole, grapefruit juice, imatinib, 
isavuconazole, verapamil. Of these, those most likely to be present are the antibacterials ciprofloxacin or 
erythromycin or the calcium channel blockers diltiazem or verapamil.
Choice of agent and dose: 
DORAs represent a promising class of agents for delirium studies. In a phase 3 trial vs placebo, 
daridorexant 50 mg reduced wake after sleep onset (WASO) and latency to persistent sleep (LPS) on 
polysomnography (-22.8 min [95% CI -28.0 to -17.6); -11.4 min [-16.0 to -6.7], respectively), as well as 


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improved self-reported total sleep time (TST) (22.1 min [14.4 to 29.7]) and Insomnia Daytime Symptoms 
and Impacts Questionnaire sleepiness scores (-1.8 [-2.5 to -1.0).52 Lower doses (10 & 25 mg) had less 
effect on sleep outcomes, with some not reaching statistical significance.52 Although the 50-mg dose had 
greater efficacy, its AEs were nearly identical to that of lower doses (Table 3, see below52). Daridorexant 
improved WASO, LPS, and subjective TST comparably in older (≥ 65 yr) and younger adults (< 65 yr), 
with nearly identical rates of AE.53 Another concern for most sleep aids is risk of falls; however, among 
older adults, falls were numerically less likely with either 25 or 50 mg daridorexant than with 
placebo (1/119 [0.8%], 1/119 [0.8%], 4/122 [3.3%], respectively).53 Daridorexant improves not only 
sleep but also next-day functioning, as one would hope for an ideal sleep aid. Given that central orexin 
deficiency is the putative cause of type 1 narcolepsy, core features of narcolepsy are theoretically possible 
with DORAs. Nevertheless, among older adults, these were extremely rare: 1/121 taking 25 mg 
daridorexant reported excessive daytime sleepiness, and 1/119 (1%) on daridorexant 50 mg reported sleep 
paralysis.53 We propose using 50 mg rather than 25 mg to maximize the chances of clinical effect, as 
this higher dose does not appear to increase the risk of AEs. 
Table 3 - Adverse events (AEs) & serious AEs (SAEs) with daridorexant (DAR) & 
placebo52
Placebo
Study 1
n=309
Placebo
Study 2
n=306
DAR 50 
mg
Study 1
n=310
DAR 25 
mg
Study 2
n=308
DAR 25 
mg
Study 2
n=308
DAR 10 
mg
Study 2
n=306
Any AE
105 
(34%)
100 
(33%)
116 
(38%)
117 
(38%)
121 
(39%)
117 
(38%)
Any SAE
7 (2%)
7 (2%)
3 (1%)
2 (1%)
3 (1%)
3 (1%)
Nasopharyngitis
20 (6%)
16 (5%)
20 (6%)
21 (7%)
13 (4%)
16 (5%)
Headache
12 (4%)
11 (4%)
19 (6%)
16 (5%)
15 (5%)
12 (4%)
Somnolence
6 (2%)
4 (1%)
5 (2%)
11 (4%)
10 (3%)
6 (2%)
Choice of dosing days/times: 
We will give 50 mg daridorexant (25 mg to those on moderate 3A4 inhibitor, as above) or placebo 8-10 
PM on the first 3 postop nights and evaluate delirium on each of the days following administration—i.e., 
POD 1–3. We give study agent the night prior to each day’s assessment because the prior night’s sleep 
directly impacts cognition the next day. Sleep restriction causes neurocognitive impairment the 
following day with the most pronounced effects in sustained attention (vigilance).93 We choose 8-10 PM 
because daridorexant’s Tmax is 1–2 hr. This (1) allows time for its soporific effect and (2) is early enough 
to mitigate next-morning sedation).52,67,68 For any subject still intubated during the 8-10 PM window, we 
will allow for administration up to midnight in the event that they are extubated prior to midnight. This is 
to maximize the likelihood of administration on the first postoperative night.
Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or subject populations are changed: 
On September 18, 2024, we received a determination from the US FDA that our proposed trial “meets all 
meets all of the requirements for exemption from the IND regulations and, therefore, an IND is not 
required to conduct [this] investigation.” See attached document, “FDA exemption determination (24-09-
18).”
Medication and matching placebo will be stored by IDS, who will be responsible for randomization 
subjects to study arms, keeping records on medication storage, and ensuring timely dispensing.


