Effect of a Dual Orexin Receptor Antagonist, Lemborexant, on Total Sleep Time in Shift Workers: a Randomized Controlled Trial
Phase: PHASE4
Conditions: Shift-Work Related Sleep Disturbance
Sponsor: University of California, San Francisco

STUDY PROTOCOL 
 
Title: Effects of Lemborexant vs placebo on total daytime sleep in shift workers: A randomized 
controlled trial 
 
Document Date: June 4, 2021 
 
NCT#: NCT05344443 
 
 

PROTOCOL SYNOPSIS 
TITLE 
Effects of Lemborexant vs placebo on total daytime sleep in shift workers: A 
randomized controlled trial 
SPONSOR 
Eisai Co, Ltd 
FUNDING 
ORGANIZATION 
Eisai Co, Ltd 
NUMBER OF SITES 
1 
1
RATIONALE 
Insomnia and daytime sleepiness are common among shift workers, 
and there is a lack of available treatments. Lemborexant, which is a 
hypocretin/orexin antagonist, is a plausible treatment to improve 
sleep in shift workers 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled phase 4 study. 
PRIMARY 
OBJECTIVE 
Test the effect of Lemborexant on daytime total sleep time (measured via 
sleep diary) compared to placebo   
NUMBER OF 
SUBJECTS 
45 night shift workers enrolled; accounting for attrition, we expect 30 
completers 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
• 
20 to 60 years old; 
• 
 Full-time night shift work (at least 6 hours per shift, 4 days per week 
or 32 hours per week);  
• 
Employed as a night shift worker for at least 3 months;  
• 
Self-reported difficulty sleeping during the daytime (Insomnia Severity 
Index>8).  
Exclusion Criteria: 
• 
Pregnancy (verified by urine pregnancy test) or plan to become 
pregnant in the next 3 months;  
• 
Currently breastfeeding;  
• 
Inadequate opportunity for sleep during the daytime (< 7 hours 
opportunity) after overnight shift.  
• 
Extreme circadian preference (based on Horne & Ostberg 
Morningness-Eveningness Questionnaire);  
• 
Severe depressive symptoms (>25 on CES-D);  
• 
Unwillingness to discontinue  sleep aids (prescription or non-
prescription) during the study period;  
• 
Presence of sleep disordered breathing (verified by Z-machine);  
• 
Self-reported diagnosis of narcolepsy, restless legs syndrome;  

• 
Intake of >600mg of caffeine per night shift or use of stimulants during 
night shift, rotational, or irregular shifts;  
• 
Unstable or untreated medical or psychiatric condition based on clinical 
interview.   
• 
Severe hepatic or renal impairment (based on chemistry panel);  
• 
Self-reported use of digoxin or strong or moderate cytochrome P450 
3A4 isozyme inhibitors or cytochrome P450 3A4 isozyme inducers for 
6 months prior to or during the study 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Product Lemborexant at 5mg dose (titration up to 10mg based on 
participants perceived benefit) 
Lemborexant will be administered immediately prior to daytime sleep 
attempt over the course of 3 weeks. The first week will constitute the 
titration week. Two-week treatment phase begins following titration 
week.  
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Placebo 
Placebo will be administered immediately prior to daytime sleep 
attempt over the course of 3 weeks. The first week will constitute ehte 
titration week. Two-week treatment phase begins following titration 
week. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 6 weeks 
Screening:  1 day 
Medication tapering (if needed): up to 1 week 
Baseline sleep assessment: 2 weeks 
Titration phase: 1 week 
Treatment phase:  2 weeks 
The total duration of the study is expected to be 12-months.   
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
• 
Primary Outcome: Daytime total sleep time (sleep diary) averaged over 
2-week treatment period. Participants will be asked to take their 
medication immediately prior to their daytime sleep attempt   
SECONDARY 
ENDPOINTS 
• 
Daytime total sleep time (actigraphy) averaged over 2-week treatment 
period 
OTHER 
EVALUATIONS 
 
SAFETY 
EVALUATIONS 
Adverse event assessment, by history, at post-intervention follow-up.   
PLANNED INTERIM 
ANALYSES  
None 

STATISTICS 
Primary Analysis Plan 
We will compare within-person changes in daytime total sleep time 
(primary: diary, secondary: actigraphy) averaged over a two-week baseline 
and treatment period between groups (Lemborexant vs. placebo) using linear 
mixed effects models (repeated measures of outcomes, with time, treatment 
group, and time by group interactions as predictors, as well as potentially 
random intercepts, and random slopes to accommodate between subject 
differences in rates of change). We will calculate 95% confidence intervals 
for the time by group interaction to provide a range of differences in change 
that are consistent with the data and test interactions using likelihood ratio 
tests. Linear mixed models will also be carried out to test the other proposed 
study outcomes. This will accommodate an intent to treat analysis.  
 
