A Two-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Sleep Latency Effects of MK-6552 in Participants With Narcolepsy Type 1
Phase: PHASE1
Conditions: Narcolepsy
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:           05-Sep-2024
NCT06179407
A Two-Part Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Sleep 
Latency Effects of MK-6552 in Participants with 
Narcolepsy Type 1

PRODUCT: MK-6552
1
PROTOCOL/AMENDMENT NO.: 004-05
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05-SEP-2024
TITLE PAGE
THIS PROTOCOL 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 Two-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Sleep Latency Effects of MK-6552 in Participants with Narcolepsy Type 1
Protocol Number: 004-05
Compound Number: MK-6552
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not applicable
EU CT
Not applicable
EudraCT
Not applicable
jRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
164999
Approval Date: 05 September 2024
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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 5
05-Sep-2024
Amendment 4
21-Aug-2024
This amendment is to include an additional 
Panel (Panel B) to assess safety, tolerability, 
 
Amendment 3
17-Apr-2024
This amendment is to provide additional 
clarification for inclusion criterion #8 around 
POCBP.
Amendment 2
02-Apr-2024
This amendment is to clarify the inclusion 
criterion (#8) around conditions and 
contraceptive requirements for participants 
assigned female sex at birth.
Amendment 1
04-Mar-2024
This amendment is to update/add a inclusion 
criterion and exclusion criteria to increase 
participant’s safety during study conduct.
Original Protocol
06-NOV-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendment:
This amendment is to add a safety laboratory assessment timepoint in each period of Part 2 
for participants in Panel B to monitor liver enzymes function after multiple days of dosing.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.3.3 
Schedule of 
Activities Part 2 
Panel B
Addition of a safety laboratory assessment time-
point for Panel B in each period of Part 2.
 
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Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1 Synopsis
Addition of Panel B (approximately 12 
participants) at MK-6552 dose levels of 1 
mg to 4 mg.
 
Section 1.1 Synopsis
Changes to the primary safety objective.
To add the safety assessment of multiple 
day dosing when MK-6552
 
Section 1.1 Synopsis
Changes to the primary PD objective.
 
 
Section 1.1 Synopsis
Updated the estimated duration of study 
from 11 to 17 months
To account for the additional 12 
participants in Panel B.
Section 1.1 Synopsis
Updated the approximate number of 
participants in the study from 12 to 24.
To account for the additional Panel B.
Section 1.1 Synopsis
Updated the Intervention Groups and 
Duration table.
To add the new dosage levels and 
corresponding treatment periods of Panel 
B.
Section 1.1 Synopsis
Updated the Total Number of Intervention 
Groups/Arms from 4 to 7.
To add the new dosage levels of Panel B.
Section 1.1 Synopsis
Updated overall Duration of Participation 
from 11 to 14 weeks.
To account for the updated screening 
period of 5 weeks and number of 
intervention weeks from 5 to 7 due to 
natural scheduling of treatment period 
every ~7 days by the sites.
Section 1.2 Schema
Addition of Panel B with corresponding 4 
sequential treatment periods of 1 mg to 
4 mg.
To account for the additional Panel B at the 
higher dose levels. 
Section 1.2 Schema
Study Diagram figure was updated to 
reflect the dose levels in Panels A and B 
To account for the additional Panel B at the 
higher dose levels.
Section 1.3.1 Schedule of 
Activities Part 1
Removed the specific number of days for 
the EDS SOC Washout Period 
To provide more flexibility in the washout 
duration requirements due to different prior 
medications taken by the participants. 
Section 1.3.1 Schedule of 
Activities Part 1
Added the screening period window of +/-
7 days. 
To clarify previous language stating 
“approximately 28 days”. 
Section 1.3.1 Schedule of 
Activities Part 1
Added “All Panels” to the first row of the 
SoA Part 1 table
To clarify that the Part 1 SoA is applicable 
to Panel A and Panel B.
Section 1.3.1 Schedule of 
Activities Part 1
Added fasting requirements on the 
“Standard Meals” row of the table.
To clarify the requirement for fasting in the 
SoA Part 1 Table.
Section 1.3.1 Schedule of 
Activities Part 1
Removed note that allowed the predose 
safety lab assessment to be collected the 
evening before planned dosing. 
To address a discrepancy with the fasting 
requirement. Since fasting is required 
before safety lab blood collection, 
operationally, the procedure cannot be 
completed the evening before dosing. 
Section 1.3.2 Schedule of 
Activities Part 2 Panel A
Added “Panel A” to the first row of the 
SoA Part 2 Panel A table
To clarify that this SoA table is applicable 
only to Panel A.
Section 1.3.2 Schedule of 
Activities Part 2 Panel A
Removed 16h time-point from the SoA Part 
2 Panel A table.
To address a typo. There are no procedures 
performed at the 16h time-point in the 
study. 
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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3.2 Schedule of 
Activities Part 2 Panel A
Added fasting requirements on the 
“Standard Meals” row of the table.
To clarify the requirement for fasting in 
Part 2 Panel A.
Section 1.3.2 Schedule of 
Activities Part 2 Panel A
Removed note that allowed the predose 
safety lab assessment to be collected the 
evening before planned dosing. 
To address a discrepancy with the fasting 
requirement. Since fasting is required 
before safety lab blood collection, 
operationally, the procedure cannot be 
completed the evening before dosing. 
Section 1.3.2 Schedule of 
Activities Part 2 Panel A
Removed the “predose” mention in the note 
column for the standard meals row.
To clarify that fasting is needed before all 
safety time-points including predose and 24 
hours postdose unless mentioned 
otherwise. 
Section 1.3.3 Schedule of 
Activities Part 2 Panel B
Added SoA Part 2 Panel B table
To account for the added Panel B in the 
study where some of the procedures have 
been modified.
Section 1.3.3 Schedule of 
Activities Part 2 Panel B
Added detail in Notes field for “Standard 
Meals” row around fasting requirement on 
Day 4 of each period.
To clarify that although there is a safety lab 
blood collection on Day 4 of each period, 
participants do not need to fast on that day. 
Section 1.3.3 Schedule of 
Activities Part 2 Panel B
Added Day 4 safety lab assessment blood 
collection.
 
Section 2.1 Study Rational
Rationale to assess higher dose range of 
MK-6552 was added
To account for the additional Panel B at the 
higher dose levels.
Section 2.2.2 Preclinical 
and Clinical Studies
Updated PN001 and PN005 completed 
study summaries.
To further clarify the design of PN001and 
provide the updated study status of PN005.
Section 2.2.2 Preclinical 
and Clinical Studies
Added PK data from PN005.
To add the final PK data from PN005 that 
is now completed.
Section 2.2.3 Ongoing 
Clinical studies
Added clinical summary from ongoing 
PN002, 003 and 007.
To provide an update on the ongoing 
clinical conduct and available preliminary 
safety data.
Section 2.2.3 Ongoing 
Clinical studies
 
 
 
Section 3 Hypotheses, 
Objectives and Endpoints
Changes to the primary safety objective.
To add the safety assessment of multiple 
day dosing when MK-6552 is administered 
bid 6 hours apart.
Section 3 Hypotheses, 
Objectives and Endpoints
Changes to the primary PD objective.
To add the PD assessment of multiple day 
dosing when MK-6552 is administered 
 
Section 3 Hypotheses, 
Objectives and Endpoints
Changes to the exploratory PD objective
To add the PD assessment of a single day 
dosing when MK-6552 is administered 
 
Section 4.1 Overall Design
Updated the study design with the 
additional Panel B participants and 
corresponding doses. 
To account for the assessment of higher 
doses of MK-6552 on safety, PK and PD in 
an additional 12 participants.
Section 4.1 Overall Design
 
 
Section 4.1 Overall Design
Added the additional visit to the site on 
Day 4 site for Panel B participants for 
safety lab assessment blood collection.
 
 
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Section Number and 
Name
Description of Change
Brief Rationale
Section 4.2 Scientific 
Rational for Study Design
Added the rationale for study design of 
Panel B.
To account for the additional Panel B at the 
higher dose levels.
Section 4.2 Scientific 
Rational for Study Design
Updated clinical half-life of MK-6552
To provide an updated half-life based on 
the totality of the data acquired in HV.
Section 4.2.1.1 Safety 
Endpoints
Doses and dosing duration were updated 
from ongoing clinical studies and current 
study.
To provide the updated doses and dosing 
durations that are investigated in HV or 
will be investigated in NT1 participants
Section 4.2.1.1 Safety 
Endpoints
To monitor participant safety labs as 
participants receive multiple higher doses 
of MK-6552.  
Section 4.3 Justification for 
Dose
Justification to assess higher dose range in 
Panel B was added.
To account for the additional Panel B at the 
higher dose levels.
Section 4.3 Justification for 
Dose
 
 
Section 4.3 Justification for 
Dose
Table 2 was added to summarize 
 
To provide supporting data justifying the 
assessment of higher dose range in 
Panel B.
Section 4.3.1 Starting Dose 
for This Study
 
 
 
Section 4.3.2 Maximum 
Dose Exposure for This 
Study
Projected 
 
To account for the additional Panel B at the 
higher dose levels.
Section 4.3.2 Maximum 
Dose Exposure for This 
Study
Added summary of PK and safety from 
ongoing PN002.
Section 4.3.2 Maximum 
Dose Exposure for This 
Study
To provide an update on latest safety data 
obtained in PN002 study.
Section 4.3.3 Rationale for 
Dose Interval and Study 
Design
Updated with the Panel B dose levels and 
study design.
To account for the additional Panel B at the 
higher dose levels.
Section 5.2 Exclusion 
Criteria
Removed CrCl wording from EC#5.
To correct a typo. Only eGFR criteria is to 
be used to assess kidney function. 
Section 5.3.1.1 Diet 
Restrictions
Added fasting requirements before safety 
lab assessment blood collection.
To clarify on which days participants must 
fast due to safety lab assessments.
Section 5.3.3 Activity 
Restrictions
Added the activity restriction requirements 
for participants that don’t need to washout 
from EDS SOC.  
To clarify that participants that don’t 
required a washout from EDS SOC must 
also avoid activities requiring high degree 
of attention such as driving a car.
Section 6.1 Study 
Intervention(s) 
Administered
Updated the Study Intervention Table with 
Panel B dosage levels and corresponding 
Treatment Periods.
To account for the addition of Panel B to 
the study.
Section 6.3.1 Intervention 
Assignment
Updated Allocation of Participants to 
Treatment Table with Panel B information.
To account for the addition of Panel B 4 
sequential Treatment Periods in Part 1 and 
2-period cross-over in Part 2. 
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Section Number and 
Name
Description of Change
Brief Rationale
Section 7.1.1 Individual 
Stopping Criteria
 