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5. INCLUSION 
Inclusion criteria:
 ≥ 60 yrs; having cardiac surgery at Strong Memorial Hospital; can provide consent; able to speak, read, 
and write English (as the instruments, including semi-structured interviews, used in this protocol have 
been validated in English); family member or close friend for collateral.
Exclusion criteria: 
Exclusion criteria with rationales are described in Table 4. Subjects will be screened in person or by 
phone for eligibility.
Table 4 - Exclusion criteria with explanation
Exclusion criteria
Definition (rationale)
Prior cardiotomy
Per self-report or chart (sequelae of prior surgery)
Infectious endocarditis
Per chart (potential septic emboli)
Emergency surgery
Per chart (baseline eval impossible)
Delirium at baseline
Positive 3D-CAM (limit to incident delirium)
Auditory/visual 
impairment prevents 
study procedures
Per self-report or demonstrated inability during baseline visit (inability to 
participate)
Alcohol/substance 
misuse
CAGE-AID score of 2 or greater (exclude cognitive effects of substances)
Psychotic disorder
Per self-report or chart (can confound delirium assessment)
Dementia-level 
deficits
Per self-report, chart, or TICS < 27 (exclude effects of dementia on delirium 
assessments)
Use of a sleep aid
Any prescribed sleep aid being taken at least every other night (potential 
confound)
Use of a strong 3A4 
inhibitor (per FDA 
website92)
Ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole, ketoconazole, 
nefazodone, nelfinavir, posaconazole, ritonavir, telithromycin, voriconazole 
(increases drug exposure)
Intolerance to 
daridorexant
Per self-report or chart (safety)
Severe kidney or liver 
impairment
Child-Pugh score ≥ 7, Cockcroft-Gault < 30 mL/min, or current dialysis 
(safety)
Narcolepsy
Per self-report or chart (daridorexant is contraindicated in narcolepsy)
Prior suicide attempt
Per self-report or chart (package insert indicates a risk of worsening 
depression or suicidality)
Suicidal ideation at 
baseline assessment
Per self-report (package insert indicates a risk of worsening depression or 
suicidality)
Any condition that in the opinion of the PI compromises patient safety or data quality if enrolled in the 
study
6. RECRUITMENT METHODS
Study personnel, including the principal investigator and research coordinator, who have routine access to 
the cardiac surgery clinic and operating room schedules, will pre-screen patients scheduled for SAVR or 
CABG in direct collaboration with cardiac surgeons and anesthesiology team. A member of the surgery or 
anesthesiology team will refer eligible study candidates to study personnel (see Referral form). Referred 
patients will be contacted by study personnel either in person during a scheduled clinic visits or by phone, 
as feasible.