Rationale for Number 
of Subjects 
We will recruit 45 nightshift workers, accounting for 30% attrition, to 
randomize 30 participants who will first carry out 2 weeks of sleep diaries 
and wrist actigraphy and then be randomized to 1 week of Lemborexant 
(5mg) or placebo during which time they will undergo a titration period. 
After the week, participants will discuss with the researcher whether they 
would like to increase their dose to 10mg. Participants will then either take 
Lemborexant (5 mg-10mg) or placebo for 2 weeks within 60 minutes of 
attempting daytime sleep. Sample size was calculated based on previously 
published study demonstrating a robust improvement in diary based daytime 
total sleep time vs placebo (d=1.39) in response to treatment with 20 mg 
Suvorexant6. Based on these data, we would require 12 participants in each 
condition to detect a large effect size with 90% power. However, to be 
conservative and ensure that we are adequately powered, we will randomize 
15 participants per condition. 
 
 

BACKGROUND 
Lemborexant is a hypocretin/orexin antagonist FDA approved to treat Insomnia Disorder. 
Prior studies support its efficacy in improve an individual’s ability to fall and stay asleep; 
however, its efficacy has not been tested in shiftworkers. 
STUDY RATIONALE 
Insomnia and daytime sleepiness are common complaints among night shift workers1,2. A meta-
analysis on sleep in shift workers indicates that fixed night shift workers sleep, on average, 0.4 
hours less than fixed day shift workers, while rotating shift workers sleep on average 1 hour less 
than fixed day shift workers3. While there may be several reasons for sleep difficulties and sleep 
loss among shift workers,  the misalignment of one’s sleep preference (i.e., goal of sleeping during 
the day) and one’s circadian rhythm (i.e., endogenous rhythm that signals the body to be awake 
during the day) is thought to be a primary cause.  Insufficient sleep among night shift and rotating 
shift workers is linked with significant health consequences, including elevated risk for 
cardiovascular disease and cancer4,5. Effective sleep treatments in shift workers are lacking.  
However, a recent randomized study of Suvorexant (20mg), a hypocretin/orexin receptor 
antagonist, produced a significant improvement in daytime total sleep time compared to placebo6.   
Available evidence suggests that the reason suvorexant is effective is because it blocks the 
hypocretin/orexin receptors that mediate signaling from the biological clock (suprachiasmatic 
nucleus of the hypothalamus) attempting to maintain sustained wakefulness during the biological 
day7.  As Lemborexant is also  a hypocretin/orexin antagonist, it would also be expected to 
improve daytime sleep in shift workers but would have the advantage over suvorexant of being 
highly effective in the dosages available for clinical use.  As such, Lemborexant may be effective 
and important treatment of sleep problems in shift workers.  
 
The aim of this Phase IV double-blind, placebo-controlled, randomized study is to test whether a 
dual orexin antagonist, Lemborexant (5mg or 10mg), which would be expected to block the clock-
driven orexin-mediated wakefulness during the day, will increase daytime sleep time in shift 
workers who complain of difficulty sleeping during the daytime compared to placebo.  
STUDY OBJECTIVES 
Primary Objective 
The primary objective is to assess the clinical efficacy, as measured by sleep diary total 
sleep time during daytime sleep attempts over a 2-week period.  
STUDY DESIGN 
Study Overview 
This will be a 5-week double blinded placebo controlled trial (2 weeks of baseline assessment 
followed a 1 week titration of 5mg Lemborexant/placebo, followed by agreed upon dose (5mg or 
10 mg) or placebo for 2-weeks). The trial design is based on a recent successful study of the 
treatment of sleep problems in shift workers with a hypocretin/orexin receptor antagonist. 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  

The following treatment regimens will be used: 
Experimental treatment Lemborexant at either 5mg or 10mg  
Placebo control 
Total duration of subject participation will be 5 weeks.   
Criteria for evaluation 
Primary Efficacy Endpoint 
• 
Daytime total sleep time (sleep diary) averaged over 2-week treatment period. 
Participants will be asked to take their medication immediately prior to their 
daytime sleep attempt   
Secondary Efficacy Endpoints 
• 
Daytime total sleep time (actigraphy) averaged over 2-week treatment period 
SUBJECT SELECTION 
Study Population 
Subjects who are shift workers and report difficulty sleeping during the daytime and who 
meet the inclusion and exclusion criteria will be eligible for participation in this study.   
Inclusion Criteria 
1. 20 to 60 years old;  
2. Full-time night shift work (at least 6 hours per shift, 4 days per week or 32 hours per 
week);  
3. Employed as a night shift worker for at least 3 months;  
4. Self-reported difficulty sleeping during the daytime (Insomnia Severity Index>8).  
5. Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study. 
Exclusion Criteria 
1. 
Pregnancy (verified by urine pregnancy test) or plan to become pregnant in the next 3 
months;  
2. 
Currently breastfeeding;  
3. 
Inadequate opportunity for sleep during the daytime (< 7 hours opportunity) after overnight 
shift.  
4. 
Extreme circadian preference (based on Horne & Ostberg Morningness-Eveningness 
Questionnaire);  
5. 
Severe depressive symptoms (>25 on CES-D);  