 
 
 
 
Section 8.1.5.1 Prior 
Medications
Added study restrictions period for 
participants that don’t required a EDS SOC 
washout.
To clarify the study restriction period for 
participants that don’t require a Washout 
Period before randomization.
Section 8.1.8.1Timing of 
Dose Administration
Added information around timing of dose 
administration for participants in Panel B.
To account 
 
 
Section 8.3.10.1 Safety 
Phone Calls During the 
Screening Period
Modified the language around a specific 
number of days for the safety phone calls.
To add flexibility for participants on 
concomitant medications that require a 
different number of safety phone calls 
based on washout requirement that may 
differ from EDS SOC listed.
Section 8.3.10.2 
Compliance and Safety 
Phone Calls in Part 2 Days 
2 to 6
Added frequency of dosing for participants 
in Panel B.
To account for the participants in Panel B 
that must take their study medication at 
home 6 hours apart.
Section 8.4.4 Regulatory 
Reporting Requirements for 
SAE
Added a note to specify that the Sponsor 
will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR 
form in compliance with CTR 536/2014.
For completeness, for applicable studies, 
the process to report SUSARs to the 
Eudravigilance database has been added.
Section 8.11.1 Screening
Added the screening period window of  1 
week (+/- 7 days). 
To clarify previous language stating, 
“approximately 4 weeks”. 
Section 8.11.5 Critical 
Procedures Based on Study 
Objectives: Timing of 
Procedure
Remove safety lab tests from the 
procedures list that can be completed 
within 24 hours of dosing.
To address a discrepancy with the fasting 
requirement. Since fasting is required 
before safety lab blood collection, 
operationally, the procedure can’t be 
completed the evening before planning 
dosing.
Section 8.11.5 Critical 
Procedures Based on Study 
Objectives: Timing of 
Procedure
Added safety lab tests procedure window.
To provide flexibility around the Part 2 
Day 4 visit needed for the participant in 
Panel B.
Section 9.5.2
Added the new panel to the 
pharmacodynamic models.
To be more explicit that separate models 
are run for each panel and each of the two 
timepoints.
Section 9.5.3
Minor adjustment for dose proportionality 
subjection for language about new panel.
To be more explicit that analysis may be 
done for each panel separately since 
completely different subjects at two 
different dose ranges between the two 
panels
Section 10.1.1 Code of 
Conduct for Interventional 
Clinical Trials
Added Regulation (EU) 536/2014 to the list 
of regulations that MSD clinical trials is in 
compliance with.
To clarify that the Sponsor is in compliance 
with EU CTR 536/2014.
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
Added a footnote to Table 8 around Part 2 
Day 4 fasting requirement for Panel B.
To clarify that although there is a safety lab 
blood collection on Day 4 of each period, 
participants don’t need to be fasted on that 
day.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 10.8 Appendix 8
Added abbreviations as applicable for 
updated text.
To capture newly added abbreviations for 
revised text.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................23
1.3.1
Part 1............................................................................................................23
1.3.2
Part 2 Panel A ..............................................................................................33
1.3.3
Part 2 Panel B...............................................................................................41
2
INTRODUCTION..........................................................................................................49
2.1
Study Rationale....................................................................................................49
2.2
Background ..........................................................................................................50
2.2.1
Pharmaceutical and Therapeutic Background .............................................50
2.2.2
Preclinical and Clinical Studies ...................................................................50
2.2.3
Ongoing Clinical Studies.............................................................................52
2.3
Benefit/Risk Assessment......................................................................................54
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................55
4
STUDY DESIGN............................................................................................................57
4.1
Overall Design......................................................................................................57
4.2
Scientific Rationale for Study Design.................................................................58
4.2.1
Rationale for Endpoints ...............................................................................59
4.2.1.1
Safety Endpoints................................................................................59
4.2.1.2
Pharmacokinetic Endpoints ...............................................................59
4.2.1.3
Pharmacodynamic Endpoints.............................................................59
4.2.1.4
Planned Exploratory Biomarker Research.........................................60
4.2.1.4.1
Planned Genetic Analysis ........................................................60
4.2.1.5
Future Biomedical Research..............................................................61
4.2.2
Rationale for the Use of Placebo .................................................................61
4.2.3
Rational for Suicidal Ideation and Behavior Monitoring ............................61
4.3
Justification for Dose...........................................................................................61
4.3.1
Starting Dose for This Study........................................................................64
4.3.2
Maximum Dose Exposure for This Study ...................................................65
4.3.3
Rationale for Dose Interval and Study Design ............................................69
4.4
Beginning and End-of-Study Definition ............................................................70
4.4.1
Clinical Criteria for Early Study Termination .............................................71
5
STUDY POPULATION ................................................................................................72
5.1
Inclusion Criteria.................................................................................................72
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5.2
Exclusion Criteria................................................................................................75
5.3
Lifestyle Considerations......................................................................................78
5.3.1
Meals and Dietary Restrictions....................................................................78
5.3.1.1
Diet Restrictions.................................................................................78
5.3.1.2
Fruit Juice Restrictions ......................................................................78
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................79
5.3.2.1
Caffeine Restrictions..........................................................................79
5.3.2.2
Alcohol Restrictions...........................................................................79
5.3.2.3
Tobacco Restrictions..........................................................................79
5.3.3
Activity Restrictions ....................................................................................80
5.3.4
Bedtime........................................................................................................80
5.3.5
Other ............................................................................................................80
5.4
Screen Failures.....................................................................................................81
5.5
Participant Replacement Strategy......................................................................81
6
STUDY INTERVENTION............................................................................................82
6.1
Study Intervention(s) Administered...................................................................82
6.2
Preparation/Handling/Storage/Accountability .................................................85
6.2.1
Dose Preparation..........................................................................................85
6.2.2
Handling, Storage, and Accountability........................................................85
6.3
Measures to Minimize Bias: Randomization and Blinding..............................86
6.3.1
Intervention Assignment..............................................................................86
6.3.2
Stratification.................................................................................................86
6.3.3
Blinding........................................................................................................86
6.4
Study Intervention Compliance..........................................................................86
6.5
Concomitant Therapy..........................................................................................87
6.5.1
Rescue Medications and Supportive Care ...................................................88
6.6
Dose Modification (Escalation)...........................................................................88
6.6.1
Stopping Rules.............................................................................................89
6.7
Intervention After the End of the Study............................................................89
6.8
Clinical Supplies Disclosure................................................................................89
6.9
Standard Policies..................................................................................................90
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................91
7.1
Discontinuation of Study Intervention...............................................................91
7.1.1
Individual Stopping Criteria ........................................................................92
7.2
Participant Withdrawal From the Study...........................................................93
7.3
Lost to Follow-up .................................................................................................94
8
STUDY ASSESSMENTS AND PROCEDURES........................................................95
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8.1
Administrative and General Procedures ...........................................................95
8.1.1
Informed Consent.........................................................................................95
8.1.1.1
General Informed Consent.................................................................96
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................96
8.1.2
Inclusion/Exclusion Criteria ........................................................................96
8.1.3
Participant Identification Card.....................................................................96
8.1.4
Medical History ...........................................................................................97
8.1.5
Prior and Concomitant Medications Review...............................................97
8.1.5.1
Prior Medications...............................................................................97
8.1.5.2
Concomitant Medications..................................................................98
8.1.6
Assignment of Screening Number...............................................................98
8.1.7
Assignment of Randomization Number.......................................................98
8.1.8
Study Intervention Administration ..............................................................98
8.1.8.1
Timing of Dose Administration.........................................................99
8.1.9
Discontinuation and Withdrawal .................................................................99
8.1.9.1
Withdrawal From Future Biomedical Research ..............................100
8.1.10
Participant Blinding/Unblinding................................................................100
8.1.11
Domiciling .................................................................................................101
8.1.12
Calibration of Equipment...........................................................................101
8.2
Efficacy/Immunogenicity Assessments ............................................................101
8.3
Safety Assessments.............................................................................................101
8.3.1
Physical Examinations...............................................................................102
8.3.2
Neurological Examinations........................................................................102
8.3.3
BMI............................................................................................................102
8.3.4
Vital Signs..................................................................................................102
8.3.4.1
Resting Vital Signs ..........................................................................102
8.3.4.2
Orthostatic Vital Signs.....................................................................103
8.3.5
Electrocardiograms ....................................................................................103
8.3.6
Clinical Safety Laboratory Assessments ...................................................105
8.3.7
Pregnancy Testing......................................................................................106
8.3.8
Suicidal Ideation and Behavior Monitoring...............................................106
8.3.8.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .......................................................................................106
8.3.9
Photograph of Rash....................................................................................107
8.3.10
Safety/Compliance Phone Calls.................................................................107
8.3.10.1
Safety Phone Calls During the Screening Period ............................107
8.3.10.2
Compliance and Safety Phone Calls
.......107
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................107
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................108
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....110
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.110
8.4.4
Regulatory Reporting Requirements for SAE ...........................................110
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................111
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................111
8.4.7
Events of Clinical Interest..........................................................................111
8.5
Treatment of Overdose......................................................................................112
8.6
Pharmacokinetics...............................................................................................112
8.6.1
Blood Collection for Plasma MK-6552 .....................................................112
8.7
Pharmacodynamics............................................................................................113
8.8
Biomarkers .........................................................................................................114
8.8.1
Planned Genetic Analysis Sample Collection............................................114
8.9
Future Biomedical Research Sample Collection.............................................114
8.10
Medical Resource Utilization and Health Economics.....................................114
8.11
Visit Requirements.............................................................................................115
8.11.1
Screening....................................................................................................115
8.11.2
Treatment Period Visit...............................................................................115
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................115
8.11.4
Poststudy....................................................................................................115
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.....115
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters ...................................................................................117
9
KEY STATISTICAL CONSIDERATIONS .............................................................119
9.1
Responsibility for Analyses...............................................................................119
9.2
Hypotheses/Estimation ......................................................................................119
9.3
Analysis Endpoints.............................................................................................119
9.3.1
Primary Endpoints .....................................................................................119
9.3.2
Secondary Endpoints .................................................................................119
9.3.3
Exploratory Endpoints ...............................................................................119
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9.4
Analysis Populations..........................................................................................120
9.4.1
All Participants As Treated Population......................................................120
9.4.2
Per-Protocol (PP) Population.....................................................................120
9.5
Statistical Methods.............................................................................................120
9.5.1
Statistical Methods for Safety Analyses ....................................................120
9.5.2
Statistical Methods for Pharmacodynamic Analyses.................................121
9.5.3
Statistical Methods for Pharmacokinetic Analyses....................................121
9.6
Interim Analyses ................................................................................................122
9.7
Multiplicity .........................................................................................................123
9.8
Sample Size and Power Calculations ...............................................................123
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................124
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......124
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................124
10.1.2
Financial Disclosure...................................................................................127
10.1.3
Data Protection...........................................................................................128
10.1.3.1
Confidentiality of Data ....................................................................128
10.1.3.2
Confidentiality of Participant Records.............................................128
10.1.3.3
Confidentiality of IRB/IEC Information..........................................129
10.1.4
Committees Structure.................................................................................129
10.1.5
Publication Policy......................................................................................129
10.1.6
Compliance with Study Registration and Results Posting Requirements .129
10.1.7
Compliance with Law, Audit, and Debarment ..........................................130
10.1.8
Data Quality Assurance .............................................................................130
10.1.9
Source Documents .....................................................................................131
10.1.10
Study and Site Closure...............................................................................132
10.2
Appendix 2: Clinical Laboratory Tests............................................................133
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................135
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................135
10.3.2
Definition of AE ........................................................................................135
10.3.3
Definition of SAE ......................................................................................136
10.3.4
Additional Events Reported.......................................................................137
10.3.5
Recording AE and SAE .............................................................................137
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................140
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................142
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10.5
Appendix 5: Contraceptive Guidance..............................................................143
10.5.1
Definitions..................................................................................................143
10.5.2
Contraceptive Requirements......................................................................145
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................146
10.7
Appendix 7: Country-specific Requirements..................................................150
10.8
Appendix 8: 12-Lead Electrocardiogram Evaluation Criteria......................151
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....153
10.10 Appendix 10: General and Targeted Neurological Examinations ................154
10.10.1
The General Neurological Examination ....................................................154
10.10.1.1
Module 1 – Mental Status Examination...........................................154
10.10.1.2
Module 2 – Cranial Nerve Assessment............................................154
10.10.1.3
Module 3 – Motor System ...............................................................155
10.10.1.4
Module 4 – Reflexes ........................................................................156
10.10.1.5
Module 5 – Coordination and Gait ..................................................156
10.10.1.6
Module 6 – Sensory .........................................................................157
10.10.2
The Targeted Neurological Examination...................................................157
10.10.2.1
Module 1 – Mental Status Examination...........................................157
10.10.2.2
Module 2 – Cranial Nerve Assessment............................................157
10.10.2.3
Module 3 – Motor System ...............................................................158
10.10.2.4
Module 5 – Coordination and Gait ..................................................158
10.10.2.5
Module 6 – Sensory .........................................................................158
10.11 Appendix 11: List of Caffeine Products and Caffeine Content .....................158
10.12 Appendix 12: Abbreviations .............................................................................160
11
REFERENCES.............................................................................................................166
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LIST OF TABLES
Table 1
Study Schema...............................................................................................21
Table 2
Preliminary PK for 4 NT1 participants from Part 1.....................................63
.......................................................................64
Table 4
Study Interventions......................................................................................83
Table 5
Allocation of Participants to Treatment.......................................................86
Table 6
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ..........................................................................109
Table 7
Pharmacokinetic Blood Collection Windows............................................116
Table 8
Protocol-required Safety Laboratory Assessments...................................133
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LIST OF FIGURES
Figure 1
Study Diagram .............................................................................................22
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Two-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Sleep Latency Effects of MK-6552 in Participants with Narcolepsy Type 1
Short Title: A Safety, Pharmacokinetic and Pharmacodynamic Study of MK-6552 in 
Participants with Narcolepsy Type 1
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Participants with NT1 18 to 55 years of age inclusive.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of a 
single-day 
 and multiple-
day 
 administration 
of MK-6552 in participants with Narcolepsy 
Type 1.
Adverse events, discontinuation of study 
intervention due to adverse events
To assess the pharmacodynamic profile of 
MK-6552 bid 
 after 
multiple-day administration in participants 
with Narcolepsy Type 1.
 