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7. CONSENT PROCESS
Verbal consent: 
When contacting study referrals, study personnel will obtain verbal consent to complete a 10-minute 
assessment to assess study eligibility and document this by signing and keeping on file a copy of the 
Recruitment Script for that study referral. To confirm eligibility, we will review inclusion and exclusion 
criteria and screen patients using the Telephone Interview for Cognitive Status (TICS)94 and CAGE-
Adapted to Include Drugs (CAGE-AID).95 As this work ultimately aims to identify an intervention to 
prevent cognitive impairment, we exclude dementia by chart review (prior diagnosis) and by phone (self-
reported diagnosis or TICS < 27 [equivalent to MMSE < 24]). We include mild cognitive impairment (MCI) 
to increase the likelihood of postoperative delirium occurring in our sample.96 These decisions balance the 
need for homogeneity vs generalizability of our sample.
Signed consent: 
Prior to conducting any study procedures, subjects will complete the full informed consent process with 
research personnel. Research staff will first describe the study to eligible subjects and review the informed 
consent document. Subjects will then be given as much time to read the consent document as they wish and 
to ask any questions or discuss any aspect of the study. The subject will be invited to sign the written 
informed consent form, which will also be signed by research personnel obtaining consent (one copy will 
be given to the subject and the other copy will be kept under double locked conditions). The consent form 
includes contact information for study personnel.
Potential subjects for this study will be presumed to have capacity, especially as they have just recently 
provided consent for anesthesia and heart surgery. However, if the PI has any concerns over whether the 
subject has the capacity to participate when discussing the study protocol and reviewing what will be 
required of the subject in this study he will assess capacity. If other trained research personnel are enrolling 
the subject and has any concerns, he or she will contact the PI (a psychiatrist) who will personally conduct 
a clinical assessment of decision-making capacity (i.e., communicate a decision of whether to join the study, 
comprehending the study’s purpose, procedures, and potential risks/benefits, appreciate the study’s 
potential impact on recovery, and the ability to make a reasoned decision), either in person or by phone. 
Patients who lack capacity to consent to study procedures will be excluded from this study, which will limit 
variance in baseline cognition.
Study partner: 
This study protocol requires that subjects have a reliable informant to allow for assessment of cognitive 
status at baseline. We complete the semi-structured Clinical Dementia Rating (CDR) items with the study 
partner to ensure we have a good understanding of the subject’s memory, problem solving ability, and daily 
activity. Our conversations with study partners usually take 10–15 minutes and can be either in person or 
by phone. If the subject develops delirium, their study partner or someone else who is a legally authorized 
representative will help them decide regarding continued study participation.
Requested Waiver of Documentation for Verbal Consent Process
https://www.rochester.edu/ohsp/documents/ohsp/pdf/policiesAndGuidance/Policy_701_Informed_Consen
t.pdf
To establish study eligibility, we will be conducting a 10-minute cognitive screen—the Telephone 
Interview for Cognitive Status (TICS). This will be performed prior to obtaining written consent and 
enrollment into the study. We will not be recording any personally identifiable information as part of this 
assessment. We will keep the screening results of individuals screened for eligibility, including TICS 
results, so we can characterize the broader sample of those referred for study participation. This will also 
allow us to compare the set of referred individuals who were found to be study ineligible vs study eligible, 


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which will inform future research in this clinical population. The potential study subject is providing verbal 
consent for screening, and the brief screen would satisfy criterion 9.1.2 under RSRB policy 701 as “the 
research presents no more than minimal risk of harm to subjects and involves no procedures for which 
written consent is normally required outside the research context [45 CFR 46.117(c) and 21 CFR 
56.109(c)].
8. STUDY PROCEDURES
See Table 5 below for the Schedule of Activities


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Table 5 - Schedule of activities
Assessment
Screenin
g
(15 min)
Baseline
(1 hr)
PON 1–3 
(with 
bedtime 
meds)
POD 1–3
(15 min)
POD 3–7
(15 min)
Verbal consent
X
CAGE-AID
X
Written consent
X
Demographics
X
CCI
X
Medication list
X
Cognition/function
TICS
X
MoCA
Full, v8.1
Lawton
X
CDR
X
WTAR
X
Delirium
3D-CAM
X
X
X†
DRS-R98
X
X†
Mental health
PHQ-9
X
GAD-7
X
Sleep-related
PSQI
X
ESS
X
RCSQ
X
X†
Medication administration
X
AEs/SAEs
Questionnaire
X
X
Chart review*
X
X†
Subject to guess whether they received 
daridorexant or placebo
POD 3
Abbreviations: 3D-CAM, 3-Minute Diagnostic Interview for Confusion Assessment Method; CAGE-AID, 
CAGE [acronym for “Cut-down, Annoyed, Guilt, Eye-opener”] adapted to include drugs; CCI, Charlson 
comorbidity index; CDR, Clinical Dementia Rating; DISH, Depression Interview and Structured Hamilton; 
DRS-R98, Delirium Rating Scale, Revised 98; ESS, Epworth Sleepiness Scale; GAD-7, 7-item Generalized 
Anxiety Disorder scale; Lawton, Lawton Instrumental Activities of Daily Living; MoCA, Montreal Cognitive 
Assessment; PHQ-9, 9-item Patient Health Questionnaire; POD, postoperative day; PON, postoperative night 
(i.e, the night of POD 0 [the day of surgery] is defined as PON 1); PSQI, Pittsburgh Sleep Quality Index; 
RCSQ, Richards-Campbell Sleep Questionnaire; TICS, Telephone Interview for Cognitive Status; WTAR, 
Wechsler Test of Adult Reading
*For evidence of adverse events, documentation of delirium, potential sleep confounds
†Daily assessments for delirium and sleep will continue if the subject is delirious on POD 3, until delirium 
resolves.
Screening procedures: 
As indicated under 7. CONSENT PROCESS above, consent will involve two steps—a verbal consent 
for study eligibility screening and, subsequently, signed consent. When obtaining verbal consent, we will 


