A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Clinical Study to Evaluate the Efficacy and Safety of MK-4305 (Suvorexant) for Reducing Incidence of Delirium in Japanese Participants at High Risk of Delirium
Phase: PHASE3
Conditions: Delirium
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
NCT04571944
Document Date:           25-Jul-2022
A Phase 3 multicenter, randomized, placebo-
controlled, double-blind clinical study to
evaluate the efficacy and safety of MK-4305
(suvorexant) for reducing incidence of delirium
in Japanese participants at high risk of delirium.

PRODUCT: MK-4305  
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PROTOCOL/AMENDMENT NO.: 085-03
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 multicenter, randomized, placebo-controlled, double-blind clinical 
study to evaluate the efficacy and safety of MK-4305 (suvorexant) for reducing incidence of 
delirium in Japanese participants at high risk of delirium.
Protocol Number: 085-03
Compound Number: MK-4305
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
Not Applicable
EudraCT
Not Applicable
Approval Date: 25 July 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
25-JUL-2022

Sponsor underwent an entity name change and update to the address.
Amendment 2
08-JUN-2021

Acceptance of the enrollment of participants with acute disease who can be 
randomized within 24 hours after admission.
Amendment 1
11-AUG-2020

Acceptance of elective surgery 2 days after admission

Addition of prohibited medications [hypnotics (prescription Chinese herbs)]

Addition of Modified Cataplexy Questionnaire (MCQ)

Setting of Clinical Adjudication Committee (CAC)
Original Protocol
28-MAY-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:

Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 2.2.1 Pharmaceutical 
and Therapeutic Background
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................24
2.2.1
Pharmaceutical and Therapeutic Background .............................................24
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................26
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................28
4.2.1
Rationale for Endpoints ...............................................................................28
4.2.1.1
Efficacy Endpoints.............................................................................28
4.2.1.2
Safety Endpoints................................................................................29
4.2.2
Rationale for the Use of Placebo .................................................................29
4.3
Justification for Dose...........................................................................................30
4.3.1
Dose for This Study .....................................................................................30
4.3.2
Rationale for Dose Interval and Study Design ............................................30
4.4
Beginning and End of Study Definition .............................................................31
4.4.1
Clinical Criteria for Early Study Termination .............................................31
5
STUDY POPULATION ................................................................................................31
5.1
Inclusion Criteria.................................................................................................31
5.2
Exclusion Criteria................................................................................................33
5.3
Lifestyle Considerations......................................................................................35
5.3.1
Non-pharmacological Therapy ....................................................................35
5.4
Screen Failures.....................................................................................................35
5.5
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................36
6.1
Study Intervention(s) Administered...................................................................36
6.2
Preparation/Handling/Storage/Accountability .................................................38
6.2.1
Dose Preparation..........................................................................................38
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6.2.2
Handling, Storage, and Accountability........................................................38
6.3
Measures to Minimize Bias: Randomization and Blinding..............................39
6.3.1
Intervention Assignment..............................................................................39
6.3.2
Stratification.................................................................................................39
6.3.3
Blinding........................................................................................................39
6.4
Study Intervention Compliance..........................................................................39
6.5
Concomitant Therapy..........................................................................................39
6.5.1
Prohibited Therapy.......................................................................................40
6.5.2
Rescue Medications and Supportive Care ...................................................40
6.6
Dose Modification ................................................................................................40
6.7
Intervention After the End of the Study............................................................40
6.8
Clinical Supplies Disclosure................................................................................41
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................41
7.1
Discontinuation of Study Intervention...............................................................41
7.2
Participant Withdrawal From the Study...........................................................42
7.3
Lost to Follow-up .................................................................................................42
8
STUDY ASSESSMENTS AND PROCEDURES........................................................43
8.1
Administrative and General Procedures ...........................................................43
8.1.1
Informed Consent.........................................................................................43
8.1.1.1
General Informed Consent.................................................................44
8.1.2
Inclusion/Exclusion Criteria ........................................................................44
8.1.3
Participant Identification Card.....................................................................44
8.1.4
Medical History ...........................................................................................45
8.1.5
Prior and Concomitant Medications Review...............................................45
8.1.5.1
Prior Medications...............................................................................45
8.1.5.2
Concomitant Medications..................................................................45
8.1.6
APACHE II..................................................................................................45
8.1.7
ECOG PS .....................................................................................................45
8.1.8
NM Scale .....................................................................................................45
8.1.9
Non-pharmaceutical Therapy.......................................................................45
8.1.10
Assignment of Screening Number...............................................................46
8.1.11
Assignment of Treatment/Randomization Number.....................................46
8.1.12
Study Intervention Administration ..............................................................46
8.1.12.1
Timing of Dose Administration.........................................................46
8.1.13
Discontinuation and Withdrawal .................................................................47
8.1.14
Participant Blinding/Unblinding..................................................................47
8.1.15
Hospitalization.............................................................................................47
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8.1.16
Calibration of Equipment.............................................................................48
8.2
Efficacy Assessments ...........................................................................................48
8.2.1
DSM-5..........................................................................................................48
8.2.2
DRS-R-98 ....................................................................................................48
8.2.3
Richards Campbell Sleep Questionnaire (RCSQ) Score .............................49
8.2.4
Undesirable Hospitalized Patient Outcomes (Fall, Accidental or 
Intentional Catheter/Tube Removal, and Body Restraint)...........................49
8.3
Safety Assessments...............................................................................................49
8.3.1
Physical Examinations.................................................................................50
8.3.2
Vital Signs....................................................................................................50
8.3.3
Clinical Safety Laboratory Assessments .....................................................50
8.3.4
Modified Cataplexy Questionnaire (MCQ) Review....................................50
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................51
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................51
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......53
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...53
8.4.4
Regulatory Reporting Requirements for SAE .............................................53
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................53
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................53
8.4.7
Events of Clinical Interest............................................................................54
8.5
Treatment of Overdose........................................................................................54
8.6
Pharmacokinetics.................................................................................................55
8.7
Pharmacodynamics..............................................................................................55
8.8
Future Biomedical Research Sample Collection...............................................55
8.9
Visit Requirements...............................................................................................55
8.9.1
Screening Period (from Screening until First Dose of Study Medication)..55
8.9.1.1
Screening/Visit 1................................................................................55
8.9.1.2
Baseline/Visit 2 (until Randomization) .............................................55
8.9.1.3
Visit 2 (from Randomization until First Dose of Study 
Medication)........................................................................................56
8.9.2
Assessment Period (from First Dose of Study Medication until Last 
Assessment Visit).........................................................................................56
8.9.3
Follow-up Period .........................................................................................57
8.9.3.1
Follow-up Visit..................................................................................57
9
STATISTICAL ANALYSIS PLAN .............................................................................57
9.1
Statistical Analysis Plan Summary.....................................................................57
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9.2
Responsibility for Analyses/In-house Blinding .................................................58
9.3
Hypotheses/Estimation ........................................................................................58
9.4
Analysis Endpoints...............................................................................................58
9.4.1
Efficacy Endpoints.......................................................................................58
9.4.2
Safety Endpoints..........................................................................................59
9.5
Analysis Populations............................................................................................59
9.5.1
Efficacy Analysis population.......................................................................59
9.5.2
Safety Analysis Population..........................................................................60
9.6
Statistical Methods...............................................................................................60
9.6.1
Statistical Methods for Efficacy Analyses...................................................60
9.6.2
Statistical Methods for Safety Analyses ......................................................61
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................63
9.7
Interim Analyses ..................................................................................................63
9.8
Multiplicity ...........................................................................................................63
9.9
Sample Size and Power Calculations .................................................................64
9.9.1
Sample Size and Power for Efficacy Analyses............................................64
9.9.2
Sample Size and Power for Safety Analyses ...............................................64
9.10
Subgroup Analyses...............................................................................................65
9.11
Compliance (Medication Adherence).................................................................65
9.12
Extent of Exposure...............................................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........67
10.1.1
Code of Conduct for Clinical Trials.............................................................67
10.1.2
Financial Disclosure.....................................................................................69
10.1.3
Data Protection.............................................................................................69
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
10.1.4
Committees Structure...................................................................................71
10.1.4.1
Clinical Adjudication Committee (CAC) ..........................................71
10.1.5
Publication Policy........................................................................................71
10.1.6
Compliance with Study Registration and Results Posting Requirements ...71
10.1.7
Compliance with Law, Audit, and Debarment ............................................72
10.1.8
Data Quality Assurance ...............................................................................72
10.1.9
Source Documents .......................................................................................73
10.1.10
Study and Site Closure.................................................................................74
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10.2
Appendix 2: Clinical Laboratory Tests..............................................................75
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................76
10.3.1
Definition of AE ..........................................................................................76
10.3.2
Definition of SAE ........................................................................................77
10.3.3
Additional Events Reported.........................................................................78
10.3.4
Recording AE and SAE ...............................................................................78
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................82