6. 
Unwillingness to discontinue  sleep aids (prescription or non-prescription) during the study 
period;  
7. 
Presence of sleep disordered breathing (verified by Apnea link);  
8. 
Self-reported diagnosis of narcolepsy, restless legs syndrome;  
9. 
Intake of >600mg of caffeine per night shift or use of stimulants during night shift, rotational, 
or irregular shifts;  
10. Unstable or untreated medical or psychiatric condition based on clinical interview.   
11. Severe hepatic or renal impairment (based on chemistry panel);  
12. Self-reported use of digoxin or strong or moderate cytochrome P450 3A4 isozyme inhibitors 
or cytochrome P450 3A4 isozyme inducers for 6 months prior to or during the study  
13. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
Concurrent Medications 
Study participants will be required to be free from prescription and non-prescription sleep aids and 
stimulants during the study. To be eligible, participants will need to undergo a washout period 
prior to baseline assessment of at least 5 half-lives of any drug with a significant effect on 
sleep/wake function.  
STUDY TREATMENTS 
Method of Assigning Subjects to Treatment Groups 
Up to 45 eligible patients will be randomly assigned to Lemborexant (5mg) or placebo 
treatment groups in a 1:1 ratio using a pre-generated randomization scheme developed by 
the study data management provider. 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.  The following study procedures will be 
in place to ensure double-blind administration of study treatments.   
Access to the randomization code will be strictly controlled.   
Packaging and labeling of test and control treatments will be identical to maintain the 
blind.  
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management. When possible, the 
Investigator should discuss the emergency with the Medical Monitor prior to unblinding.   
Formulation of Test and Control Products 
The study drug, Lemborexant (5mg) and placebo will be provided by the sponsor, Eisai 
Co, Ltd.  

Supply of Study Drug at the Site 
The Sponsor will ship Study Drug to the investigational site.  The initial study drug 
shipment will be shipped after site activation (i.e., all required regulatory documentation 
has been received by the Sponsor and a contract has been executed). Subsequent study 
drug shipments will be made after site request for resupply. 
Dosage/Dosage Regimen 
Following the baseline assessment, participants will be randomized to either drug or 
placebo. Those in the drug condition will be provided 5mg Lemborexant and re-evaluated 
one week later as part of the titration period. Those who wish to increase their dose to 
10mg may do so for the 2-week drug period. The same option will be provided to the 
placebo condition.  
Dispensing 
The drug will be dispensed by the study physician, Dr Andrew Krystal, MD, who is Co-PI 
on this study.  
Storage of drug 
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 
to 86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or falls 
below this range, this should be reported to the Sponsor or designee and captured as a 
deviation. Subjects will be instructed to store the medication in original packaging (foil pouch 
and protected from light) at room temperature according to the instructions outlined on the 
Drug Administration Instructions. 
Measures of Treatment Compliance 
Medication adherence will be monitored using electronic pill caps (Mems caps) which 
monitor each time the pill bottle is opened.  
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
Clinical Assessments 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening, and at early termination when applicable.  Dose, route, unit frequency 
of administration, and indication for administration and dates of medication will be 
captured. 

Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded. 
Clinical Laboratory Measurements  
Blood Chemistry Profile 
Blood will be obtained and clinical chemistry lab for determination of serum sodium, 
potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline 
phosphatase, total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), albumin 
and LDH. 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study. 
EVALUATIONS BY VISIT 
Visit 1  
1. 
Confirm eligibility (self-report) 
2. 
Medical history interview 
3. 
Medication assessment 
4. 
Psychiatric clinical interview  
5. 
Sleep disorder clinical interview  
6. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
7. 
Questionnaires. 
8. 
Blood draw for blood chemistry 
Baseline sleep assessment (2-weeks in duration) 
1. 
Wrist actigraphy 
2. 
Sleep diary 
3. 
Obstructive sleep apnea evaluation (Z-machine, 1night) 
Visit 2  
1. 
Medication assessment 

2. 
Pregnancy test (if applicable) 
3. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and dosing compliance. 
4. 
Randomization 
5. 
Patient global impression/clinician global impression completed. 
Visit 3  
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and dosing compliance. 
2. 
Medication assessment 
3. 
Patient global impression/clinician global impression completed. 
4. 
Decision made on medication dose based on PGI. 
Treatment sleep assessment (2-weeks) 
1. 
Wrist actigraphy 
2. 
Sleep diary  
Visit 4 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and exclusionary medication use. 
2. 
Medication assessment 
3. 
Patient global impression/clinician global impression completed. 
4. 
Questionnaires 
5. 
Collect unused medication.  
Open-label (if opt in; 2-weeks). 
1. Record any Adverse Experiences. 
 