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indicate to study prospects that the eligibility questions take 5–10 minutes. We indicate that we keep 
responses to screening questions, even for those who don’t end up taking part, so, as a result and explain 
that we do not record personally identifying information during the screening process. Before proceeding 
with the remainder of the eligibility assessment, we also ask the prospective subject to affirm the 
availability of a study partner should they participate in the study.
Study duration: 
Study subjects will participate from the initial screening evaluation prior to surgery, which is usually 1–2 
weeks prior to scheduled surgery, through the third postoperative day after surgery (note: as in the 
following paragraph, assessments may be continued past POD 3 if the subject is found to have delirium 
on POD 3). Most subjects, then, will be enrolled in the study for roughly 2 weeks. However, the duration 
of study participation will be dependent on the scheduling of preoperative anesthesiology visit in relation 
to date of surgery.
Choice of POD and assessments for delirium: 
We assess delirium on POD 1–3 with the DRS-R-98 as validated based on clinical interview under the 
supervision of a psychiatrist.99 We omit delirium assessment on POD 0 because (1) patients are intubated 
and sedated until the evening of POD 0 and (2) to exclude emergence delirium (n.b., a distinct 
physiological event due to anesthetic effects100). With one exception (see below), we restrict delirium 
assessments to POD 3 because (1) patients are often discharged on POD 3 or 4, (2) postop delirium peaks 
on POD 2 and 3, coincident with the peak of postop inflammation,101,102 and (3) this allows a 
commensurate 3-day period across subjects to evaluate for delirium during the days of greatest risk. We 
use DRS-R-98 as it is well validated and the most robust tool for characterizing delirium 
phenomenology.1,16,17,20,21,103 Regarding the exception referenced above: to determine delirium duration in 
all subjects, we continue to perform daily delirium assessments for any subject positive for delirium on 
POD 3 until no longer positive. Regardless of whether delirium assessments continue beyond POD 3, 
subjects will still receive study drug for only the first three nights after surgery.
Number of visits: 
Subjects will have four (or up to a maximum of 8, if a person continues to score positive for delirium on 
POD 3 through POD 6) in-person visits with study personnel (see Figure 1, Timeline of Study 
Assessments in Section 4. STUDY DESIGN).
Blinding, including justification: 
Blinding of study staff, clinical staff, and the patient is critical for this trial, which test whether 
daridorexant prevents postoperative delirium.
Justification of why subjects will not receive routine care or will have current therapy stopped: 
Subjects will receive routine surgical and postoperative care. This trial adds exposure only to daridorexant 
or placebo to test whether daridorexant prevents delirium. No current therapy will be stopped or modified.
Justification for inclusion of a placebo group:
The use of a placebo treatment is essential to understand the effects (both positive and negative) of 
daridorexant exposure. Placebo comparison is the only way that we can understand what is likely due to 
daridorexant and what is not. 
9. RISKS
Medical risks, listing all procedures, their major and minor risks and expected frequency
Below, Table 6  lists the most common risks of daridorexant based on two pre-marketing studies. 


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Table 6 - Adverse events (AEs) and serious adverse events (SAEs) with daridorexant (DAR) and 
placebo52
Placebo
Study 1
n=309
Placebo
Study 2
n=306
DAR 50 
mg
Study 1
n=310
DAR 25 
mg
Study 2
n=308
DAR 25 
mg
Study 2
n=308
DAR 10 
mg
Study 2
n=306
Any AE
105 
(34%)
100 
(33%)
116 (38%)
117 (38%)
121 (39%)
117 (38%)
Any SAE
7 (2%)
7 (2%)
3 (1%)
2 (1%)
3 (1%)
3 (1%)
Nasopharyngitis
20 (6%)
16 (5%)
20 (6%)
21 (7%)
13 (4%)
16 (5%)
Headache
12 (4%)
11 (4%)
19 (6%)
16 (5%)
15 (5%)
12 (4%)
Somnolence
6 (2%)
4 (1%)
5 (2%)
11 (4%)
10 (3%)
6 (2%)
The following three images are taken from the daridorexant package insert: 