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................83
10.5
Appendix 5: Contraceptive Guidance................................................................84
10.5.1
Definitions....................................................................................................84
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................85
10.7
Appendix 7: Country-specific Requirements....................................................86
10.8
Appendix 8: Abbreviations .................................................................................87
11
REFERENCES...............................................................................................................88
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LIST OF TABLES
Table 1
Local Laboratory Exclusion Criteria (at Baseline/Visit 2) ........................34
Table 2
Examples of Non-pharmacological Therapy .............................................35
Table 3
Study Interventions....................................................................................37
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................52
Table 5
Analysis Strategy for Key Efficacy Variables...........................................61
Table 6
Analysis Strategy for Safety Parameters....................................................63
Table 7
True Proportion of Participants With Delirium in the Suvorexant and 
Placebo Groups Required to Provide 90 (80) % Power (N =100 / arm)....64
Table 8
Differences in Incidence of Adverse Events Between the 2 Treatment 
Groups That Can be Detected With an ~80% Probability (N =100 / 
arm)............................................................................................................65
Table 9
Protocol-required Safety Laboratory Assessments....................................75
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 multicenter, randomized, placebo-controlled, double-blind clinical 
study to evaluate the efficacy and safety of MK-4305 (suvorexant) for reducing incidence of 
delirium in Japanese participants at high risk of delirium.
Short Title: Phase 3 placebo-controlled, double-blind study of MK-4305 (suvorexant) in 
Japanese participants at high risk of delirium (085 study)
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
In Japanese participants at high risk of delirium:
Objectives
Endpoints
Primary
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
proportion of participants with delirium as 
assessed by DSM-5 during the assessment 
period.
•
Hypothesis: Suvorexant reduces the 
proportion of participants with delirium 
compared with placebo as assessed by DSM-
5.
•
Delirium as assessed by DSM-5
•
Objective: To evaluate the safety and 
tolerability of suvorexant compared with 
placebo.
•
Adverse Events
•
Study medication discontinuations 
due to adverse events
Secondary
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
severity of delirium as assessed by DRS-R-
98 (maximum of the daily total score) 
during the assessment period.
•
Severity of delirium as assessed by
DRS-R-98 (maximum of the daily 
total score)
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Objectives
Endpoints
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
proportion of participants with delirium as 
assessed by DRS-R-98 (any daily total 
score ≥14.5) during the assessment period.
•
Delirium as assessed by DRS-R-98 
(any daily total score ≥14.5)
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Reducing incidence of delirium
Population
Japanese participants at high risk of delirium
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects, Investigator, Monitor, Data 
Analyst, and Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 16 months from the time the first 
participant (and their legally acceptable representative as 
needed) provides documented informed consent until the 
last participant’s last study-related contact.
Number of Participants:
Approximately 200 participants will take study medications.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Intervention
Period
Use
Suvorexant
MK-4305
15 mg
QD
Oral
One tablet QD 
before bedtime
for 5 - 7 days
Experi-
mental
Placebo
Placebo
0 mg
QD
Oral
One tablet QD 
before bedtime
for 5 - 7 days
Placebo
Abbreviations: QD=once daily
Total 
Number of 
Intervention 
Groups/ 
Arms
2
Duration of 
Participation
Each participant will participate in the study for up to approximately 5 
weeks from the time the participant provides documented informed consent 
through the final contact. After a screening period of up to 14 days, each 
participant will enter in the assessment period for up to 8 days. After the 
end of intervention each participant will be followed for 14 days.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
The last assessment visit is the next day after the last dose of study medication for the 
completed participants, OR the timing that the assessment is performed after decision of 
discontinuation of study medication for the discontinued participants.  The assessment period 
is from the first dose of study medication to the last assessment visit.
Figure 1
Study Design
Discon SM= Discontinuation of study medication, R = Randomization
*
For the participant hospitalized due to acute disease, the randomization is performed within 24 hours after 
admission.
†
For the participant hospitalized due to elective surgery, the procedures of Visit 1 are performed within 14 
days before admission.
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1.3
Schedule of Activities
Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Administrative Procedures
Informed Consent
X
Informed consent must be obtained 
before any study procedures 
(Informed consent may be obtained 
before 14 days prior to the first 
dose).
Inclusion/
Exclusion Criteria
X
X
Participant 
Identification Card
X
X
At Visit 2, add Randomization 
Number in ID card and provide to 
the participant.
ID card may be provided at the 
discharge.
Medical History 
(including history 
of delirium)
X
X
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Prior/Concomitant 
Medication 
Review
X
X
X
X
X
X
X
APACHE II (Only 
for acute disease)
X
Perform laboratory tests locally for 
assessment of APACHE II.
ECOG PS (Only 
for acute disease)
X
NM Scale
X
Non-
pharmacological 
Therapies for 
Delirium
X
X
X
See Section 5.3.1.
Participant 
Registration
X
X
X
Randomization
X
Study Medication 
(MK-4305 or 
Placebo)
Dispensing
X
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Study Medication 
(MK-4305 or 
Placebo)
Administration
and Compliance
X
X
Administer study medications for 5 
- 7 days.
Hospitalization
X
(Acute disease)
X
(Elective 
surgery)
X
X
For the hospitalization period, see 
Section 5.1.
When Visit 1 and Visit 2 are the 
same day, the participants will be 
hospitalized at Visit 1/Visit 2.
Surgery (Only for 
elective surgery)
X
(Day 2 or 
Day 3)
For acute disease, the need for 
surgery, the timing of surgery and 
the operative method is not limited.
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Efficacy 
Procedures
DSM-5
X
X
X
(every day)
X
X
Assess if the participant develops 
delirium after randomization and 
maximum of 3 hours prior to the 
first dose. If the assessment before 
randomization is performed within 
3 hours before the first dose, the 
re-assessment after randomization 
is not needed.
At Visit 3 and Visit 4, assess in the 
morning.
DRS-R-98
X
X
(every day)
X
X
X
At Visit 3 and Visit 4, assess in the 
morning.
RCSQ
X
X
(every day)
X
X
In the assessment period, assess in 
the morning.
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Undesirable 
hospitalized 
patient outcomes
(fall, accidental or 
intentional 
catheter/tube 
removal [i.e., 
bladder, 
intravenous], and 
body restraint)
X
(every day)
X
X
X
In the follow-up period, collect
undesirable hospitalized patient 
outcomes from hospitalized 
participant.
Safety Procedures
Physical 
examination
X
X
X
X
Vital Signs (blood 
pressures, pulse 
rate, and body 
temperature)
X
X
(every day)
X
X
Utilize same procedure, and the 
same position/side and the same 
timing of procedure throughout the 
study as much as possible.
Hematology
X
(Central)
X
(Central)
X
(Central)
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
Chemistry
X
(Central
and 
Local)
X
(Central)
X
(Central)
Measure ALT, AST and total 
bilirubin locally for assessment of 
exclusion criteria at Visit 2. For the 
participants hospitalized due to 
acute disease, the local laboratory 
test results after the admission may 
be referred.
Urinalysis
X
(Central)
X
(Central)
X
(Central)
AE Review
X
     X
Review AEs which occur for 14 
days after the last dose at follow-
up visit.  If Visit 5 occurs less than 
14 days after the last dose of study 
intervention, a subsequent follow-
up telephone call should be made 
more than 14 days post the last 
dose of study intervention.
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Study Period:
Screening Period
Assessment Period
(From the first dose to last assessment visit)
Follow-up
Period
Notes
Visit Title:
Screening
Baseline
Last Assessment
Follow-up
Screening Period: For the participant 
hospitalized due to acute disease, the 
randomization is performed within 
24 hours after admission. For the 
participant hospitalized due to 
elective surgery, the procedures of 
Visit 1 are performed within 14 days 
before admission.
When Visit 1 and Visit 2 are the 
same day, the overlapping 
procedures at both visits (e.g., 
checking the inclusion/exclusion 
criteria) should be performed only
once.
If the allowance range is not 
described, the visit does not have the 
allowance.
Visit Number:
1
2
3
4
Discontinuation 
of study 
medication
5
Visit Timing 
(Allowance):
Acute disease:
within 24 hours
Elective surgery:
within 14 days
Day 1
Day 2 to 
Day 7
The next
day after 
last dose
14 days
post last 
dose
(± 3 days)
Before 
Randomi-
zation
After 
Randomi-
zation
MCQ Review
X
       X
Review MCQ completed by the 
participant, if receiving any report 
of an adverse event of cataplexy 
including cataplexy-like event or 
fall.
If receiving any report of an adverse event 
of cataplexy including cataplexy-like event 
or fall
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2
INTRODUCTION
Pathophysiology and Diagnosis of Delirium
Delirium is a disease state presenting with various psychiatric symptoms including cognitive 
dysfunction such as disorientation, hallucination delusion, fluctuation of the mood with the 
consciousness disorder (consciousness change) which develops acutely due to the change of 
the body condition and drug use.
There are three categorized factors for delirium: predisposing factor (which is vulnerability 
for delirium), precipitating factor (which triggers delirium), and facilitating factor (which 
induces delirium easily and aggravates and prolongs delirium), and delirium is developed 
with multiple combined factors. Patients who have multiple predisposing factors are at high 
risk of delirium. Because these predisposing factors are individual factors and unlikely to 
improve, they serve as "indicators of intervention" to determine whether hospitalized patients 
are at high risk. Precipitating factors include physical illness, drugs, surgery. Examination of
disease treatment and stop and/or changes in drug regimen could be considered, if physical 
illness or drug is the precipitating factor. Predisposing factors include older age, cognitive 
dysfunction, severe physical illness, a history of head disease (e.g., cerebral infarction, 
cerebral hemorrhage, head trauma), a history of delirium, alcohol abuse, and before highly 
invasive surgery (e.g., long surgery procedure or surgery requiring general anesthesia). 
Facilitating factors include physical factors, mental factors, environmental changes, and 
sleep. Many of the facilitating factors are able to be intervened, and it is essential to reduce or 
eliminate the individual factors [Inoue S, et al. 2013].
The gold standard for delirium diagnosis is the criteria of the " DSM-5 (diagnostic and 
statistical manual of mental disorders 5th edition)" issued by the American Psychiatric 
Association. Delirium is classified into three subtypes; hyperactive characterized by 
agitation, restlessness, irritation, hallucinations, delusions; hypoactive with symptoms like 
dementia and depression such as listlessness, somnolence, and decreased spontaneity; and a 
mixed type that presents with both symptoms. In DSM-5, the identification of subtype is 
required during diagnostics [American Psychiatric Association. 2013].
Epidemiology of Delirium
The prevalence of delirium varies depending on the individuals’ characteristics, setting of 
care, and sensitivity of the detection method, but is known to be highest among older 
individuals. The estimates of the incidence of delirium arising during hospitalization range 
from 6 to 56% in general hospital population [American Psychiatric Association. 2013]. In 
addition, among the elderly aged 65 years and older, the incidence rate has been reported as 
10 to 42% of hospitalized patients, 17 to 61% of postoperative patients, and 80% of 
postoperative ICUs patients [Japanese Society of General Hospital Psychiatry. 2015].
2.1
Study Rationale
In Japan, the number of hospital beds per population is higher than in other countries [Maeda 
Y. 2009], and the rate of elderly hospitalized patients is increasing with the aging of the 
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population [Ministry of Health, Labour and Welfare. 2017]. Therefore, the number of elderly 
hospitalized patients at risk to develop delirium is increasing. Once a patient develops 
delirium, it not only disturbs continuation of treatment to the underlying disease and his/her
recovery but can also lead to undesirable hospitalized patient outcomes such as accidental or 
intentional catheter/tube removal (i.e., bladder, intravenous) and fall. Identifying measures to
reduce delirium is an important medical issue, since the number of medical staff treating 
these patients are limited in the clinical practice and their burden is greatly increased when 
patients develop delirium. Though it was previously considered that the occurrence of 
delirium was a transient disease state, it has been clarified that delirium affects not only the 