 
 
 
Maintenance of wakefulness test trial 
conducted one hour after each dose on 
Secondary Objectives
Secondary Endpoints
 
 
 
 
 
 
 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Narcolepsy
Population
Participants with narcolepsy type 1
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study.
Type of Control
Placebo 
Study Blinding
Unblinded open-label study Part 1
Double-blind study Part 2 
Blinding Roles
No blinding for study Part 1
Participants or Subjects for study Part 2 
Investigator for study Part 2
Sponsor for study Part 2
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 17 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 24 participants will be randomized in the study in order to provide evaluable 
data on 16 participants (minimum of n=8 per panel). 
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Active
MK-6552
 
Oral
Part 1 Panels 
A and B:
Period 1
Period 2
Period 3
Period 4
Part 2
Panels A and 
B:
Days 1 to 7 in 
Periods 1 and 
2
Test Product
Placebo
Placebo
0 mg
Part 2 Panel 
A:
0 mg bid q8h
Panel B:
0 mg bid q6h 
Oral
Part 2 Panels 
A and B: 
Days 1 to 7 in 
Periods 1 and 
2
Placebo
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Total Number of Intervention Groups/Arms
7
Duration of Participation
Each participant will participate in the study 
for approximately 14 weeks, from the time 
the participant provides documented 
informed consent through the final contact. 
After a screening phase of up to 5 weeks, 
each participant will receive assigned 
intervention for approximately 7 weeks. 
After the end of treatment each participant 
will be followed for 2 weeks.
Study Governance Committees:
Executive Oversight Committee
No 
External Data Monitoring Committee
No 
Clinical Adjudication Committee
No 
There are no governance committees in this study. Regulatory, ethical and study oversight 
considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No 
A list of abbreviations is in Appendix 12.
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1.2
Schema
The study design is depicted in Table 1 and Figure 1.
Table 1
Study Schema
Part 1- Panel Aa,b,c 
Period 1d
Period 2d
Period 3d
Period 4d
mg
Part 1- Panel Ba,b,c
Period 1d
Period 2d
Period 3d
Period 4d
mg
Part 2- Panel Ae,f,g
Period 1i
Period 2
MK-6552/PBO
MK-6552/PBO
Part 2- Panel Bf,g,h
Period 1i
Period 2
MK-6552/PBO
MK-6552/PBO
a
The suggested doses (with the exception of the starting dose) may be adjusted downward based on evaluation of 
safety, tolerability, and pharmacokinetic data observed in previous intervention periods. Refer to Section 6.6 (Dose 
Modification) and Section 7.1.1 (Individual Stopping Criteria) for the safety data that will be reviewed prior to dose 
escalation.
b
Part 1 of the study will be open label in which all participants will receive MK-6552.
c.
In Part 1, MK-6552 will be administered 
 in each treatment period.
d.
At least 4 days will separate study drug administration in between periods of Part 1. 
e.
In Part 2 Panel A, MK-6552/PBO will be administered 
 in each treatment period. 
f.
The suggested dose may be adjusted downward based on evaluation of safety, tolerability, and available 
pharmacokinetic data from Part 1.
g.
At least 4 days will separate study drug administration in between Part 1 and Part 2 of the study.
h.
In Part 2 Panel B, MK-6552/PBO will be administered 
i.
At least 2 days will separate study drug administration between periods of Part 2. 
PBO=placebo, bid=twice a day.
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Figure 1
Study Diagram
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1.3
Schedule of Activities
1.3.1
Part 1
Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Administrative/Study 
Procedures
Informed Consent
X
Sec. 5.1, 8.1.1.1
Informed Consent for 
FBR
X
Sec. 5.1, 8.1.1.2
Participant ID Card
X
X
Sec. 8.1.3
Inclusion/Exclusion 
Criteria
X
X
Sec 5, 1, 5.2, 8.1.2
Review of 
inclusion/exclusion 
criteria will occur at 
Screening and after 
predose procedures (if 
applicable) in Period 1 
only. Based on IC/EC, 
only specific criteria 
will be reviewed at 
predose (Period 1 only) 
prior to randomization.
Medical History
X
X
X
Sec. 8.1.4
Substances: Includes 
substance usage (drugs, 
alcohol, tobacco, and 
caffeine).
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 5.2, 6.5, 8.1.5
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Assignment of 
Screening Number
X
Sec. 8.1.6
Any participant who is 
screened multiple 
times will retain the 
original screening 
number assigned at the 
initial Screening Visit.
Assignment of 
Randomization 
Number
X
Sec. 5.5, 8.1.7
MK-6552 
Administration
X
X
Sec. 8.1.8.1
In each treatment 
period, a second dose 
of study intervention 
~ 6 hours (+/- 30 mins) 
following the first dose 
will be administered to 
participants
Domiciling
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.11
In each treatment 
period, participants 
will report to the CRU 
the day before (Day -1) 
the first scheduled day 
of study intervention 
administration and 
remain in the unit at 
least up to 24-hours 
postdose #2
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Standard Meals
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Safety Procedures
C-SSRS 
Baseline/Screening
X
Sec. 8.3.8.1
Full physical 
examination
X
X
X
Sec. 8.3.1
In each treatment 
period full PE will be 
conducted as follows: 
Dose 1: Predose, and 
24-hour postdose 1
Dose 2: 24-hour 
postdose 2
Predose physical exam 
may be conducted 
upon admission within 
24 hours of dosing.
General neurological 
examination
X
X
Sec. 8.3.2, Appendix 
10 (Sec 10.10.1)
Applicable at 
Screening and at each 
treatment period at 
Predose #1 only
Predose #1 general NE, 
may be conducted 
upon admission within 
24 hours of dosing
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Targeted neurological 
examination 
X
X
X
Sec. 8.3.2, Appendix 
10 (Sec 10.10.2)
In each treatment 
period, targeted NE 
will be conducted as 
follows: 
 
Height
X
Sec. 8.3.1
Weight
X
Sec. 8.3.1, 8.3.3
BMI to be taken only 
at Screening
Resting VS (HR, BP)
X
X
X
X
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Orthostatic VS
(HR, BP)
X
X
X
X
X
X
Sec 8.3.4.2
In each treatment 
period orthostatic VS 
will be measured as 
follow: 
 