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Safety assessments:
In this trial, we obtain demographics and baseline assessment of medical morbidity, medications, cognitive 
status, and self-report sleep & mental health. Obtaining such information does not entail significant 
foreseeable risk beyond limited risk of psychological distress or questionnaire fatigue. As we will be 
completing the 9-question Patient Healthcare Questionnaire (PHQ-9), which assesses suicidal ideation, we 
have developed a safety plan for anyone who answers positively to question 9 on the PHQ-9 (see Steps 
taken to minimize risk below).
Adverse event definition: 
This is an observational study of medically and surgically ill patients undergoing open-heart surgery, and 
this population—independent of this study—is at significant risk for a range of medical and surgical 
complications because of their underlying heart disease, open-heart surgery, and care provided during the 
perioperative period. In this study, we define an adverse event as any symptom, sign, illness, or experience 
that develops or worsens during the study that is reasonably attributable to the study assessments or receipt 
of daridorexant.
Serious adverse event: 
A serious adverse event is defined as any adverse event resulting in any of the following: 
•
Sleep paralysis (inability to move or speak when going to sleep or waking up)
•
Cataplexy (discrete episode of muscle weakness, typically associated with strong emotion)
•
Complex behaviors while asleep that pose danger to the patient or others (e.g., sexually inappropriate 
acts)
•
Angioedema or anaphylactic reaction to daridorexant
•
Death/suicide
•
Prolongation of existing hospitalization
•
Persistent or significant disability or incapacity
•
Medical or surgical intervention required to prevent permanent impairment or damage
Recording adverse events: 
Each adverse event—whether observed by the PI or elicited from or volunteered by the subject—will be 
documented. Each adverse event will include a brief description of the experience, the date of onset, the 
date of resolution, the duration and type of experience, the severity, the nature of any potential relationship 
to study assessments, contributing factors, and any action taken with respect to the assessments. Any such 
adverse event will be reported to the Data and Safety Monitoring Advisory Council (see 16. Data and 
Safety Monitoring Plan).
Responsibilities for reporting serious adverse events: 
The PI will record all serious adverse experiences that occur during the study period in the appropriate 
source documents and/or adverse events log as applicable. The timeframe for adverse event reporting will 
begin from the time of study enrollment to the final study assessment on POD 3 (or on a subsequent 
postoperative day for those with delirium on POD 3).
Steps taken to minimize risk: 
We will adhere to the exclusion criteria listed above which will help avoid the recruitment of patients 
most at risk of side effects and adverse consequences. Patients will be interviewed each day for any side 
effects and the medical records will be reviewed and the data collected for Aim 4 of this study.
Risks pertaining to clinical assessment: 
The risks pertaining to clinical assessment (neuropsychological testing and questionnaires) are anticipated 
to be no more than minimal. If the patient exhibits any distress or hesitation in answering specific 