physical and medical economic prognoses, but also can result in sustained impairment of 
cognitive function, once it occurs [Davis DH et al. 2012] [Inouye SK, et al. 2014] [Kishi Y. 
2016] [Salluh JI, et al. 2015] [Sano S, et al. 2013] [Sasaki Y, et al. 2014] [Witlox J, et al. 
2010] [Yamaguchi T, et al. 2014] [Zhang Z, et al. 2013]. Therefore, the importance of 
preventing delirium development is now recognized in addition to the one of treatment of 
delirium in onset.
Sleep is one of facilitating factors of delirium, and improvement of sleep-awake cycle might 
contribute the prevention of delirium. Recently, interest in the preventive effect of suvorexant 
on delirium by improving sleep-wake cycle through orexin receptors has increased in Japan. 
Based on these circumstances, the Sponsor plans to conduct a phase III study to investigate 
the efficacy and safety of suvorexant in Japanese elderly participants who will be 
hospitalized for acute disease or elective surgery requiring general anesthesia, AND has 
cognitive impairment or a history of delirium (hereinafter referred to as “at high risk of 
delirium”).
2.2
Background
Refer to the IB/approved labeling for detailed background information on suvorexant.
2.2.1
Pharmaceutical and Therapeutic Background
The measures for delirium have non-pharmacological and pharmacological therapy as 
approaches and preventive and therapeutic interventions as objectives. Non-pharmacological 
therapies (e.g., encouraging cognitive function and orientation such as setting a calendar 
and/or a clock, treating physical factors including dehydration, constipation and pain, and 
countermeasure for sleeping such as controlling light and noise) have been recommended as 
preventive interventions but have limited efficacy. Regarding preventive pharmacological 
therapy, preventive interventions such as antipsychotics, cholinesterase inhibitors, melatonin, 
and melatonin receptor agonists have been studied in order to investigate drugs with fewer 
risks of side effects and effective for delirium prevention [Japanese Society of General 
Hospital Psychiatry. 2015]. However, no drugs have been approved for preventive 
intervention yet. As a pharmacological therapy for therapeutic intervention, tiapride was 
approved in Japan, but the target of patients eligible for treatment is limited to the delirium 
associated with sequelae of cerebral infarction, and there are no other drugs that can be used 
widely. Therefore, the antipsychotic drug is used in the clinical practice, though it is the off-
label use. However, the use of antipsychotics poses a number of problems, including FDA 
alert that "both conventional and atypical antipsychotics are associated with an increased risk 
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of mortality in elderly patients treated for dementia-related psychosis", increasing the 
incidence of adverse events in the elderly in general, side effects such as oversedation and 
extrapyramidal disorders, the risk of sudden death, and contraindications for patients with 
diabetes mellitus.
Suvorexant (MK-4305) is a potent and reversible orexin receptor antagonist developed by 
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD). In September 2014, suvorexant was 
approved for manufacturing and marketing in Japan as a new class of insomnia treatment that 
facilitates sleep by blocking strongly and selectively both orexin receptor 1 and orexin 
receptor 2, which are broadly expressed in cortical, thalamic and hypothalamic neuronal 
circuits involved in the regulation of wakefulness, and controlling orexin neurotransmission, 
which maintains a high physiological function of sleep and wakefulness. Since suvorexant is 
not chemically related to benzodiazepines, non-benzodiazepines, barbiturates or other drugs 
with hypnotic properties, nor does suvorexant possess the intrinsic myorelaxant or anxiolytic 
properties accompanying interaction with GABA type A receptors, it provides a new 
treatment option for insomnia.
The relationship between delirium and sleep disturbances has been studied for many years, 
but it is still uncertain. However, based on previous findings, many variable factors affecting 
the peripheral, systemic, and central nervous systems are risk factors for developing delirium, 
but sleep-disruption are more likely to interact with each other [Weinhouse GL, et al. 2009]. 
Actually, multiple clinical research studies have also shown an association between sleep 
disruption and delirium [Evans JL, et al. 2017] [Fadayomi AB, et al. 2018] [Leung JM, et al. 
2015] [Meagher DJ, et al. 2007] [Trompeo AC, et al. 2011]. Thus, improvement of sleep-
awake cycle might contribute the prevention of delirium. Recently, in Japan, several 
investigator-initiated prospective clinical trials [Azuma K, et al. 2018] [Hatta K, et al. 2017]
and retrospective studies [Masuyama T, et al. 2018] [Tamura K, et al. 2019] have been 
conducted to evaluate the preventive effect of suvorexant on delirium. The investigator-
initiated prospective randomized controlled trials [Azuma K, et al. 2018] [Hatta K, et al. 
2017] demonstrated that suvorexant reduced the incidence of delirium compared with the 
placebo or the conventional treatment in patients admitted due to emergency, and all reports 
including retrospective studies consistently suggested the efficacy of suvorexant in reducing 
incidence of delirium.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
intervention during participation, as clinical studies are designed to provide information 
about the safety and effectiveness of an investigational medicine.
Because suvorexant has demonstrated efficacy and safety in treating disturbances of sleep 
initiation and maintenance in patients with insomnia, and disrupted sleep-wake cycle is a 
potential contributing factor to delirium, administration of suvorexant may reduce delirium 
incidence. The safety and tolerability of suvorexant has been previously demonstrated in 
Phase 3 clinical studies, post-marketing surveillance and in ongoing review of post-
marketing data in patients with insomnia. In the clinical studies in patients with insomnia 
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including Japanese, the main adverse reactions of suvorexant were somnolence, headache, 
and fatigue.
Additional details regarding other specific benefits and risks for participants participating in 
this clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In Japanese participants at high risk of delirium:
Objectives
Endpoints
Primary
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
proportion of participants with delirium as 
assessed by DSM-5 during the assessment 
period.
•
Hypothesis: Suvorexant reduces the 
proportion of participants with delirium 
compared with placebo as assessed by
DSM-5.
•
Delirium as assessed by DSM-5
•
Objective: To evaluate the safety and 
tolerability of suvorexant compared with 
placebo.
•
Adverse Events
•
Study medication discontinuations 
due to adverse events
Secondary
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
severity of delirium as assessed by DRS-R-
98 (maximum of the daily total score) 
during the assessment period.
•
Severity of delirium as assessed by
DRS-R-98 (maximum of the daily 
total score)
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the
proportion of participants with delirium as 
assessed by DRS-R-98 (any daily total 
score ≥14.5) during the assessment period.
•
Delirium as assessed by DRS-R-98 
(any daily total score ≥14.5)
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Objectives
Endpoints
Exploratory
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the 
sub-item score of DRS-R-98 related to 
sleep (sleep-wake cycle disturbance)
during the assessment period.
•
Sub-item score of DRS-R-98 related 
to sleep (sleep-wake cycle
disturbance)
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on 
Richards-Campbell Sleep Questionnaire
(RCSQ) score during the assessment 
period.
•
RCSQ score
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the 
proportion of participants with undesirable 
hospitalized patient outcomes (fall, 
accidental or intentional catheter/tube
removal [i.e., bladder, intravenous], and 
body restraint) until the follow-up visit.
•
Undesirable hospitalized patient 
outcomes (fall, accidental or 
intentional catheter/tube removal [i.e., 
bladder, intravenous], and body 
restraint) (composite and each event)
•
Objective: To evaluate the impact of 
suvorexant compared with placebo on the 
use of antipsychotic medications (CP 
equivalent and proportion of individuals)
until the follow-up visit
•
Antipsychotic medications
consumption
•
Objective: To evaluate the efficacy of 
suvorexant compared with placebo on the 
sub-item scores of DRS-R-98 related to 
cognitive function (orientation, attention, 
short-term memory, long-term memory, 
and visuospatial ability) until the follow-up 
visit
•
Sub-item scores of DRS-R-98 related 
to cognitive function (orientation, 
attention, short-term memory, long-
term memory, and visuospatial 
ability)
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind clinical 
study to evaluate the efficacy and safety of suvorexant for reducing incidence of delirium in 
Japanese participants at high risk of delirium.
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This study consists of a screening period of up to 14 days (for acute disease, within 24 hours 
after admission; for elective surgery, within 14 days before admission), an assessment period 
of up to 8 days (from the first dose of study medication to the last assessment visit: for 6 to 8 
days), and a follow-up period of 14 days.
The target population includes Japanese participants at high risk of delirium between the ages 
of 65 and 90 years, inclusive. Participants judged as eligible in the screening period will be 
randomized in a 1:1 ratio to receive either suvorexant or placebo at Visit 2, and they will take 
one tablet of study medication (suvorexant 15 mg tablet or matching placebo tablet) once 
daily (q.d.) orally before bedtime for 5-7 days in a double-blind manner. The participants 
who develop delirium after randomization but prior to the first dose of study medication will 
be withdrawn from the study without the study medication administration. The participants 
hospitalized due to elective surgery will receive surgery on the next day or 2 days after 
admission/the first dose of study medication and will take study medications for 4 days at 
least after surgery. For the participants who develop delirium during the assessment period, 
the study intervention is discontinued at this timing. The use of prohibited medications 
including antipsychotics for treatment of delirium is allowed in the opinion of the
investigator after completion or following a decision of discontinuation of study medication 
administration. The follow-up visit 14 days after last dose of study intervention will be 
performed for all participants received study medication.
The target number of participants receiving study medication is approximately 200 
participants. Intervention randomization will be stratified according to hospitalization reason 
(acute disease, elective surgery) and age category (<75 years, ≥75 years). If either the 
proportion of participants hospitalized due to acute disease or those hospitalized due to 
elective surgery exceeds approximately 60% of the total targeted sample size, the remaining 
participants will only be enrolled into the other stratum within this stratification factor.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are some guidelines related to delirium in Japan; "Clinical guidelines for delirium 
[Treatment guidelines for delirium, Second version]" issued by delirium guideline revision 
group of the Japan society of general hospital psychiatry, "Japanese clinical practice  
guidelines for the management of pain, agitation, and delirium in adults patients in the 
intensive care unit" issued by J-PAD guidelines preparation committee of the Japanese 
society of intensive care medicine, and "Delirium guidelines for patients with cancer 2019" 
issued by Japan psycho-oncology society and the Japanese association of supportive care in 
cancer, respectively. All guidelines mention that the gold standard for delirium diagnosis is 
the criteria of the “DSM-5 (diagnostic and statistical manual of mental disorders 5th edition)”
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issued by the American Psychiatric Association. Based on the above, the primary efficacy 
endpoint of this study is the proportion of participants with delirium as assessed by DSM-5.
DRS-R-98 is a structured diagnostic scale for delirium assessment, with established 
reliability and validity, and already available in Japanese. While it may be difficult to 
diagnose the presence or absence of delirium based solely on scores, the DRS-98 covers the 
items necessary for delirium evaluation and is useful for the evaluation of delirium severity.  
Because of this, the secondary efficacy endpoints are the severity of delirium as assessed by 
DRS-R-98 (maximum of the daily total score) and the proportion of participants with
delirium as assessed by DRS-R-98 (any daily total score ≥14.5) in this study.
The symptoms of delirium tend to fluctuate in severity during course of a day, and it is 
difficult to detect the fluctuation of the symptoms' severity based on only the condition which 
are observed at the time of the assessment. Therefore, DSM-5 and DRS-R-98 will be 
assessed not only on participants' symptoms at the time of assessment but also on the basis of 
symptoms observed from the previous assessment until the next assessment, so that all 
symptoms developing during the assessment period can be confirmed continuously without 
missing. The frequencies of assessments of DSM-5 and DRS-R-98 are once a day, so that the 
fluctuation of severity such as sleep-wake cycle can be assessed comprehensively based on 
medical records and information from a medical staff.
4.2.1.2
Safety Endpoints
The following endpoints will be collected to assess the safety of suvorexant.  Pre-specified 
ECIs will be reviewed by an external CAC (see Section 10.1.4.1).