 
 
RR and BT
X
X
X
X
X
Sec. 8.3.4.1
In each treatment 
period RR and BT will 
be measured as follow:
 
12-lead ECG
X
X
X
X
X
X
X
X
Sec. 8.3.5, Appendix 8
In each treatment 
period all ECGs are to 
be conducted in 
triplicate. At screening 
and poststudy, ECG 
will be conducted as 
single measurements.
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
 
 
Serum (hCG; POCBP 
only)
X
Sec. 8.3.6, Appendix 2
Urine Pregnancy Test 
(POCBP only)
X
Sec. 5.1, 8.3.7
Urine pregnancy test to 
be completed in each 
treatment period
Serum FSH -
(POCBP only)
X
Appendices 2 and 5
HIV, hepatitis B and 
C screen (per site 
SOP)
X
Sec. 5.2, Appendix 2
Drug screen (per site 
SOP)
X
X
Appendix 2
Screening drug screen 
is mandatory, any 
additional drug screens 
are conducted per site 
SOP. Alcohol test will 
be conducted using a 
breathalyzer.
To be collected in 
Period 1 only
Predose drug screen 
and alcohol test may be 
collected upon 
admission within 
24 hours of dosing.
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Hematology, 
Chemistry, Urinalysis
X
X
Sec, 8.3.6, Appendix 2
In Period 1 only, blood 
for safety laboratory 
tests will be collected 
as follow:
Dose 1: Predose 
Safety Phone Calls
X
Sec. 8.3.10.1, 8.1.5.1
Washout period may 
vary based on the EDS 
SOC
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.4, Appendix 3
Pharmacokinetics
Blood for Plasma 
MK-6552 and or 
Metabolites Assay
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.6.1, 8.11.5
In each treatment 
period, PK blood 
collection will be as 
follow:
 
 
 
 
 
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Pharmacodynamics
PSG
X
Sec. 8.7.1
X
X
X
X
X
Sec. 8.7.3
In each treatment 
period completed at: 
 
 
X
X
Sec. 8.7.4
 
 
 
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Part 1/All Panels/All Periods/Dose 1 and Dose 2a
Study Period:
Screening
Intervention
Notes: 
Scheduled Day
Screening/Rescreeningb
EDS SOC 
Washout Before 
Randomization 
(Remote Visit 
Through Phone 
Call)
D1
D2
Screening procedures 
to be completed 
within approximately 
28 days ± 7 days from 
randomization
Biomarkers
Blood for Planned 
Genetic Analysis 
X
Sec. 8.8.1
Collected from 
enrolled participant in 
Period 1 only.
Blood for HLA 
DQB1*0602 
Genotyping
X
Sec. 8.8
AE=adverse event; BDS=blood drug screen; BMI=body mass index; BP=blood pressure; BT=body temperature; CRU=clinical research unit; C-SSRS=Columbia-
Suicide Severity Rating Scale; D=day; EC=exclusion criteria; ECG=electrocardiogram; EDS=excessive daytime sleepiness; FBR=future biomedical research; 
FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HLA-DQB1=human leukocyte antigen DQ Beta 1; 
HR=heart rate; IC=inclusion criteria; ID=identification; 
; NE=neurological 
examination; PE=physical examination; PGA=planned genetic analysis; PK=pharmacokinetic; POCBP=participant of childbearing potential; 
; 
RR=respiratory rate; SAE=serious adverse event; SOC=standard of care; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs.
a.
Predose time-point is applicable to Dose #1 only.
b.
Rescreening is defined as a separate screening period. All activities conducted during Screening must be completed as part of Rescreening. See Section 8.11.1.
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1.3.2
Part 2 Panel A
Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Administrative/Study 
Procedures
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 5.2, 6.5, 8.1.5
Study Intervention 
(MK-6552 or Placebo) 
Administration
X
X
X
X
Sec 8.1.8.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 administration 
should be taken around the 
same time every day. 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Study Medication Diary 
Dispensing/Review
X
X
X
Sec. 6.4, 8.1.8
In each treatment period, 
Study Medication Diary 
will be dispensed to 
participants on Day -1.
 
 
 
 
 
 
 
Domiciling
X
X
X
X
X
X
X
X
X
X
X
Sec 8.1.11
 
 
 
 
 
day and remain in the unit 
up to 24 hours
postdose #1.
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Standard Meals
X
X
X
X
X
X
Sec 5.3.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
 
 
Safety Procedures
Full physical 
examination
X
X
X
Sec 8.3.1
Not applicable for predose 
#2
 
 
 
 
 
 
 
 
General neurological 
examination
X
X
Sec. 8.3.2, Appendix 10 
(Sec 10.10.1)
 
 
 
 
 
 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Targeted neurological 
examination 
X
X
X
Sec. 8.3.2, Appendix 10 
(Sec 10.10.2)
In each treatment period 
targeted NE will be 
conducted as follows: 
 
VS (HR, BP)
X
X
X
X
Sec 8.3.4.1
In each treatment period 
predose (baseline) will be 
in triplicate 
measurements.
Postdose time-points will 
be in single measurement.
Dose1: Predose, 2-, 6-
hours postdose 1
Dose 2: 2 hour postdose 2
12-lead ECG
X
X
X
Sec 8.3.5, Appendix 8
In each treatment period 
ECG at Predose (baseline) 
will be in triplicate 
measurements.
Postdose ECG time-points 
will be in single 
measurement.
 
 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Urine Pregnancy Test 
(POCBP only)
X
X
Sec. 5.1, 8.3.7
In each treatment period 
urine pregnancy test to be 
completed on Day 1 only 
Hematology, 
Chemistry, Urinalysis
X
X
X
Sec. 8.3.6, Appendix 2
In each treatment period 
blood for safety laboratory 
tests will be collected as 
follow:
 
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec 8.4, Appendix 3
Safety/Study 
Medication Compliance 
Phone Calls
X
X
Sec 8.3.10.2
 
 
 
C-SSRS Since Last 
Assessment
X
X
Sec 8.3.8.1
 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Blood for Plasma MK-
6552 and or Metabolites 
Assay
X
X
X
X
X
X
Sec 8.6.1
In each treatment period, 
PK blood collection will 
 
 
 
 
 
  
 
Pharmacodynamic
MWT
X
X
X
X
Sec 8.7.2, 8.11.5
 
 
 
 
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Part 2/Panel A/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
X
X
X
Sec 8.7.3
 
 
 
 
X
X
Sec 8.7.4
 
 
AE=adverse event; BDS=blood drug screen; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; FBR=future 
biomedical research; FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HR=heart rate; ID=identification; 
 
; PE=physical examination; NE=neurological examination; 
PGA=planned genetic analysis; POCBP=participant of childbearing potential;
; SAE=serious adverse event; SOP=standard operating 
procedure; UDS=urine drug screen; VS=vital signs.
a.
Predose time-point is applicable to Dose #1 only.
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1.3.3
Part 2 Panel B
Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Administrative/Study 
Procedures
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 5.2, 6.5, 8.1.5
Study Intervention 
(MK-6552 or Placebo) 
Administration
X
X
X
X
Sec 8.1.8.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Study Medication Diary 
Dispensing/Review
X
X
X
Sec. 6.4, 8.1.8
In each treatment period, 
Study Medication Diary 
 
 
 
 
 
 
 
 
Domiciling
X
X
X
X
X
X
X
X
X
X
X
Sec 8.1.11
In each treatment period 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Standard Meals
X
--
--
--
---
--
Sec 5.3.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Safety Procedures
Full physical 
examination
X
X
X
Sec 8.3.1
 
 
 
 
 
 
 
 
 
General neurological 
examination
X
X
Sec. 8.3.2, Appendix 10 
(Sec 10.10.1)
 
 
 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Targeted neurological 
examination 
X
X
X
Sec. 8.3.2, Appendix 10 
(Sec 10.10.2)
 
 
Resting VS (HR, BP)
X
X
X
X
Sec 8.3.4.1
 
 
 
12-lead ECG
X
X
X
 
 
 
 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Urine Pregnancy Test 
(POCBP only)
X
X
Sec. 5.1, 8.3.7
In each treatment period 
urine pregnancy test to be 
completed on Day 1 only 
Hematology, 
Chemistry, Urinalysis
X
X
X
X
Sec. 8.3.6, Appendix 2
In each treatment period 
blood for safety laboratory 
tests will be collected as 
follow:
 
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec 8.4, Appendix 3
Safety/Study 
Medication Compliance 
Phone Calls
X
X
Sec 8.3.10.2
 
 
 
C-SSRS Since Last 
Assessment
X
X
Sec 8.3.8.1
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
Pharmacokinetics
Blood for Plasma MK-
6552 and or Metabolites 
Assay
X
X
X
X
X
X
Sec 8.6.1
 
 
 
 
 
 
 
  
 
MWT
X
X
X
Sec 8.7.2, 8.11.5
 
 
 
 
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Part 2/Panel B/All Periods/Dose 1 and Dose 2a
Poststudy
Notes: 
X
X
X
Sec 8.7.3
 
 
 
 
LSEQ
X
X
Sec 8.7.4
 
 
AE=adverse event; BDS=blood drug screen; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; FBR=future 
biomedical research; FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HR=heart rate; ID=identification; 
 
 PE=physical examination; NE=neurological examination; 
PGA=planned genetic analysis; POCBP=participant of childbearing potential; 
; SAE=serious adverse event; SOP=standard operating 
procedure; UDS=urine drug screen; VS=vital signs.
a.
Predose time-point is applicable to Dose #1 only.
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2
INTRODUCTION
2.1
Study Rationale
This study constitutes the first administration of MK-6552 to participants with NT1. 
The primary objectives of Part 1 are to evaluate the safety, tolerability and PK of MK-6552 
after administration of ascending oral doses (MK-6552 
) in a single day 
to participants with NT1. 
 
 
 
 
The primary objectives of Part 2 are to investigate the PD profile of MK-6552 
 
 
 
 
This trial amendment to include administration of multiple oral doses of MK-6552 from 
 
 which will provide additional information on the 
relationships between MK-6552 and safety, tolerability, pharmacokinetics and potential 
alerting effects in NT1 patients. 
 