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questions or completing a questionnaire in general, the evaluation will be suspended and the subject asked 
whether they wish to either take a break, skip a given section, or withdraw from the study. The PI Dr. 
Oldham is a board-certified psychiatrist with clinical expertise in mental health evaluation. If he is 
conducting the assessment, he will use his medical judgment to determine whether to suspend evaluation 
or skip portions of the interview. If study personnel are conducting the evaluation, they will be instructed 
to contact Dr. Oldham to join the interview and conduct additional assessment as necessary to determine 
whether the interview should be suspended or modified.
Similarly, if a patient responds affirmatively to question 9 on the PHQ-9, which asks about “Thoughts 
that you would be better off dead, or of hurting yourself,” the PI will conduct a safety evaluation to 
determine whether the patient should be referred for immediate clinical attention. (This will be done by 
the PI Dr. Oldham at the time of the evaluation if he is completing the evaluation. If the evaluation is 
being conducted by research personnel, a licensed clinical member of the study team will be contacted, 
and they will join the interview either in person or remotely to conduct a safety evaluation.) If, in the 
clinical judgment of the PI, the patient is assessed to be at imminent risk of self-harm, we will ensure 
appropriate emergency care for safety. Because this study is enrolling outpatients who have agreed to 
undergo a life-preserving, function-enhancing surgery, we expect the likelihood that any subject will be 
acutely suicidal will be exceptionally low.
See below CONFIDENTIALITY OF DATA AND INFORMATION STORAGE > Risks pertaining to 
data transmission for protection against potential disclosure of data analyzed using Esprit Nova.
Risks pertaining to study participation:
Study personnel will not enter results of assessments into a patient’s medical record; however, study 
participation would entail that their treatment team are aware of the clinical trial and be responsible for 
ordering study drug for the three first postoperative nights. The fact that the patient is in the study will be 
included in the patient’s medical record. Study team members will provide education to all providers of 
study subject teams so that they are aware (1) of the clinical trial, (2) the study methods, (3) their need to 
order study drug for the first three postoperative nights, and (4) their responsibility to report to the PI any 
potential adverse events and serious adverse events as defined in this trial.
A DSMB will review the data (as described below) and the study will be halted if there is evidence of 
harm significantly associated with the intervention. We will also inform subjects of the risks of 
daridorexant in the consent form and ask them to notify their treatment team at SMH should they 
experience any serious adverse events.
Plan for reporting unanticipated problems or study deviations: 
All AEs and SAEs will be reported to the RSRB and DSMB as required. Data on adverse effects will be 
collected each postoperative day that subjects are enrolled.
Plan for breaking the blind for a subject
If a patient has a medical emergency that requires immediate clinical care for stabilization, including 
angioedema, anaphylaxis, attempted suicide, or any other condition that is considered—in the opinion of 
the PI or the primary medical team—as potentially attributable to daridorexant, we will contact the IDS 
pharmacist to identify whether the patient has received daridorexant or placebo. If this occurs, the subject 
will be withdrawn from the study, and this will be reported to the RSRB and DSMB.
Legal risks such as the risks that would be associated with breach of confidentiality: 
As with any study incorporating research into clinical care, there is a small but real risk of unintentional 
release of HPI. We will make every effort to secure data and study records under double lock/key and 
encryption in keeping with institutional standards to prevent this from occurring.


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10. POTENTIAL BENEFITS TO SUBJECTS
There is no anticipated benefit to subjects who take part in this research study.
11. COSTS FOR PARTICIPATION
There are no anticipated costs for study participation.
12. PAYMENT FOR PARTICIPATION
Study subjects will be compensated $50 by check sent from the University of Rochester Medical Center 
to that subject’s home address. Study medication—either daridorexant or placebo—will be provided and 
administered free of charge to the patient.
13. SUBJECT WITHDRAWALS
Definition of treatment failure or subject removal criteria: 
All consented subjects will be retained in the study, and all primary analyses will be performed per 
protocol. All daridorexant arm subjects who develop postop delirium represent patients for whom 
daridorexant failed to prevent delirium. However, we do not expect daridorexant to prevent all delirium, 
so we would not use the term “treatment failure” to describe incident delirium in these patients. We would 
remove patients from the study only in the event of serious adverse events.
What happens to subjects when study ends or if a subject’s participation in the study ends 
prematurely: 
Patients will be thanked for their participation in the study and will be advised to call the PI with any 
questions. Study agent—either daridorexant or placebo—is being provided for up to the first three nights 
after surgery, but we will not be providing this to those who discharge prior to this. Early discharges are 
not only rare but indicate that the patient is doing so well that they no longer require inpatient level of 
care, which implies that they would not have delirium at the time.
14. PRIVACY AND CONFIDENTIALITY OF SUBJECTS AND RESEARCH DATA
See also Appendix I – University of Rochester Human Subject Research Electronic Data Security 
Assessment Form
Risks pertaining to confidentiality of data and information storage: 
Study data will be collected confidentially from the patient and collateral informant. Patients will be 
assigned a sequential study identification number, which is used for all study purposes. Data from 
interviews and self-report questionnaires including consent forms will be recorded in hardcopy. All 
hardcopies will be permanently stored in a locked filing cabinet at SMH either in the PI’s personal office 
or the office of study personnel. Name, date of birth, and other identifying information will be kept in a 
separate locked file. All data will be entered into an electronic database (REDCap, described in next 
paragraph) into a final dataset that will be de-identified and reside on a secure URMC server. Study 
personnel will have access to research data. In performing analyses, the PI may share de-identified data 
with any member of the mentorship team for guidance on analyses.
Study data will be collected and managed using Research Electronic Data Capture (REDCap) tools hosted 
at URMC.104 REDCap is a secure, web-based application designed to support data capture for research 
studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 