Adverse events including ECIs (for ECIs, see Section 8.4.7.)

Vital signs (blood pressures, pulse rate, and body temperature)

Laboratory tests
4.2.2
Rationale for the Use of Placebo
The comparison between suvorexant group and a control group enables an exclusion of 
influences of the target population, changes over time, and other factors, and an objective 
characterization of reducing incidence of delirium of suvorexant.  In addition, any 
measurements in the target population requires a control group to adequately characterize any 
potential positive/negative effects of suvorexant in the target population.  Considering the 
importance of this study in adequately characterizing the efficacy and safety of suvorexant 
use in participants deemed at high risk for development of delirium, the control group is 
designed into the assessment period.
Additionally, because no approved medication is indicated for delirium prevention to use as 
active comparator, placebo is the best appropriate intervention for the control arm of this 
study.
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4.3
Justification for Dose
4.3.1
Dose for This Study
Delirium and disrupted sleep have a close relationship, and improvement of sleep-awake 
cycle might contribute to the prevention of delirium. Thus, the dose which is established for 
efficacy for sleep (suvorexant 15 mg once daily, approved dose for elderly insomnia in 
Japan) is considered appropriate to investigate the potential for suvorexant to reduce 
incidence of delirium in elderly patients.
In a combined analysis of phase 3 studies conducted in patients with insomnia at the time of 
its development, the incidence of adverse events in elderly patients aged 65 years or older are 
comparable among 15 mg, 30 mg (unapproved dose) and placebo groups. In addition, and the 
incidences of serious adverse events, and adverse events leading to discontinuation were low, 
and no differences between treatment groups. These suggested that suvorexant 15 mg and 
30 mg is generally safe and well tolerated in the doses studied. Furthermore, as for post-
marketing surveillance for suvorexant, the efficacy and safety information of suvorexant was 
collected in patients with insomnia who were first treated with suvorexant in Japan, with a 
follow-up of up to 6 months after the initiation of treatment [Asai Y, et al. 2018]. The 
administration of suvorexant 15 mg q.d. to hospitalized elderly patients was well tolerated in 
clinical practices.
Additionally, the efficacy of suvorexant 15 mg in reducing incidence of delirium when 
administered to elderly patients has been consistently suggested in several investigator-
initiated clinical trials, and was well tolerated [Azuma K, et al. 2018] [Hatta K, et al. 2017].
Based on the above, suvorexant 15 mg q.d. before bed time is for this study.
4.3.2
Rationale for Dose Interval and Study Design
The frequent onset timing of delirium is about 3 days after hospitalization in patients with 
acute disease [Azuma K, et al. 2018] [Hasegawa M. 1999] [Hatta K, et al. 2014] [Hatta K, et 
al. 2017] [Regal PJ. 2017] and about 3 days after surgery in patients with postoperative 
delirium [Booka E, et al. 2017] [Chaiwat O, et al. 2019] [Lee HJ, et al. 2011]. It is reported 
most cases of delirium occur within 7 days after admission or surgery. On the other hand, 
although timing and duration of hospitalization is defined based on the physical condition of 
each patient such as underlying disease and/or policy of each hospital, in recent years, length 
of stay at general hospital has become shorter in tendency. Considering those points, to 
evaluate the efficacy of suvorexant in reducing incidence of delirium during the period of the 
most frequent occurrence of delirium, the administration of study medication will be started
from the day (for acute disease or elective surgery) or the next day (for acute disease only) of 
admission and treated 5 days at least according to the length of stay for each patient in this 
study. The study medication will be administered for preventive objective in this study, 
therefore, the administration duration should be limited. The maximum administration 
duration is set as up to 7 days considering the period of developing delirium.
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For participants hospitalized due to elective surgery, if the period from hospitalization to 
elective surgery is longer, it may affect the evaluation because the administration period of 
the study medication after surgery becomes shorter. Therefore, in case of hospitalization for 
elective surgery, participants who schedule surgery on the next day or 2 days after hospital 
admission are eligible for this study, since such participants can have enough the 
administration period of the study medication after surgery.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (and their legally acceptable 
representative as needed) provides documented informed consent. The overall study ends 
when the last participant completes the last study-related contact, withdraws consent, or is 
lost to follow-up (ie, the participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female Japanese participants at high risk of delirium between the ages of 65 and 90 
years, inclusive will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is hospitalized for any one of followings;
(1) Acute disease: meets all following criteria;
a)
Is hospitalized due to any one of following diseases;
Infections
pneumonia, urinary tract infection, soft tissue infection, intra-
abdominal infection, cerebral infection, bacteraemia, and sepsis
Cerebral disorders
cerebrovascular disorders (e.g., cerebral infarction, and cerebral 
haemorrhage)
Heart disorders
cardiac failure, and myocardial infarction
Respiratory diseases
respiratory failure
Injuries
fracture, traumatic injury, and thermal burn
Neoplasms
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AND
b)
Meets any one of followings at Screening;