 
 
 
 
 
 
 
 
 
 
 
The number of participants (n≤24) was chosen for this early Phase 1 study to balance 
scientific requirements for statistical significance with the study’s objectives regarding the 
ethical use of human participants in a clinical study. Details regarding specific benefits and 
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risks for participants in this clinical study may be found in the accompanying IB and ICF 
documents.
2.2
Background
Refer to the IB for detailed background information on MK-6552.
2.2.1
Pharmaceutical and Therapeutic Background
MK-6552 is a small molecule agonist of the OX2R being developed for the treatment of 
 
 
 
 
 
 
 
 
 
MK-6552 is a selective agonist of the OX2R and is not considered a compound with a high 
potential risk of harm to participants (EMA 2007). MK-6552 is not a biological molecule, 
does not exhibit species-specific action, and is not directed towards immune system targets. 
2.2.2
Preclinical and Clinical Studies
Refer to the IB for detailed preclinical studies for MK-6552.
MK-6552 has been investigated in two completed Phase 1 study in healthy male participants: 
MK-6552-001 (PN001), conducted in Belgium; and MK-6552-005 (PN005), conducted in 
the US. 
PN001
MK-6552-001 (PN001) was a randomized, placebo-controlled, double-blind, single 
ascending dose study to evaluate the safety, tolerability, and PK of MK-6552 in healthy male 
participants, This study consisted of 2 alternating panels (A and B) followed by a third panel 
(Panel C) consisting of 8 participants each, all of whom were administered single-oral doses 
of MK-6552 or placebo (3:1 ratio) as an on-site formulation (oral suspension).. In this study, 
24 healthy male participants were administered single oral doses of MK-6552 (0.5 to 4.5 
mg), except in Panel C Periods 3 and 4, in which participants received 2 doses of MK-6552 1 
mg on a single day, administered q6h and q8h, respectively.
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PN005
MK-6552-005 (PN005) was a single-panel, 3-period, open label study in healthy male 
participants to assess the potential PK interaction effect of MK-6552 with modafinil, a 
CYP3A4 inducer. PN005 evaluated the impact of the moderate CYP3A inducer modafinil on 
MK-6552 exposure. In humans, MK-6552 is anticipated to be predominately eliminated by 
CYP3A-mediated metabolism based on the in vitro reaction phenotyping experiments 
conducted with recombinant CYP enzymes. Therefore, MK-6552 has the potential to be a 
victim of DDIs through inhibition and induction of CYP3A. Approximately 11 healthy study 
participants were administered single oral doses of MK-6552 1.0 mg on 3 separate days 
during the study: once alone, once in combination with modafinil 200 mg daily dosed to 
steady-state plasma concentrations, and once in combination with modafinil 400 mg daily 
dosed to steady-state plasma concentrations. Single doses of MK-6552 1.0 mg were generally 
well tolerated in single dose administration when administered alone as well as when co-
administered with modafinil 200 mg and modafinil 400 mg. 
 
 
  
 
 
 
 
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2.2.3
Ongoing Clinical Studies
Ongoing clinical investigations of MK-6552 include MK-6552-002 (PN002); MK-6552-003 
(PN003); and MK-6552-007 (PN007). PN003 is clinically complete; however, as of 21-
AUG-2024, database lock has not been achieved and study data are still blinded. PN002 is 
being conducted at 1 site in Belgium in conformance with GCP. PN003 is being conducted at 
2 sites in the US, and PN007 is being conducted in 1 site in the US, both under the MK-6552 
IND. 
PN002
MK-6552-002 (PN002) is a double-blind, placebo-controlled multiple ascending dose study 
to assess the safety and tolerability of multiple doses of MK-6552 in healthy participants. It 
includes 8 panels of n=8 study participants, assigned 6:2, active: placebo. Panels A-C will 
receive10 days of bid dose administration of MK-6552 at 0.25, 0.5 mg and 1.0 mg dose 
levels and Panels D, F, and G received 5 days of bid dose administration of MK-6552 at the 
2.0 mg, 5.0 mg, and 7.0 mg dose levels. Additionally, 1 panel (Panel E) received 2 days of 
bid administration of MK-6552 4.0 mg followed by 3 days of bid administration of MK-6552 
3.25 mg. Panel H will receive 5 days of bid administration of MK-6552 4.0 mg q3h. 
 
 
 
 
 
 
As of 13-AUG-2024, PN002 has completed multiple dosing of MK-6552 up to 7.0 mg q6h 
BID and data remain blinded. Approximately 40 healthy male and female participants have 
been administered multiple daily oral doses of MK-6552/PBO 0.25 to 7.0 mg. 
 
 
 
 
 
 
 
 
 
 
 
 
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PN003
MK-6552-003 (PN003) is a randomized, double-blind, 3-period crossover study to assess the 
effects of MK-6552 on sleep latency in sleep-deprived healthy study participants with 
modafinil as a positive control. This study assessed the effect of MK-6552 on sleep latency 
as measured by the MWT in 18 healthy study participants who were allocated to receive 
either MK-6552, modafinil, or PBO to MK-6552 or modafinil in each of the 3 treatment 
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periods. All participants received all treatment allocations during the study in a double-
dummy fashion, with period-specific treatment allocation being randomized for a given 
participant according to the randomized allocation schedule. Participants received a 
maximum of one active treatment (MK-6552 
 or modafinil 200 mg 
once) in any given treatment period. As of 13-AUG-2024, this study is clinically complete 
although database lock has not yet been achieved and study data are still blinded. Single day 
administration of MK-6552 2.0 mg q8h x 2 doses were generally well tolerated. The most 
frequently reported AEs (≥2 occurrences) in participants receiving MK-6552 2.0 mg, 
modafinil or PBO were headache (5) and nausea (2). All reported AEs have been mild to 
moderate in intensity. There have no SAEs or deaths in this study.
PN007
MK-6552-007 (PN007) is a study to evaluate the effects of coadministration of diltiazem on 
the plasma pharmacokinetics of a single dose of MK-6552 in healthy study participants.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Participants with NT1 18 to 55 years of age inclusive.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of a 
single-day 
 and multiple-
day
administration 
of M
with Narcolepsy 
Type 1.
Adverse events, discontinuation of study 
intervention due to adverse events
To assess the pharmacodynamic profile of 
MK-6552 
 after 
multiple-day administration in participants 
with Narcolepsy Type 1.
 
 
 
 
 
 
Secondary Objectives
Secondary Endpoints
To characterize the plasma 
pharmacokinetics of MK-6552 following 
administration of single-day bid 
 
 oral doses in participants with 
Narcolepsy Type 1.
 
 
 
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
To explore the relationship between genetic 
variation and response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in the study
Germline genetic variation and association 
to clinical data collected in this study
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, 2-part, placebo-controlled (Part 2 only), double-blind (Part 2 only), 
multisite study to evaluate the safety, tolerability, PK and pharmacodynamics of MK-6552 in 
participants with NT1. The study is to be conducted in conformance with GCP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Because this is a Phase 1 assessment of MK-6552 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study constitutes the first administration of MK-6552 to participants with NT1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
 
 
 
 
 
 
The safety and tolerability of MK-6552 will be assessed throughout the study by monitoring 
AEs/SAEs, physical/ neurological examinations, VS, ECGs, and laboratory safety tests 
(chemistry, hematology, urinalysis). The timing of the safety endpoints has been planned to 
ensure adequate safety monitoring throughout the treatment period also taking into 
consideration the demonstrated clinical half-life of MK-6552 
 
 
 
 
 
 
 
 
 
 
 
4.2.1.2
Pharmacokinetic Endpoints
 
4.2.1.3
Pharmacodynamic Endpoints
 
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4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
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DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
Part 1 will not include placebo in order to maximize collection of safety data supporting 
administration of MK-6552 in all participants at all dose levels. Part 2 will include placebo to 
allow for an appropriate assessment of pharmacodynamic data of MK-6552 and to maintain 
study blinding to reduce bias.
4.2.3
Rational for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
 
 
 
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Table 2
Preliminary PK for 4 NT1 participants from Part 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The methods used in calculating doses and estimated exposures are detailed in Section 4.3.1 
and Section 4.3.2.
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As this is a Phase 1 assessment of MK-6552 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.3.1
Starting Dose for This Study
 
 
 
 
 
 
 
 
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4.3.2
Maximum Dose Exposure for This Study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
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PN002 is an ongoing multiple ascending dose Phase 1 study to assess the safety and PK of 
multiple-day administration of twice daily oral doses of MK-6552 in healthy male and 
female participants. 
 
 
 
 
 
 
 
 
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4.3.3
Rationale for Dose Interval and Study Design
 