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manipulation and export procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages; and 4) procedures for importing data from external sources.
15. DATA / SAMPLE STORAGE FOR FUTURE USE
De-identified data will be stored indefinitely both for subsequent analyses and to support anticipated 
future grant applications. The data will be stored on the PI’s office UR computer, UR research laptop, in a 
UR Box folder, and in REDCap. Upon study completion, only the PI will have direct access to de-
identified study data.
16. DATA AND SAFETY MONITORING PLAN
Overview: 
This Data and Safety Monitoring Plan (DSMP) specifies the procedures and rationales of the current 
prospective trial to ensure the safety of subjects and the validity and integrity of the data collected. The 
DSMP identifies who will look at the data and review any adverse events, how often, and what they are 
authorized to do.
For this study, the PI will be responsible for monitoring the project as the Data and Safety Monitor under 
advisement of an independent Data and Safety Monitoring Board (DSMB). All adverse events will be 
recorded and reports created by the PI in collaboration with the research coordinator.
The DSMB will include individuals with clinical experience relevant to this population and sleep 
pharmacology.
The risks associated with this trial are described in section 9 above.
Data and Safety Monitor: 
As the Data and Safety Monitor, the PI will be responsible to maintain protocols and consent documents 
for this study, monitor safety issues throughout the study, and provide an overview of the quality of the 
accumulating data. DSM Monitor responsibilities and actions include:
a.
Review and approve, disapprove, or suggest modifications to the study protocols and/or consent 
documents to assure both scientific integrity and study adherence to human subject protection 
policies.
b.
Monitor, provide feedback, and report on scientific and ethical issues related to study 
implementation for the protection of human subjects and advise on ethical issues related to 
adverse events. 
Data and Safety Monitoring Board: 
a.
The DSMB will monitor adverse event reports for purposes of determining whether their nature, 
frequency and severity are consistent with expectations. 
b.
The DSMB, in coordination with the PI, will report to the Research Subjects Review Board any 
unanticipated problems involving risks to subjects (per 45CFR46). If considered related to the 
study, adverse events involving risks to subjects or to others must be reported by the PI to the 
University of Rochester Research Subjects Review Board.
c.
The DSMB can recommend remedies or other appropriate actions such as introducing new 
monitoring protocols, altering inclusion or exclusion criteria, or recommending changes in the 
informed consent documents.  


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d.
Ensure that the study protocol maintains patients’ confidentiality in a manner that is appropriately 
balanced with issues of clinical care and safety.
e.
Monitor data management activities. The DSMB may ask to review data relevant to quality 
control. This Board will review requests for interim analyses and approve, disapprove, require 
additional information, or defer decisions.
Schedule: 
The DSMB will review study conduct and data collected after the first six enrolled subjects have 
completed the study and then again after the full study sample of 12 subjects have completed the study. 
Given block randomization with a block size of six, we expect the initial review of six subjects will 
include three subjects receiving daridorexant and three receiving placebo. The DSMB and study PI will 
decide the format of meetings. Additional meetings or telephone conferences will be held on the 
recommendation of the DSMB.
17. DATA ANALYSIS PLAN
The first 3 aims outlined for this study pertain to the viability of the currently outlined study methods and 
do not avail themselves to formal statistical analysis. We will collect these data to inform an anticipated 
follow-on RCT of daridorexant to prevent postoperative delirium. 
Aim 4 pertains to AE and SAE, which are also essential for the investigational application of daridorexant 
to delirium prevention. The rates of AE reported with daridorexant are extremely low and very nearly 
close to placebo in published studies. These will be collected for this feasibility study, although we do not 
expect to identify concerns.


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