Has severe disease state (APACHE II: 8 -30)

Shows decreased daily living function (ECOG PS: 3 or 4)
(2) Elective surgery: meets all following criteria;
a)
Requiring general anesthesia
AND
b)
Scheduled on the next day or 2 days after admission/Day 1
2. Meets any one of followings;

Has mild cognitive impairment or mild dementia

Has a history of delirium in any prior hospitalization
Demographics
3. Is male or female, from 65 years to 90 years of age inclusive, at the time of signing the 
informed consent.
Informed Consent
4. Has provided documented informed consent/assent for the study (or legally acceptable 
representative in addition to the participant, as needed).
Other Criteria
5. Requires hospitalization of any one of following estimated period for acute disease or 
elective surgery.
(1) For acute disease;

For the randomization/the first dose of study medication on the day of
admission: for 6 days and 5 nights or longer

For the randomization/the first dose of study medication on the next day after
admission: for 7 days and 6 nights or longer
(2) For elective surgery;

For elective surgery scheduled on the next day after admission/Day 1: for 6 
days and 5 nights or longer
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
For elective surgery scheduled 2 days after admission/Day 1: for 7 days and 6 
nights or longer
6. Is able to take study medications orally during the assessment period.
7. Is confirmed that he/she has an ability to follow study procedures and complete the study 
by the investigator prior to randomization. (e.g., has vision and hearing abilities to 
perform the clinical study and can speak.)
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has moderate or severe dementia.
2. Has whose APACHE II is 31 or more at Screening (Only for acute disease).
3. Has a history of epilepsy or Parkinson's disease.
4. Currently uses any of psychotropic agents, or has unstable mental condition including
schizophrenia, other mental diseases, bipolar disorder and major depression.
5. Has a history of drug or alcohol abuse within 5 years before Screening, or consumes over 
60 g per day of alcohol on average (e.g., 60 g alcohol is 3 goes of Japanese sake, 3
middle bottles of beer, or 5 glasses of wine), or has alcoholic disease such as alcoholic 
liver disease or gastritis alcoholic.
6. Has delirium as assessed by DSM-5 or DRS-R-98 (total score ≥14.5) during the 
screening period.
7. Is at imminent risk of self-harm or of harm to others in the opinion of the investigator. 
Participants must be excluded if they report suicidal ideation with intent, with or without 
a plan or method in the past 2 months or suicidal behavior in the past 6 months.
8. Has history of narcolepsy or cataplexy.
9. Has history of hypersensitivity to suvorexant.
10. Meets any contraindication or warning listed on package inserts of suvorexant and which 
are not contained in the exclusion criteria of this protocol.
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Prior/Concomitant Therapy
11. Has used any of following medications within 2 weeks before Randomization.

Hypnotics (benzodiazepine receptor agonists, orexin receptor antagonists, melatonin 
receptor agonists, and/or prescription Chinese herbs)

Antipsychotics

Mood stabilizers

Antidepressants

Anxiolytics

Psychostimulants

Anticonvulsants

Tiapride
12. Is likely to require during time periods specified by this protocol the treatment with a 
prohibited medication specified in Section 6.5.1.
Prior/Concurrent Clinical Study Experience
13. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 30 days before Screening.
14. Has previously participated AND been randomized in this study.
Diagnostic Assessments
15. Has any exclusionary local laboratory values as listed in the table below at Baseline.
Table 1
Local Laboratory Exclusion Criteria (at Baseline/Visit 2)
Parameter
Study Limit for Exclusion
ALT
3 or more times ULN
AST
3 or more times ULN
Total bilirubin
1.5 or more times ULN
Note: For the participants hospitalized due to acute disease, the local laboratory test 
results after admission may be referred.
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Other Exclusions
16. Is unable to participate in and complete the requirements of the trial in the investigator's 
or the Sponsor's judgment for other unlisted reasons.
Example: 

Has mental condition which affects the study participation.

Is likely to increase the risk associated with study participation or study 
intervention or to interfere with the interpretation of study result.
17. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Non-pharmacological Therapy
From the day of Randomization to the end of the assessment period, the investigator and/or 
the site staff will confirm the need for the non-pharmacological therapy and take appropriate 
actions considering the individuals’ conditions.
See the following table for the non-pharmacological therapy to be performed;
Table 2
Examples of Non-pharmacological Therapy
Items
Examples of Specific Action Items
Measures to orientation
Setting of a calendar and a clock, and/or conversation with the participant at 
care, treatment and medical examinations
Measures to physical factors 
(dehydration and pain)
The confirmation and measures to cause
Dehydration: correction of dehydration, promotion of water intake
Pain: adjustment of the body position, massage, cooling/heating, 
psychological support, administration of analgesic, etc.
Measures to inactivity
Promotion of early mobilization, daytime movement of range of motion 
(passive movement or rehabilitation by physiotherapist if active movement 
is difficult), avoiding body restraint as possible.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy
If a participant discontinues the study due to delirium after randomization before the first 
dose of study medication, a replacement participant may be enrolled. The replacement 
participant will generally receive the same intervention as the participant being replaced. The 
replacement participant will be assigned a unique treatment/randomization number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies study intervention(s) provided by the Sponsor will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
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Table 3
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Intervention 
period
Use
IMP/
NIMP
Sourcing
Suvorexant
Experimental MK-4305
Drug
Tablet
15 mg
15 mg
Oral
One tablet 
QD before 
bedtime
for 5 - 7 days
Experimental
IMP
Provided
centrally
by the 
Sponsor
Placebo
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
One tablet 
QD before 
bedtime
for 5 - 7 days
Placebo
IMP
Provided
centrally
by the 
Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.12 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to suvorexant and 
placebo, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Hospitalization reason (acute disease, elective surgery)
If either the proportion of participants hospitalized due to acute disease or those 
hospitalized due to elective surgery exceeds approximately 60% of the total targeted 
sample size, the remaining participants will only be enrolled into the other stratum 
within this stratification factor.
2. Age category (<75 years, ≥75 years)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-4305 and placebo will 
be packaged identically so that blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
See Section 8.1.14 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified intervention plan for ≥2 days in total require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol for that medication. If there is a clinical indication for any 
medication specifically prohibited, discontinuation from study intervention may be required. 
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director. The final decision on any supportive therapy rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
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The use of concomitant medications and medications that may cause delirium should be 
limited to a bare minimum to minimize the impact on efficacy and safety assessment.
6.5.1
Prohibited Therapy
From 2 weeks before Randomization to the end of the assessment period

Hypnotics (including prescription Chinese herbs, and other than study medications)

Antipsychotics

Mood stabilizers

Antidepressants

Anxiolytics

Psychostimulants

Anticonvulsants

Tiapride
From the day of Randomization to the end of the assessment period

Strong CYP3A inhibitors
Examples: Itraconazole, clarithromycin, ritonavir, nelfinavir, voriconazole, and 
posaconazole.
From 30 days before Screening to the end of the study