 
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4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
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 (Section 
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7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, PD, 
or other items of interest, prior to a final decision on continuation or termination of the study. 
It may be necessary to keep the study open for gathering/reviewing of additional supportive 
data to optimally complete the objective(s) of the study. If necessary, the appropriate 
amendment(s) to the protocol and/or appropriate communication(s) will be generated. If the 
decision has been made to end the study following this review period, the study end will be 
defined as the date of the Sponsor decision, and this end of study date supersedes the 
definitions outlined above. The Competent Authority(ies) and IRB(s)/IEC(s) will be apprised 
of the maximum duration of the study beyond the last participant out and the justification for 
keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has a diagnosis of NT1, including a valid PSG within the previous 5 years and a current 
diagnosis of NT1 for at least 6 months based on criteria established by the International 
Classification of Sleep Disorders- Third Edition. A current NT1 diagnosis based on the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [American 
Psychiatric Association 2013] is also acceptable.
Note: At the discretion of the investigator, a valid PSG within the past 10 years may be 
acceptable. Alternatively:
A PSG including MSLT can be repeated at the site during the Screening period or,
A CSF hypocretin A level < 110 pg/ml is also acceptable as confirmatory of a NT1 
diagnosis in the absence of valid PSG data. If not available, a CSF sample can be 
collected for hypocretin A level assessment at the discretion of the investigator.
2. Is positive for HLA-DQB1*06:02 allele supporting a diagnosis of NT1 
Note: At the discretion of the investigator, participants with a negative HLA-
DQB1*06:02 genotyping, but a PSG and/or a CSF hypocretin A level (per IC#1) 
supporting a diagnosis of NT1 may be enrolled in the study.
3. Has a baseline history of unequivocal cataplexy prior to initiation of anti-cataplexy 
medications.
4. Is free of any disease that in the opinion of the investigator would interfere with trial 
evaluations based on medical history, physical and targeted neurological examinations, 
VS measurements and ECG performed prior to enrollment (abnormal VSs and ECGs may 
be repeated once to confirm eligibility).  Subjects with chronic medical conditions 
including but not limited to hyperlipidemia, and hypothyroidism which have been well-
controlled on a stable dose of medication for the past two months, may be enrolled if 
clinically acceptable to the investigator and the Sponsor.
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5. Has a BMI between 18 and 32 kg/m2, inclusive. See Section 8.3.3 for criteria on rounding 
to the nearest whole number. BMI = weight (kg)/height (m)2.
Note: Participants who have a BMI up to 35.0 kg/m2 may be enrolled at the discretion of 
the investigator.
Demographics
6. Is an individual of any sex/gender, from 18 years to 55 years of age inclusive, at the time 
of providing the informed consent.
Assigned Male Sex at Birth
7. If capable of producing sperm, the participant agrees to the following during the 
intervention period and for at least the time needed to eliminate the study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for the study intervention is:
-
Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a 
long-term and persistent basis) and agrees to remain abstinent
OR
Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause, documented from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview) as detailed below:
-
Uses a penile/external condom when having penile-vaginal intercourse with a 
nonparticipant of childbearing potential who is not currently pregnant and should also 
be advised of the benefit for that partner to use an additional method of contraception, 
as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is pregnant or 
breastfeeding must agree to use penile/external condom during each episode of sexual 
activity in which the partner is at risk of drug exposure via ejaculate.
-
Contraceptive use by participants capable of producing sperm should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. If the contraception requirements in the local label for any of the 
study interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
Assigned Female Sex at Birth
8. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
-
Is not a POCBP
OR
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-
Is a POCBP and must meet all the bullet points below:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), or is abstinent from penile-vaginal intercourse as their preferred and usual 
lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 
during the intervention period and for at least 7 days after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by POCBPs should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the study 
interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.7.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
9. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
10. Is willing to forego operating a motor vehicle or heavy machinery from the EDS SOC 
washout period through Part 1 and Part 2 and until reinitiation of EDS SOC after 
completion of all study procedures in the last treatment period of Part 2. 
11. Reports a total sleep time of > 6 hours on at least 4 out of 7 nights each week within the 4 
weeks prior to screening visit.
12. Has regular sleep initiation times no later than midnight.
13. Agrees not to engage in night shift work, and not to cross more 3 times zones during the
2 weeks prior to randomization and throughout the course of the study.
14. Willing to comply with the study restrictions (see Section 5.3 for a complete summary of 
study restrictions).
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5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. History of or current hypertension defined as a SBP ≥140 mm Hg and a DBP 
≥90 mm Hg.
2. Has underlying cardiovascular or cerebrovascular conditions in which an acute rise in 
blood pressure would pose a clinical concern, including but not limited to aneurysms or 
arteriovenous malformations.
3. Has a history of renal or hepatic impairment.
4. Has screening safety laboratory findings consistent with moderate or severe hepatic 
impairment, including but not limited to clinically significant elevations in AST, ALT, 
alkaline phosphatase, or bilirubin above normal range; clinically significant decreases in 
albumin below normal range; clinical significant decreases in platelet count below 
normal range.
5. Has an estimated eGFR ≤80 mL/min/1.73 m2 based on the 2021 CKD-EPI.
CKD-EPI Equation:
Where Scr is serum creatinine, K is 0.7 for females and 0.9 for males, α is -0.241 for females 
and -0.302 for males, min indicates the minimum of Scr/K or 1, max indicates the maximum 
of Scr/K or 1
Participants who have an eGFR of up to10% below 80 mL/min/1.73 m2 may be enrolled in 
the study at the discretion of the investigator.
6. Has a history of cardiac ischemia or cerebral ischemia including but not limited to history 
of stroke, transient ischemic attack, or transient global amnesia.
7. Based on clinical interview and responses on the C-SSRS, 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 (eg, 
positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the 
past 5 years or suicidal behavior in their lifetime.
8. Mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
9. History of cancer (malignancy). Participants with definitively treated disease who, in the 
opinion of the study investigator, are highly unlikely to have a recurrence for the duration 
of the study may be enrolled at the discretion of the investigator.
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10. Has a history of any of the following sleep disorders: 

obstructive sleep apnea (OSA) defined as an Apnea Hypopnea Index > 15 per hour 
per the AASM alternate criteria,