ADVERSE Experience REPORTING AND DOCUMENTATION 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  

Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 

Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
Include appropriate wording here 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
   
DISCONTINUATION And Replacement of subjects 
Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
Subject withdrawal of consent (or assent) 
Subject is not compliant with study procedures 
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
Protocol violation requiring discontinuation of study treatment 

Lost to follow-up 
Sponsor request for early termination of study 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures. 
 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 2) should have an early discontinuation 
visit.  
STATISTICAL METHODS AND CONSIDERATIONS 
We will analyze data from all participants who undergo randomization.  
Analysis of Primary Endpoint 
We will compare within-person changes in daytime total sleep time (primary: diary, secondary: 
actigraphy) averaged over a two-week baseline and treatment period between groups 
(Lemborexant vs. placebo) using linear mixed effects models (repeated measures of outcomes, 
with time, treatment group, and time by group interactions as predictors, as well as potentially 
random intercepts, and random slopes to accommodate between subject differences in rates of 
change). We will calculate 95% confidence intervals for the time by group interaction to provide a 
range of differences in change that are consistent with the data and test interactions using 
likelihood ratio tests. Linear mixed models will also be carried out to test the other proposed study 
outcomes. This will accommodate an intent to treat analysis. Covariates, such as number of sleep 
entries (i.e., number of available diary/actigraphy daytime sleep attempts), will be included is 
analyses if needed.  

Sample Size and Randomization 
We will recruit 45 nightshift workers, accounting for 30% attrition, to randomize 30 participants 
who will first carry out 2 weeks of sleep diaries and wrist actigraphy and then be randomized to 1 
week of Lemborexant (5mg) or placebo during which time they will undergo a titration period. 
After the week, participants will discuss with the researcher whether they would like to increase 
their dose to 10mg. Participants will then either take Lemborexant (5 mg-10mg) or placebo for 2 
weeks within 60 minutes of attempting daytime sleep. Sample size was calculated based on 
previously published study demonstrating a robust improvement in diary based daytime total sleep 
time vs placebo (d=1.39) in response to treatment with 20 mg Suvorexant6. Based on these data, 
we would require 12 participants in each condition to detect a large effect size with 90% power. 
However, to be conservative and ensure that we are adequately powered, we will randomize 15 
participants per condition. 
 

 
 
 
 
 
APPENDIX 1.   
 
 
Screening  
• 
Computer assessed eligibility 
Visit #1 
• 
Eligibility confirmed 
• 
Medical history interview 
• 
Medication assessment 
• 
Psychiatric clinical interview 
• 
Sleep disorder clinical interview (SCISD) 
• 
Informed consent 
• 
Blood chemistry 
• 
Questionnaires 
Medication tapering (if needed) 
• 
Tapering protocol (supervised by Dr. Krystal; 
washout period prior of at least 5 half-lives of any 
drug with a significant effect on sleep/wake 
function) 
Baseline Sleep Assessment (2-weeks) 
• 
Wrist actigraphy 
• 
Sleep diary 
• 
OSA evaluation (Z-machine, 1-night) 
Visit #2 
• 
Eligibility confirmed 
• 
Medication assessment 
• 
Adverse Event form 
• 
Pregnancy test 
• 
Randomization (5mg Lemborexant/placebo) 
- 
15 participants (Lemborexant, 5mg) 
- 
15 participants (placebo) 
• 
Drug/Placebo distribution (MemsCaps) 
• 
Patient global impression 
• 
Clinician global impression  
Titration (1-week) 
• 
Wrist actigraphy 
• 
Sleep diary 

 
 
 
 
 
Visit #3 
• 
Adverse event form 
• 
Medication assessment 
• 
Patient global impression  
• 
Clinician global impression 
• 
Drug/Placebo distribution (MemsCaps) 
Treatment (2-weeks) 
• 
Wrist actigraphy 
• 
Sleep diary 
Visit #4 
• 
Adverse event assessment 
• 
Medication assessment 
• 
Patient global impression 
• 
Clinician global impression 
• 
Questionnaires