Other investigational medications
The use of these prohibited medications including antipsychotics for treatment of delirium is
allowed in the opinion of the investigator after completion or following a decision of 
discontinuation of study medications administration.
6.5.2
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modifications are permitted in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
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6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.14). The 
Sponsor will not provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.14 for a description of the method of unblinding a participant during the 
study should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified intervention
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.9.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.13 and Section 
8.9.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Developing delirium as assessed by DSM-5
After randomization, when the qualified rater judges that a participant developed delirium 
as assessed by DSM-5.
•
Adverse events
In the case that the investigator assesses that administration of the study medication 
should be discontinued due to the occurrence of adverse experiences.
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•
Protocol Violation
It becomes inappropriate to continue study intervention as a result of a significant 
protocol deviation.
•
Non-Compliance with Study Drug
When a participant has not agreed with or followed the instructions related to the study 
medication, or a study intervention is not initiated on the day of Randomization.
•
In addition, the investigator and/or the Sponsor judges that participant should discontinue
the study medications for any other reason.
Example: When a participant has either transferred to another hospital after the initiation 
of study medication and is no longer able to participate in the study.
The study procedures of assessment period after discontinuation from study intervention are 
not performed, since the objectives of this study is to investigate the efficacy of suvorexant 
on reduction in incidence of developing delirium.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.13. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
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known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (and their legally 
acceptable representative as needed) prior to participating in this clinical study. If there are 
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changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant (and their legally acceptable representative as 
needed) must be documented on a consent form. The form must include the study protocol 
number, study protocol title, dated signature, and agreement of the participant (and his/her 
legally acceptable representative as needed) and of the person conducting the consent 
discussion.
A copy of the signed and dated informed consent form should be given to the participant 
before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant, and his/her legally acceptable representative as needed, should be informed in a 
timely manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s dated signature, and by the participant’s legally 
acceptable representative’s dated signature as needed.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator to ensure that the 
participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
The investigator will review a medical history including a history of delirium in any prior 
hospitalization.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator will review prior medication use, and record prior medication taken by the 
participant within 30 days before Screening.
8.1.5.2
Concomitant Medications
The investigator will record medication, if any, taken by the participant during the study.
8.1.6
APACHE II
The investigator will assess APACHE II [Knaus WA, et al. 1985] for participants 
hospitalized due to acute disease and confirm the eligibility of the enrollment.
Procedures conducted after the admission as part of the participant’s routine clinical 
management (e.g., the measurement of vital signs and laboratory tests) and obtained before 
signing of ICF may be utilized for the assessment of APACHE II.
8.1.7
ECOG PS
The investigator will assess ECOG PS [Oken MM, et al. 1982] for participants hospitalized 
due to acute disease and confirm the eligibility of the enrollment.
8.1.8
NM Scale
The investigator will assess the cognitive function using NM scale [Otsuka T, et al. 1991] for 
all participants and refer to the assessment at the enrollment (mild cognitive impairment or 
severity of dementia).
8.1.9
Non-pharmaceutical Therapy
According to Section 5.3.1, the non-pharmaceutical therapy to be performed (See Table 2) 
will be confirmed and it will be mentioned in the medical record. From the day of 
Randomization to the end of the assessment period, the investigator and/or the site staff will
conduct the non-pharmaceutical therapy per the nursing plan.
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The investigator will confirm whether non-pharmaceutical therapy had been conducted per 
the nursing plan and record it.
8.1.10
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.11
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.12
Study Intervention Administration
Each participant will take the first dose before bedtime on the day of randomization.
If the rater judges a participant develop delirium after randomization and before the first dose, 
the participant must discontinue the study without taking study medication.
8.1.12.1
Timing of Dose Administration
From the day of randomization, each participant will take one tablet of study medication
once daily orally before bedtime for 5 – 7 days in double-blind manner according to the 
individuals’ hospitalization duration. On the day of the last assessment visit, the study 
medication should not be administered.
If the participant missed a dose of study medication, the missed dose of last night should not 
be administered and one tablet of study medication should be administered before the next 
bedtime. The study medication must not be taken upon awakening in the middle of the night, 
even if the participant failed to take study medication at bedtime that previous night. Two or 
more tablets of the study medication must not be taken a night.
If the participant is not able to take study medication due to his/her condition, the investigator 
should inform the Sponsor promptly and discuss the continuation of study medications 
administration of this participant with the Sponsor.
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8.1.13
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the assessment period
should be encouraged to complete the follow-up visit as outlined in the SoA and Section 
8.9.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the last assessment visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.14
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should complete the follow-up visit.
8.1.15
Hospitalization
The participants hospitalized due to acute disease will be randomized within 24 hours after 
admission to the clinical site. 
The participants hospitalized due to elective surgery will be admitted to the clinical site on 
the day or 2 days before the surgery AND before randomization on the day of the first dose 
of study medication. If the scheduled date of the surgery is changed by any reasons after 
randomization, the investigator should contact the Sponsor promptly to discuss whether the 
participant should continue the study or not.
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The participant will be hospitalized for 6 days and 5 nights from the day of the first dose of 
study medication or longer in cases of acute disease OR elective surgery scheduled on the 
next day after admission/Day 1, OR, for 7 days and 6 nights in cases of elective surgery 
scheduled 2 days after admission/Day 1.  In the case that the hospitalization duration from 
the day of the first dose of the study medication is for over 7 days, the intervention duration 
will be for 7 days.
8.1.16
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
The raters of DSM-5 and DRS-R-98 must receive the training provided by the Sponsor and 
meet the qualification before rating of this study. The rater qualifications, training and 
applicable certification process are established in a separate document. The rater should 
assess according to the manuals as a separate document. To minimize variability, it is 
preferred that the same rater(s) perform the same evaluation(s) for each participant during the 
study.
8.2.1
DSM-5
During the assessment period, the qualified rater will review the medical record including the 
nursing record and question from the participant.  The necessary information for the 
assessment will be collected from the family of the participant and/or the site staff as well, as 
needed. Based on this information, the rater will assess whether the participant had 
developed delirium or not as measured by DSM-5 since the last assessment once daily in
morning at least, and will record it. DSM-5 assessment should be performed anytime if the 
rater finds symptoms of suspected delirium in the participant. Assessing DSM-5, the 
information for assessment of DRS-R-98 should be referred, in principle. If assessing that the 
participant develops delirium during the assessment period, the subtype and causes of 
delirium (using the etiology checklist [Trzepacz PT, et al. 2009]) will be assessed, they will 
be recorded.
If the rater assess that the participant developed delirium as measured by DSM-5, that should 
be entered in AE eCRF as well.
8.2.2
DRS-R-98
During the assessment period, the qualified rater will review the medical record including the 
nursing record and question from the participant.  The necessary information for the 
assessment will be collected from the family of the participant and/or the site staff as well, as 
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needed. Based on this information, the rater will assess the condition of the participant since 
the last assessment using the items specified in DRS-R-98 once daily in morning at least. The 
scores will be recorded.
At the follow-up visit, the qualified rater will collect the necessary information from the 
interview of the participant (and his/her family or site staff(s), and/or the medical record, as 
needed), and assesses items specified in DRS-R-98. The scores will be recorded.
8.2.3
Richards Campbell Sleep Questionnaire (RCSQ) Score
During the assessment period, the participant will complete 5-item visual analog scale (VAS)
about the last-night sleep in the sleep questionnaires once daily in the morning. The clinical 
coordinator measures the mark written by the participant with a ruler and enters it in 
millimeter (mm) unit in the eCRF.
8.2.4
Undesirable Hospitalized Patient Outcomes (Fall, Accidental or Intentional 
Catheter/Tube Removal, and Body Restraint)
The investigator will collect the information related to all events of falls, accidental or 
intentional catheter/tube removal (i.e., transfusional line, bladder catheter, drain), and body 
restraints which occur during hospitalization (including the follow-up period when the
participant is hospitalized). When falls, accidental or intentional catheter/tube removal, 
and/or body restraints occur, the investigator will evaluate its relationship to delirium
referring to the following criteria.
-
Related to delirium: There is evidence of occurrence of delirium. The temporal 
sequence of the undesirable hospitalized patient outcome onset relative to the 
occurrence of delirium is reasonable. The undesirable hospitalized patient outcome is 
more likely explained by delirium than by another cause, e.g., an adverse event other 
than delirium, a patients’ background and/or an environmental factor including use of 
a concomitant medication or a complication.
-
Not related to delirium: Participant did not develop delirium OR temporal sequence of 
the undesirable hospitalized patient outcome onset relative to the occurrence of 
delirium is not reasonable OR the undesirable hospitalized patient outcome is more 
likely explained by another cause than delirium.
“Fall” should be entered in AE eCRF as ECIs as well.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
A physical examination will be conducted by the investigator at Screening as per institutional 
standard evaluations, the last assessment visit and the follow-up visit.
8.3.2
Vital Signs
Blood pressures, pulse rate, and body temperature will be measured once daily from the day 
of Randomization to the last assessment visit. It is preferred that vital signs are utilized same 
procedure, same position/side and the same timing of procedure throughout the study.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
For the participants hospitalized due to acute disease, the measurements of heart rate and 
respiratory rate are necessary at Screening for assessment of APACHE II.
8.3.3
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4
Modified Cataplexy Questionnaire (MCQ) Review
If the investigator receives a report that the participant had cataplexy including cataplexy-like 
event or fall after randomization, he/she will ask the participant to complete the MCQ (a 
modified version of Cataplexy Questionnaire [Anic-Labat S, et al. 1999]) and will review it. 
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If an event is fall, the investigator will review MCQ in order to rule out cataplexy. The 
administration of the MCQ is provided in a separate document.
All reports of cataplexy including cataplexy-like event and fall, which occurred after 
randomization, must be recorded as ECIs (See Section 8.4.7). The MCQ, administered in 
conjunction with documentation of these, will be provided to the CAC.
Falls which occur during hospitalization must be reported as Undesirable Hospitalized 
Patient Outcomes as well (See Section 8.2.4).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through 14 days after cessation of study 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days of 
learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since target population of this study is elderly 
participants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or
SAEs in this study. Note that delirium as measured by DSM-5 should be reported as an AE 
eCRF as well, if the investigator assesses that the participant developed delirium as measured 
by DSM-5.
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8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
2. Complex sleep-related behaviors
3. Sleep paralysis (including sleep onset paralysis [adjudicated])
4. Hypnagogic or hypnopompic hallucinations
5. Somnolence resulting in discontinued intervention
6. Fall (adjudicated to rule out cataplexy)
7. Suicidal ideation, suicidal behaviors
8. Selected events associated with potential for abuse
9. Cataplexy (adjudicated)
CAC will adjudicate events, which occurred after randomization, of “cataplexy”, “sleep onset 
paralysis” and “fall” reported by the investigators (For the details, see Section 10.1.4.1).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 15 mg per night (i.e., 1 tablet per night).
For the specific treatment for an overdose, see the IB/approved labeling.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor based on the clinical evaluation of the participant.
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8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.9.1
Screening Period (from Screening until First Dose of Study Medication)
8.9.1.1
Screening/Visit 1
After the documented informed consent from the participant, the investigator will review 
whether he/she meet the inclusion and does not meet exclusion criteria.
Note: For participants hospitalized due to acute disease, APACHE II and ECOG PS will 
be assessed.
Note: For participants hospitalized due to elective surgery, the operative method (i.e., 
surgery requiring general anesthesia) will be confirmed.
After completing the above, the participants will be registered.
In case Visit 1 and Visit 2 occur on the same day, the overlapping procedures at both visits 
(e.g., reviewing the inclusion/exclusion criteria) specified in SoA should be performed only 
once.
In case Visit 1 and Visit 2 occur on different days, the procedures of Visit 1 and the 
randomization should be performed within 24 hours after admission for participants 
hospitalized due to acute disease, and the procedures of Visit 1 should be performed within 
14 days before admission for participants hospitalized due to elective surgery.
8.9.1.2
Baseline/Visit 2 (until Randomization)
The qualified rater will assess DSM-5 and DRS-R-98 on the day of randomization. The 
participant will complete RCSQ.
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After reviewing whether the participant meets the inclusion and does not meet exclusion 
criteria based on the above assessments, the eligible participant will be registered and 
randomized. In addition, the participant will receive appropriate non-pharmacotherapy based 
on his/her condition (See Section 5.3.1).
The received randomization number will be entered in the participant identification card. The 
study medication will be prescribed to the participant according to the Component ID. The 
investigator will instruct the participant to take one tablet of study medication once daily 
orally before bedtime from the day.
8.9.1.3
Visit 2 (from Randomization until First Dose of Study Medication)
Within 3 hours before the first dose of study medication, the qualified rater will assess DSM-
5 again to confirm whether the participant does not develop delirium after randomization. If 
the assessment before randomization is performed within 3 hours before the first dose of 
study medication, the re-assessment after randomization is not needed.
If the participant has symptom suspected delirium after the rater assessed before the first dose 
of study medication, the rater will reassess DSM-5 based on the information to confirm 
whether the participant does not develop delirium. If the rater judges the participant develops
delirium as assessed by DRM-5 or if the rater cannot deny that the participant develops 
delirium as assessed by DRM-5, the participant must be discontinued from the study without 
administering study medication.
After the rater assessed before the first dose of study medication, in the case that the 
participant did not have symptom suspected delirium or in the case that the rater assessed the 
participant had not developed delirium even if he/she had symptom suspected delirium, the 
study medication will be administered to him/her.
The investigator or the clinical research coordinator will enter whether the participant had 
initiated to take the study medication or not to IRT.
8.9.2
Assessment Period (from First Dose of Study Medication until Last 
Assessment Visit)
The qualified rater will assess the efficacy once daily in the morning at least from the day 
after the first dose of study medication. The participant will complete RCSQ once daily in the 
morning.
At the last visit, the procedures specified in SoA will be performed in addition to the above.
The clinical coordinator should make sure that the participant has the participant 
identification card when he/she is discharged.
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8.9.3
Follow-up Period
8.9.3.1
Follow-up Visit
Participants will be required to return to the clinical site 14±3 days after the last dose of study 
intervention for the follow-up visit. If the follow-up visit occurs less than 14 days after the 
last dose of study intervention, a subsequent follow-up telephone call should be made more 
than 14 days post the last dose of study intervention to determine if any AEs have occurred 
since the follow-up visit.
In the event any serious drug-related adverse event occurred later than 14 days after the last 
dose of study intervention, it will be subjected to the follow-up evaluation.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to the database lock, changes are made to the primary 
hypothesis, or the statistical methods related to the hypothesis, then the protocol will be 
amended (consistent with ICH Guideline E-9).  Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to the database 
lock, will be documented in a supplemental Statistical Analysis Plan (sSAP) and referenced 
in the Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be 
clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 3 multicenter, randomized, placebo-controlled, double-blind clinical 
study to evaluate the efficacy and safety of MK-4305 (suvorexant) for reducing 
incidence of delirium in Japanese participants at high risk of delirium.
Treatment Assignment
Participants will be randomized to suvorexant or placebo in a 1:1 ratio, stratified 
by hospitalization reason (acute disease, elective surgery) and age category (<75 
years, ≥75 years).
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Proportion of participants with delirium during the assessment period as assessed 
by DSM-5
Statistical Methods for 
Key Efficacy Analyses
The treatment difference in the proportion of participants with delirium during 
the assessment period as assessed by DSM-5, along with the corresponding 95% 
confidence interval (CI) and the p-value based on the Miettinen and Nurminen 
method [Miettinen O, et al. 1985], will be provided. The analysis will be 
stratified by hospitalization reason (acute disease, elective surgery) and age 
category (<75 years, ≥75 years). The Cochran-Mantel-Haenszel weight will be 
used to obtain stratum-adjusted proportion difference.
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Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach.  The tiers differ with 
respect to the analyses that will be performed. p-Values for treatment comparison 
(Tier 1), and treatment differences along with 95% CIs (Tiers 1 and 2), will be 
calculated based on the unstratified Miettinen and Nurminen method for the 
proportion of participants with respective events.
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is planned as the study has a single primary 
hypothesis that will be addressed with a single comparison of two treatments 
using one endpoint.
Sample Size and Power
A total of 200 participants will be randomized to suvorexant or placebo in a 1:1 
ratio. The study will have a power of 90 (80) % with a two-sided significance 
level of 0.05 to detect a difference between treatments if the true proportion of 
participants with delirium in the suvorexant group is 11.6 (13.7) % compared to
30% in the placebo group. If there are occurrences of delirium after 
randomization but prior to the first dose of study medication, then the number of 
randomized participants will be increased to account for such participants.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. The randomized allocation schedule(s) for study treatment assignment will be 
generated by a clinical schedule manager who is otherwise not involved in the study. 
Randomization will be implemented using IRT (or equivalent).
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Key efficacy and safety endpoints are listed below. The baseline value is defined as the last 
available measurement prior to the first dose of study medication.
9.4.1
Efficacy Endpoints
The primary efficacy endpoint is the proportion of participants with delirium during the 
assessment period as assessed by DSM-5.
The secondary efficacy endpoints are:
1. Severity of delirium during the assessment period as assessed by DRS-R-98, defined 
as the maximum (i.e., worst) of total score among those obtained daily during the 
assessment period.
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2. Proportion of participants with delirium during the assessment period assessed by
DRS-R-98, defined as the proportion of participants with the maximum total score of 
14.5 or greater during the assessment period.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events, laboratory values and vital signs. The a priori safety events of interest are as 
follows: complex sleep-related behaviors, sleep paralysis (including sleep onset paralysis 
[adjudicated]), hypnagogic or hypnopompic hallucinations, somnolence resulting in 
discontinued intervention, falls (adjudicated to rule out cataplexy), suicidal ideation and/or 
behaviors, selected events associated with potential for abuse, cataplexy (adjudicated). Those 
events which consist of multiple AE terms (e.g., complex sleep-related behaviors, selected 
events associated with potential for abuse) will be defined separately prior to unblinding.
9.5
Analysis Populations
9.5.1
Efficacy Analysis population
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who have at least one 
assessment of delirium by DSM-5 following administration of at least one dose of study 
medication. Occurrences of delirium after randomization but prior to the first dose of study 
medication will thus be excluded from the analysis.
A supportive analysis using the Per-Protocol (PP) population may be performed for the 
primary efficacy endpoint if there is a substantial number of protocol violators (>10% of 
FAS) that will be excluded from the PP population. The PP population excludes participants 
due to major deviations from the protocol that may substantially affect the results of the 
primary efficacy endpoint. Potential deviations that may result in the exclusion of a 
participant from the PP population include:

Significant violation to the inclusion/exclusion criteria that may affect the results of 
the primary efficacy endpoint

Missing assessment of delirium by DSM-5 at any time during the assessment period

Treatment duration of less than 5 days, with the exception of discontinuation due to 
delirium as assessed by DSM-5

Missed dose(s) of study treatment at any time during the trial

Use of prohibited concomitant medications
The final determination on major protocol deviations, and thereby the composition of the PP 
population, will be made prior to the unblinding of the database and will be documented in a 
separate memo.
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Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data.  
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study treatment. Participants will be included 
in the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population.  For most participants this will be the 
treatment group to which they are randomized. Participants who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of the respective safety parameters.  
To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
Unless otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods for supportive analyses and those related to exploratory objectives will 
be described in the sSAP.
Primary endpoint
The treatment difference in the proportion of participants with delirium during the 
assessment period as assessed by DSM-5, along with the corresponding 95% CI and the p-
value based on the Miettinen and Nurminen method, will be provided. The analysis will be 
stratified by hospitalization reason (acute disease, elective surgery) and age category (<75 
years, ≥75 years). The Cochran-Mantel-Haenszel weight will be used to obtain stratum-
adjusted proportion difference.
Missing assessments will be considered not having delirium. A supportive analysis using 
survival analytic methods will be conducted to assess the robustness of the conclusion from 
the primary analysis to the assumption about the missing assessment of delirium. Details will 
be described in the sSAP.
Secondary endpoints
The proportion of participants with delirium during the assessment period as assessed by 
DRS-R-98 will be analyzed in the same manner as the primary endpoint. The severity of 
delirium during the assessment period as assessed by DRS-R-98 will be compared between 
treatments using an aligned rank test [Mehrotra DV, et al. 2010], taking into consideration 
the potential non-normality of the data. Within each stratum, the data from individual 
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participants will be pooled across treatments and transformed by subtracting the Hodges-
Lehmann estimate. The transformed values from all strata will then be analyzed for treatment 
comparison using the unstratified Wilcoxon rank-sum test.
Missing responses for the individual items of DRS-R-98 will be scored as the midpoint of the 
smallest and the largest possible scores (e.g., as 1.5 for those items rated as 0, 1, 2 or 3), 
which is consistent with the approach employed in the validation of DRS-R-98 
[Trzepacz PT, et al. 2001]. If the assessment is entirely missing on a particular day, the score 
will be considered missing on that day.
Table 5 summarizes key efficacy analyses.
Table 5
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Hypothesis
Proportion of participants with 
delirium during the assessment 
period as assessed by DSM-5
Stratified Miettinen 
and Nurminen†
FAS
Missing data due to missed 
assessments will be considered 
not having delirium
Secondary Objective #1
Severity of delirium during the 
assessment period as assessed by
DRS-R-98
Aligned rank test
FAS
Missing responses for the 
individual items of DRS-R-98 
will be scored as the midpoint 
of the smallest and the largest 
possible scores. If the 
assessment is entirely missing 
on a particular day, the score 
will be considered missing on 
that day.
Secondary Objective #2
Proportion of participants with 
delirium during the assessment 
period as assessed by DRS-R-98, 
defined as the proportion of 
participants with the maximum 
total score of 14.5 or greater 
during the assessment period
Stratified Miettinen 
and Nurminen†
FAS
Missing responses for the 
individual items of DRS-R-98 
will be scored as the midpoint 
of the smallest and the largest 
possible scores. If the 
assessment is entirely missing 
on a particular day, the score 
will be considered missing on 
that day.
† Miettinen and Nurminen method stratified by hospitalization reason (acute disease, elective surgery) and 
age category (<75 years, ≥75 years). The Cochran-Mantel-Haenszel weight will be used to obtain stratum-
adjusted proportion difference.
9.6.2
Statistical Methods for Safety Analyses
The analysis of safety results will follow a tiered approach (Table 6).  The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change (PDLCs) in laboratory and vital 
sign parameters are either pre-specified as “Tier 1” endpoints, or will be classified as 
belonging to "Tier 2" or "Tier 3" based on the number of participants with events.
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Tier 1 events
Safety parameters or AEs of special interest that are identified a priori (see Section 9.4.2) 
constitute “Tier 1” safety endpoints that will be subject to inferential testing for statistical 
significance with p-values and 95% CIs to be provided for between-treatment differences in 
the proportion of participants with events; these analyses will be performed using the 
unstratified Miettinen and Nurminen method.
Tier 2 events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the unstratified Miettinen and 
Nurminen method).
Membership in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event.  The threshold of at least 4 events was chosen because the 95% CI for the between-
group difference in percent incidence will always include zero when treatment groups of 
equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals for Tier 2 events 
may be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events and safety parameters that 
meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a drug 
related AE, a serious AE, an AE which is both drug-related and serious, and discontinuation 
of study medication due to an AE will be considered Tier 2 endpoints. 
Tier 3 events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events.  Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous safety measures
For continuous measures such as changes from baseline in laboratory and vital sign
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.  
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Table 6
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Difference
Descriptive 
Statistics
Tier 1
Complex sleep-related behaviors
X
X
X
Sleep paralysis (including sleep onset paralysis 
[adjudicated])
Hypnagogic or hypnopompic hallucinations
Somnolence resulting in discontinued intervention
Falls (adjudicated to rule out cataplexy)
Suicidal ideation and/or behaviors
Selected events associated with potential for abuse
Cataplexy (adjudicated)
Tier 2
Any AE†
X
X
Any drug-related AE
Any serious AE
Any drug-related serious AE
Discontinuation of study medication due to AE
Specific AEs, SOCs, or PDLCs (incidence ≥4 
participants in at least one of the treatment groups)
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 
participants in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital Signs)
† Indicates broad AE category of the number of participants reporting any adverse event
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs.  No statistical hypothesis 
tests will be performed on these characteristics.  The number and percentage of participants 
screened and randomized, and the primary reasons for screening failure and discontinuation 
will be displayed.  Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
There are no planned interim analyses for this study.
9.8
Multiplicity
No multiplicity adjustment is planned as the study has a single primary hypothesis that will 
be addressed with a single comparison of two treatments using one endpoint.
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
A total of 200 participants will be randomized to suvorexant or placebo in a 1:1 ratio. The 
study will have a power of 90% with a two-sided significance level of 0.05 to detect a 
difference between treatments if the true proportion of participants with delirium in the 
suvorexant group is 11.6 % compared to 30% in the placebo group. The power will be 80% if 
the true proportion in the suvorexant group is 13.7%. If there are occurrences of delirium 
after randomization but prior to the first dose of study medication, then the number of 
randomized participants will be increased to account for such participants. 
Previous researches show that delirium was observed at least in 10% – 20% of elderly 
hospitalized patients hospitalized for surgery or internal diseases (See Section 2). Since this 
study will enroll participants with higher risk of delirium than the general elderly 
hospitalized patients, it is anticipated that the incidence of delirium will be greater and the 
true proportion of participants with delirium is assumed to be 30% in the placebo group. 
Furthermore, the studies which prospectively assessed the treatment effect of suvorexant for 
delirium prevention [Azuma K, et al. 2018] [Hatta K, et al. 2017] resulted in treatment 
differences of ~17% - 18% versus the control group, and it is assumed that this study will 
have a similar treatment effect. 
The table below provides true proportions of participants with delirium in the suvorexant
group required to provide 90 (80) % power, under varying assumptions for the true 
proportion of participants with delirium in the placebo group.
Table 7
True Proportion of Participants With Delirium in the Suvorexant and Placebo 
Groups Required to Provide 90 (80) % Power (N =100 / arm)
% delirium in Placebo
% delirium in MK-4305
required to provide 90 (80) % Power
25%
8.1% (10.0%)
30%
11.6% (13.7%)
35%
15.3% (17.6%)
40%
19.2% (21.8%)
45%
23.4% (26.1%)
50%
27.8% (30.6%)
Farrington and Manning method, α=0.05 (two-sided)
9.9.2
Sample Size and Power for Safety Analyses
Table 8 summarizes the percentage point differences between the 2 treatment groups that 
could be detected with ~80% probability for a variety of hypothetical underlying incidences 
of an adverse event. These calculations assume 100 participants in each group and are based 
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on a 2-sided 5% alpha level. The calculations are based on an asymptotic method proposed 
by Farrington and Manning [Farrington CP, et al. 1990], with no multiplicity adjustments.
Table 8
Differences in Incidence of Adverse Events Between the 2 Treatment Groups 
That Can be Detected With an ~80% Probability (N =100 / arm)
Incidence of Adverse Event
Risk Difference
Suvorexant (%)
Placebo (%)
(N =100)
(N =100)
Percentage Point
7.7
0.1
7.6
12.1
2.0
10.1
17.4
5.0
12.4
24.9
10.0
14.9
37.8
20.0
17.8
49.3
30.0
19.3
Based on an asymptotic method proposed by Farrington and Manning, α=0.05 (two-sided)
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated for the following subgroups using the unstratified Miettinen and 
Nurminen method.

Hospitalization reason (acute disease, elective surgery)

Age category (<75 years, ≥75 years)
Additional subgroup analyses will be described in the sSAP.
9.11
Compliance (Medication Adherence)
Participants are to take 1 tablet of study medication per day. A day within the study will be 
considered an “On-Therapy” day if the participant takes 1 tablet of study medication. The
“Number of Days Should be on Therapy” is the total number of days from randomization to 
the last scheduled day for treatment administration for that participant [which is the day 
before the last assessment visit (Visit 4)].
For each participant, percent compliance will then be calculated using the following formula:
x 100.
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Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
9.12
Extent of Exposure
The distribution of the number of participants with respect to the number of days on study 
medication will be tabulated by treatment for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Clinical Adjudication Committee (CAC)
A CAC will evaluate the following events for the purposes of confirming them according to 
the criteria in Section 9, as well as evaluating the presence of confounding factors.
ECIs pre-specified for adjudication are those that suggest potential intrusion of REM into 
either:
1.
Wakefulness (cataplexy or cataplexy-like event) or,
2.
Initiation of sleep (sleep onset paralysis) or,
Falls will also be adjudicated to enhance data collection for these events, and to further 
evaluate whether an event might be due to cataplexy.
All personnel involved in the adjudication process will remain blinded to study intervention
allocation throughout the study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 9 will be performed by the central laboratory.
•
Local laboratory results are required for the assessment of eligibility. Even if a local 
sample will be collected at the scheduled visit that the collection of the central laboratory 
samples is required, it is important that the sample for central analysis has to be obtained
in addition to a local sample.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
CK
LDH
Magnesium
Uric acid
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen
Other Screening 
Tests
All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of the assessment of eligibility, e.g., APACHE II and exclusionary 
laboratory criteria (refer to Table 1).
The investigator must document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment,
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This section is not applicable to this study.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
This section is not applicable to this study.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
This section is not applicable to this study.
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10.7
Appendix 7: Country-specific Requirements
This section is not applicable to this study.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALT
alanine aminotransferase
APACHE II
Acute Physiology and Chronic Health Evaluation II
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
CAC
clinical adjudication committee
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DILI
drug-induced liver injury
DRS-R-98
Delirium Rating Scale-Revised-98
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice 
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
IRB
Institutional Review Board
IRT
interactive response technology
LDH
lactate dehydrogenase
MCQ
Modified Cataplexy Questionnaire
NIMP
Non-Investigational Medicinal Product
NM Scale
Nishimura Mental State Scale for the Elderly
PK
pharmacokinetic
PP
per-protocol
RCSQ
Richards Campbell Sleep Questionnaire
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
VAS
Visual Analog Scale
WBC
white blood cell
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11
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