primary insomnia (within the past 6 months),

circadian rhythm sleep disorder,

shift work sleep disorder (within the past 6 months),

clinically significant parasomnia at the discretion of the investigator.
11. Has a medical condition that in the opinion of the investigator, may account for the 
patient's excessive daytime sleepiness, e.g., pain, cardiac disease, nocturia 
(>3 times/night), or hot flashes.
12. For participants requiring lumbar puncture to determine study eligibility: Has a medical 
condition that in the opinion of the investigator may increase the risks associated with a 
lumbar puncture (eg, individuals with increased intracranial pressure, bleeding diathesis). 
13. Has a history of seizure disorder, clinically significant head trauma, or past invasive 
intracranial surgery or clinically significant dementia.
14. Participants has, in the opinion of the investigator, a confounding psychiatric disorder 
such as any history of a psychotic disorder (e.g. schizophrenia, schizoaffective disorder, 
delusional disorder, bipolar disorder) or currently has active, inadequately-treated 
depression, post-traumatic stress disorder, or other anxiety disorder.
15. History of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or 
has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription drugs or food.
16. Positive test(s) for HBsAg, hepatitis C antibodies or HIV.  Note: Participants with a 
documented cure and/or a positive serologic test for HCV with a negative HCV viral load 
may be included upon consultation with the Sponsor.
17. The participant had a major surgery and/or donated or lost 1 unit of blood (approximately 
500 mL) within 4 weeks prior to the prestudy (screening) visit.
18. Participants, in the opinion of the investigator, has a history or current evidence of any 
condition, therapy, lab abnormality or other circumstances that might confound the 
results of the study, or interfere with the patient's participation for the full duration of the 
study, such that it is not in the best interest of the patient to participate.
Prior/Concomitant Therapy
19. Unable to refrain from or anticipates the use of CYP3A4 inhibitor and/or inducer drugs 
and food, drug, supplements or other products with known stimulating or sedating 
properties beginning ~ 2 weeks (or 5 half-lives) prior to administration of the first dose of 
the study intervention, throughout the study (including washout intervals between 
treatment periods and study parts), and until the poststudy visit: TCAs, amphetamine, 
hypnotics, tranquilizers, sedating antihistamines, benzodiazepines, anticonvulsants, 
clonidine, pemoline, melatonin, guarana, ma huang, kava-kava, valerian, hoodia, St. 
Johns wort and any other stimulants and alerting agents prescribed for use on a daily 
basis. There may be certain medications that are permitted (see Section 6.5).
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Prior/Concurrent Clinical Study Experience
20. Participated in another investigational study within 4 weeks (or 5 half-lives, whichever is 
greater) prior to the prestudy (screening) visit. The window will be derived from the date 
of the last visit in the previous study.
Diagnostic Assessments
21. QTc interval ≥450 msec.
Other Exclusions
22. Is under the age of legal consent.
23. Has a history of substance abuse or dependence within the past two years (except if 
currently in sustained full remission for at least one year or meets criteria for early full 
remission, according to DSM-IV-TR). Substances include alcohol, hypnotics, cannabis, 
nicotine (only if the nicotine dependence is affecting sleep) and any illicit drugs of abuse.  
Participants must have a negative drug screen prior to randomization.
24. Consumes the equivalent of more than 10 cigarettes a day or routinely smokes during the 
night.
25. Has history of tobacco use associated with maintaining wakefulness (i.e., participants 
who smoke or use tobacco products to stay awake) or a need for a cigarette within 30 
minutes of waking in the morning. 
26. Does not agree to follow the smoking restrictions as defined by the CRU.
27. Unable to refrain from alcohol intake from the EDS SOC washout period through Part 1 
and Part 2 and until reinitiation of EDS SOC after completion of all study procedures in 
the last treatment period of Part 2 or until return to baseline at the discretion of the 
investigator.  
28. Participant is, in the opinion of the investigator, at risk for alcohol withdrawal.
29. Consumes greater than 3 servings (1 serving is approximately equivalent to 120 mg of 
caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
30. A POCBP who has a positive urine pregnancy test within 24 hours before first dose of 
study intervention (see Appendix 5). If the urine test cannot be confirmed as negative, a 
serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
31. 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.
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
In Part 1, in each treatment period, and in Part 2 on Days 1 and 7, participants will fast from 
all food and drinks, except water, for at least 8 hours before the first dose of study 
intervention administration. Participants will fast from all food and drinks, except water, 
between first dose of study intervention administration and the first scheduled meal. Meals 
and snack(s) will be provided by the site staff at time points indicated in the study flowchart. 
Participants will fast from all food and drinks, except water, between meals and snacks. The 
overall composition of the meals will be at the discretion of the investigator however the 
meal content must be in compliance with the caffeine and the alcohol restrictions (see 
Section 5.3.2). 
After the 24-hour postdose #2 procedures (for Part 1) or 24-hour postdose #1 procedures (for 
Part 2) have been completed, subsequent meals and snacks will be unrestricted in 
composition, and timing.
Approximately 240 mL of water will be provided during study intervention administration. 
Additional water may be provided in 50-mL increments if desired. Water will be restricted 
1 hour before and 1 hour after study intervention administration.
Participants will also fast before laboratory safety evaluations in Part 1 Day 1 (Period 1 only) 
and in
 Fasting requirements for laboratory safety evaluations 
are at least 8 hours prior to collection.
Although there will be no diet composition and timing restrictions while the participants are 
taking the study intervention at home on Day 2 to Day 6, the meal content must be in 
compliance with the caffeine and the alcohol restrictions (see Section 5.3.2). 
Instructions on whether to take MK-6552 with or without food and/or drink may be modified 
during the study based on newly available data.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention, throughout the study including the washout interval between treatment periods 
and Parts 1 and 2 and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after study intervention administration in each treatment periods (Part 1) and on Days 1 and 7 
(Part 2). On all other days during the study, consumption of fruits and fruit juices (except for 
grapefruit, grapefruit juices, and grapefruit products) is allowed.
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants are advised to refrain from consumption of caffeinated beverages or xanthine-
containing products from 12 hours prior to the Screening Visit. A recheck may be needed if 
participants did not refrain from consuming caffeinated beverages or xanthine-containing 
products 12 hours prior to the Screening Visit.
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from:
-
12 hours before and after study intervention administration in each treatment period 
of Part 1 and on Days 1 and 7 of Part 2
-
12 hours before poststudy visit.
At all other times, caffeinated beverages or xanthine-containing products will be limited to 
no more than 3 units per day (1 unit = 120 mg of caffeine).
A list of common caffeine-containing products and their caffeine content is provided in 
Appendix 11.
5.3.2.2
Alcohol Restrictions
Participants are advised to refrain from consumption of alcohol 24 hours prior to the 
screening visit. A recheck may be needed if participants did not refrain from consuming 
alcohol 24 hours prior to the Screening Visit.
Participants will refrain from consumption of alcohol from:
-
The EDS SOC washout period through Part 1 and Part 2 and until reinitiation of EDS 
SOC after completion of all study procedures in the last treatment period of Part 2 or 
until return to baseline at the discretion of the investigator.
-
24 hours before poststudy visit.
At all other times, alcohol consumption is limited to no more than approximately 2 alcoholic 
beverages or equivalent servings (1 serving is approximately equivalent to: beer 
<354 mL/12 ounces>, wine <118 mL/4 ounces>, or distilled spirits <29.5 mL/1 ounce>) per 
day.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU.
During the study, if the participant is a smoker, they will limit the number of cigarettes
(including ecigarettes/vaping) to 10 per day.
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5.3.3
Activity Restrictions
Parts 1 and 2
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods and study parts), and until the poststudy visit.
Participants will avoid activities requiring high degree of attention such as driving a car from 
EDS SOC Washout Period until reinitiation of EDS SOC after completion of all study 
procedures in Part 2, Period 2. 
Participants not on EDS SOC will also avoid activities requiring high degree of attention 
such as driving a car from participant randomization in Part 1 Period 1 Day 1 until 
completion of all study procedures in Part 2, Period 2.
Participant transportation needs will be covered by the Sponsor from the time driving 
restriction is in effect (EDS SOC Washout Period or randomization in Part 1 Period 1 Day 1) 
until completion of all study procedures in study Part 2, Period 2. Transportation options 
covered may include public transportation, family member, taxi, Uber, Lyft share rides, etc. 
Part 2
Participants will avoid vigorous physical activity (ie, strength training, running, hiking or 
biking uphill, etc.) up to 4hours after study medication administration from Day 1, Period 1 
until reinitiation of EDS SOC after completion of all study procedures in Period 2.
5.3.4
Bedtime
Throughout the study, participants should go to bed at their usual bedtime. To ensure at least 
6 hours of sleep per night, starting in the first treatment period of Part 1 and throughout the 
study until reinitiation of EDS SOC treatment (after completion of all study procedures in 
Part 2 Period 2), participants will avoid going to bed pass midnight time.
5.3.5
Other
Participants will NOT engage in the following activities from the EDS SOC washout period, 
throughout the study (including washout intervals between treatment periods and study parts) 
and until reinitiation of EDS SOC treatment after completion of all study procedures in 
Part 2, Period 2).
•
nighttime shift work
•
travel across >3 time zones
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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 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
Participants may be rescreened as appropriate per Section 8.11.1. 
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention or withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number.
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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 and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. 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 4.
Country-specific requirements are noted in Appendix 7.
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Table 4
Study Interventions
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EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 4 will be provided per the “Sourcing” column depending on 
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 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is 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
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
A sample allocation table is provided below in Table 5.
Table 5
Allocation of Participants to Treatment
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
Part 1 of this study is conducted as open label; therefore, the Sponsor, investigator, and 
participant will know the intervention administered.
In Part 2 of this study, a double-blinding technique will be used. MK-6552 and placebo will 
be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified 
study-site personnel. 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 8.1.10 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
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When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second unblinded member of the study-site staff.
In Part 1 when participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention. Study-site personnel will examine each participant’s mouth to ensure that the 
study intervention was ingested.
In Part 2 (Day 2 [afternoon dose only] and Days 3 to 6) when participants self-administer the 
study intervention at home, daily phone calls will be made to check study intervention 
administration compliance. Compliance with study intervention will also be assessed at the 
next on-site visit by direct questioning and site review of the completed study intervention 
dosing diary as captured by the participant. Compliance will also be assessed by counting 
returned capsules during the next on-site visit and documented in the source documents and 
CRF. Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
A record of the number of MK-6552/placebo capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the CRF.
When participants are dosed at the site 
, study 
intervention administration will be witnessed by the CRU staff.  The staff will witness the 
participant record the dosing in the study medication diary.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of study intervention, they may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination, 
during time periods specified by this protocol for that medication must first be discussed 
between the investigator and Sponsor before administration, unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree.
COVID-19 and flu vaccines may be administered. Study intervention must be given at least 
72 hours following or at least 48 hours prior to any COVID-19 vaccination.
Investigational COVID-19 (ie, those not licensed or approved for Emergency Use) are not 
allowed.
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Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
In addition, the following concomitant medications are permitted:
Medications for treatment of cataplexy may be continued for the duration of the trial include 
selective serotonin reuptake inhibitors (SSRIs) and/or serotonin noradrenaline reuptake 
inhibitors (SNRIs).
Systemic contraceptives and hormone replacement therapy are permitted for POCBP 
participants.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
CRUs will be staffed with medically trained personnel with appropriate access to full-service 
acute care hospitals to facilitate rapid institution of medical intervention.
6.6
Dose Modification (Escalation)
Dose escalation decisions are applicable only to Part 1.
All dose-escalation decisions will be made jointly by the investigator and the Sponsor. 
Members of the Sponsor safety review team will include: the trial clinical director, trial 
clinical scientist(s), senior level clinical director and trial biostatistician. Additional Sponsor 
attendees may include a clinical research associate and a pharmacologist. The Sponsor safety 
review team will obtain input from the investigator regarding their evaluation of safety and 
tolerability from the previous dosing period and their recommendation to dose escalate in the 
next period.
Each dose-escalation decision will occur on an individual basis as the study enrollment of 
participants will be progressive and on-going throughout the study. 
Dose-escalation decisions will be based on key safety variables, including VS, 12-lead ECG, 
laboratory safety tests, PE, NE, and AEs/SAEs from the previous dose levels up to at least 
24 hours postdose #2. Additionally, individual stopping rules (Section 7.1.1) will be 
reviewed to confirm none of the rules are met. Pharmacokinetic data may be included in the 
dose-escalation decisions (Section 2.1 and Section 2.2).
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose escalation, the dose will not be increased as planned. Instead, individual participants 
may:
Receive the same dose level to further explore safety and tolerability at that level,
Receive a lower dose of the study intervention (with or without food),
Dosing in Part 1 may be stopped and participants may proceed to Part 2 at a dose up to the 
maximum safe and well tolerated dose reached in Part 1.
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Participant discontinuation criteria are outlined in Section 7.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
If any of the below stopping rules are met, the study will be paused, and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. To continue the study 
(on joint agreement with the Sponsor and investigator), an  amendment will be submitted for 
approval.
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator.
2. Two (2) or more participants within a Panel (at the same dose level) report Severe 
Nonserious AEs considered related to the study intervention by the investigator.
If any of the below stopping rules are met, subsequent higher doses in Part 1will be lowered 
based on joint agreement of the Sponsor and investigator in order for the study to continue.
3. Should the emerging PK (mean) data indicate that the maximum clinical exposure (Cmax
or AUC), as defined in Section 4.3.2 will be exceeded, subsequent higher doses will be 
adjusted based on joint agreement of the Sponsor and investigator.
4.
 
 
5.
 
6.
 
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded, but in Part 1 supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
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 8.1.10). The 
Sponsor will not provide random code/disclosure envelopes or lists with the clinical supplies.
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6.9
Standard Policies
Not applicable
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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 before completion of the protocol-specified treatment period 
will still continue to participate in the study as specified in Section 1.3 and Section 8.1.9, or 
if available, a PCL.
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 8.1.9.
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.
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
The participant has a confirmed positive serum pregnancy test.
The participant has a positive drug screen at any time during the course of the study. The 
drug screen can be confirmed by a recheck at the discretion of the investigator after 
discussion with the Sponsor.
The participant meets any of the individual stopping rules described is Section 7.1.1.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
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7.1.1
Individual Stopping Criteria
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. 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.
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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 known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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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 providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet 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.
Procedures conducted as part of a site generic screening (with an ERC/IRB approved site 
generic screening consent) on potential participants (eg, blood count, vital signs, ECG, etc) 
and obtained before signing of study ICF may be used for screening or baseline purposes 
provided the procedures met the protocol specified criteria and were performed within the 
screening window defined in this protocol.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed the volume mentioned in Appendix 8.
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
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The ICF, any subsequent revised ICF, and any written information 
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provided to the participant must receive the IRB/IEC’s approval/favorable opinion in 
advance of use.
Informed consent given by the participant (or their legally acceptable representative) 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 (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
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
Specifics about the study and the study population are to be included in the ICF.
The participant (or their legally acceptable representative) 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 or the participant’s legally acceptable 
representative’s dated signature.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, 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 
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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.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 2 months before starting the study.
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
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 before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Part 1
Study intervention will be administered by the investigator and/or an appropriately qualified 
designee at the site. 
Part 2 
Participants will be instructed on how to administer at home study intervention by the site 
staff. 
While participants are at the site, the study medication will be taken by the participant under 
supervision from the site staff. Following study administration, the participant will complete 
the Study Medication Diary followed by site staff verification that the diary has been 
completed properly. 
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In each treatment period, on Day 2 before being discharged from the site, participants will 
receive their assigned bottle of study intervention for unsupervised administration at home 
for Day 2 afternoon dose and for Days 3 to 6. Upon participants return to the site on Day 6, 
the study intervention bottle will be collected by the site staff in preparation for Day 7 
treatment administration at the site.
8.1.8.1
Timing of Dose Administration
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.11.4. to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
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as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a 
follow-up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any 
AEs have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
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. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is 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 
record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If 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.
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Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
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 continue to be monitored in the study.
8.1.11
Domiciling
 
 
 
 
8.1.12
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/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in the Central Laboratory Services Manual.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Neurological Examinations
General and targeted neurological examinations will be conducted according to the 
procedures outlined in Appendix 10.
8.3.3
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI = kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weights and height will be obtained with the participant’s shoes off and jacket or coat 
removed. 
8.3.4
Vital Signs
Body temperature, PR, RR, and BP will be assessed. The same method must be used for all 
measurements for each individual participant and should be the same for all 
participants at a given site.
Resting and orthostatic BP and HR will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. Resting BP and 
HR position can be seated or semi-recumbent. The same position must be used for all 
measurements for each individual participant and should be the same for all participants at a 
given site.
VS will be measured after at least 10 minutes rest for the participant in a quiet setting without 
distractions and will include temperature, systolic and diastolic BP, HR and RR.
8.3.4.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions for at least 10 minutes 
before having VS measurements obtained. VS will include HR, systolic and diastolic BP, 
RR, and body temperature at timepoints indicated in the SoA. The correct size of the BP cuff 
and the correct positioning on the participant’s arm is essential to increase the accuracy of BP 
measurements.
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At screening, HR and BP will be in triplicate measurements, obtained at least 1 minute apart 
(all 3 sets completed within 6 minutes). The median of the three measurements will be used 
to assess for participants eligibility. 
Part 1
In each treatment period, the predose (baseline) HR and BP will be in triplicate 
measurements, obtained at least 1 minute apart (all 3 sets completed within 6 minutes) within 
3 hours of dosing MK-6552. The median of these measurements will be used as the baseline 
to calculate change from baseline for safety evaluations (and for rechecks, if needed). 
Postdose VS measurements will also be measured in triplicate measurements.
Part 2
In each treatment period, on Days 1 and 7, the predose (baseline) HR and BP will be in 
triplicate measurements, obtained at least 1 minute apart (all 3 sets completed within 
6 minutes) within 3 hours of dosing MK-6552/placebo. The median of these measurements 
will be used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). All postdose VS measurements will be single measurements.
Poststudy visit HR and BP will be in triplicate measurements, obtained at least 1 minute apart 
(all 3 sets completed within 6 minutes).
Participants will continue to rest from dosing until 1 hour postdose except to stand for the 
measurement of orthostatic VS (if needed) or other study-related procedure.
Body Temperature
Body temperature will be measured in Part 1 only. The same method must be used for all 
measurements for each individual participant and should be the same for all participants at a 
given site.
8.3.4.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained for Part 1 only. 
Participants should be resting for at least 10 minutes and then stand upright for 
approximately 2 minutes before measurement of orthostatic VS.
8.3.5
Electrocardiograms
All 12-lead ECGs will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. Refer to 
Appendix 8 for evaluation and potentially significant findings.
At each time point when triplicate ECG are required, 3 individual ECG tracings should be 
obtained at least 1 minute apart. The full set of triplicates should be completed in no more 
than 6 minutes.
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Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Participants may need to remove interfering garments.
Participants should be resting for at least 10 minutes before each ECG measurement. The 
resting position may include seated, semi-recumbent or supine, but the same position must be 
used for all measurements for each individual participant and should be the same for all 
participants at a given site.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
For all participants, screening and poststudy ECG recordings are to be obtained in single 
measurements.
Part 1
Before each treatment period, predose ECGs will be obtained in triplicate at least 1 minute 
apart within 3 hours before dosing MK-6552. The median of these measurements will be 
used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed).
In all treatment periods, postdose ECG will be in triplicate measurements at the time-points 
specified in the SoA.
Part 2
Before each treatment period, on Days 1 and 7, predose ECGs will be obtained in triplicate at 
least 1 minute apart within 3 hours before dosing MK-6552. The median of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). 
All postdose ECG will be obtained as single measurements at the time-points specified in the 
SoA.
For both study parts
During each treatment period, if a participant demonstrates a median increase in QTc interval 
≥60 msec, or ≥ 25% compared to the median predose baseline measurement, the participant 
will continue to be monitored by triplicate repeat ECGs every 30 minutes for at least 2 hours 
or until the abnormality is resolved. If prolongation of the QTc interval ≥60 msec persists 
over 120 minutes, a consultation with a cardiologist may be appropriate and the Sponsor 
should be notified (see Section 7.1.1).
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During each treatment period, if the median QTc interval is ≥500 msec for postdose 
measurements and sustained for 120 minutes (see Section 7.1.1), the Sponsor should be 
notified, and the ECGs should be reviewed by a cardiologist. The participant should be 
telemetry monitored (until the QTc interval is <500 msec) or should be considered for 
transfer to a location where closer monitoring and definitive care (eg, a CCU or ICU) is 
available.
If the median increase in QTc interval ≥60 msec, or ≥ 25% compared to the median predose 
baseline measurement or median QTc interval is ≥500 msec for postdose measurements and 
these changes are sustained for 120 mins, the QTc individual stopping rule will be met and 
dosing to the particular participant should be halted and the Sponsor’s clinical director 
informed within 24 hours:
If at any time the QRS interval is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted, the participant should be immediately transferred to an acute care setting for definitive 
therapy.
If prolongation of the QTc interval is noted, concomitant medications that prolong QTc 
interval should be held until the QTc interval is within 60 msec of baseline and the QTc 
interval is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.6
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 Central Laboratory Services 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).
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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.
8.3.7
Pregnancy Testing
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.8
Suicidal Ideation and Behavior Monitoring 
8.3.8.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior at screening, the 
assessor should also inquire and document if this is also present at the time of the Screening 
Visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). After that evaluation, only those participants whose suicidal ideation is considered by 
the evaluator to be passive, and who expressly deny any intent to act, and who, after 
evaluation, are not judged to be at serious risk for self-harm during the course of the study 
may continue in the study; other participants must be discontinued from study participation 
and receive appropriate clinical follow-up care to ensure their safety. In addition, all AEs of 
suicidal ideation or behavior must be recorded as an ECI (see Section 8.4.7). Sites are to 
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designate which health care professionals are to be responsible for acute care on-site and to 
specify referral center(s) to be used for further evaluation.
8.3.9
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship. See 
Investigator Site Binder for additional guidance.
8.3.10
Safety/Compliance Phone Calls
8.3.10.1
Safety Phone Calls During the Screening Period
During the EDS SOC washout period, safety phone calls will be performed every day for the 
duration of the required EDS SOC washout period before study intervention randomization 
to confirm EDS SOC washout and collect any AEs/SAEs. The safety phone calls start day 
may be adjusted based on the specific EDS SOC washout requirements. 
For participants on EDS SOC modafinil, armodafinil and/or pitolisant: safety phone calls will 
be completed from Day -7 to Day -1
For participants on EDS SOC solriamfetol, Xyrem or methylphenidate: safety phone calls 
will be completed on Day -1. 
8.3.10.2
Compliance and Safety Phone Calls 
 
 
 
 
 
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).
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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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
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
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 under any of the following circumstances:
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,
if it is the result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention randomization through 14 days after cessation of 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 any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
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 the investigator 
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 6.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 6
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
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
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout, 
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does 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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
24 hours of 
learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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. 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). The investigator will also make every attempt to 
follow 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 toward 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.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Disease-related events and /or disease-related outcomes not qualifying as AEs or SAEs are 
not applicable to this study.
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 overdose of Sponsor’s product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
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*Note: These criteria are based on 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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3. Suicidal ideation, suicidal behavior.
4. Events associated with potential for abuse (the Operations Manual will contain a list of 
specific terms associated with potential for abuse).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any study intervention 
administered that exceeds the dose prescribed by the protocol. It is up to the investigator or 
the reporting physician to decide whether a non-study intervention dose (eg, rescue or 
concomitant medication) is to be considered an overdose, with notification of  the Sponsor.
Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be measured for evaluation of PK 
will be collaboratively determined by the Sponsor (eg, samples at lower doses may not be 
measured if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be measured and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers. Blood samples collected may be 
stored and further analysis may be performed, if required.
8.6.1
Blood Collection for Plasma MK-6552
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Central Laboratory Services Manual.
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8.7
Pharmacodynamics
8.7.1
 
 
 
 
 
 
 
 
8.7.2
 
 
 
 
 
 
 
 
 
 
8.7.3
 
 
 
 
 
 
 
 
 
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8.7.4
 
 
 
 
 
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research will be collected from all participants as specified in the 
SoA:

Blood (DNA) for genetic analysis

Blood for HLA-DQB1*06:02 Genotyping
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be collected for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for FBR if the participant provides 
documented informed consent for FBR. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled visit, if needed. Sample collection, storage, and shipment 
instructions for planned genetic analysis samples will be in the Operations/Laboratory 
Manual.
8.9
Future Biomedical Research Sample Collection
If the participant has provided documented informed consent for FBR, FBR-specific sample 
collections, including leftover samples, will be obtained. The following specimens will be 
included for FBR:

Leftover samples listed in Section 8.8
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Within approximately 4 weeks ± 1 week (or 7 days); before intervention randomization, 
potential participants will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 5.
Rescreening is defined as a separate screening period and can be initiated as appropriate, 
including for screen failures (Section 5.4). Rescreening is to include all screening procedures 
listed in the SoA (Section 1.3), including consent review. Rescreen procedures cannot be 
conducted the day prior to intervention randomization if there are Day -1 procedures planned 
per protocol. 
8.11.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
In Part 1, each treatment period will be separated by ≥ 4 days to allow for a full washout of 
the study intervention and data entry in the EDC. 
In Part 2, each treatment period will be separated by ≥ 2 days to allow for a full washout of 
the study intervention.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL. 
8.11.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
Part 1 
The blood sample for MK-6552 is the critical procedure.
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At any postdose time point, the blood sample for MK-6552 needs to be collected as close to 
the exact time point as possible. 
 
All other procedures should be completed as close to the prescribed/scheduled time as 
possible. Study procedures can be performed before or after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
-
PK Collection as outlined in Table 7.
Table 7
Pharmacokinetic Blood Collection Windows
PK Collection
PK Collection Window
Predose
Up to -1h
0 to <1 h
±5 min
1 to <18 h
±15 min
18 to ≤24 h
±1 h
Study Intervention Administration
Study intervention administration: within 30 minutes of the theoretical administration time
Predose and Postdose Procedures
 
 
 
Postdose VS evaluations:
-
Prior to 1 hour postdose may be obtained within 5 minutes of the scheduled sampling 
time
-
Prior to 24 hours postdose may be obtained within 15 minutes of the scheduled 
sampling time
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-
24 hours postdose may be obtained within 1 hour of the scheduled sampling time.
 
 
 
.
Laboratory safety tests collected for Panel B participants in each period of Part 2 on Day 4 
can be obtained ± 1 day (from Day 3 to Day 5) from the scheduled sampling time. 
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-6552 in participants with NT1, and the PK, 
pharmacodynamic, and safety profiles of the compound are still being elucidated. This 
protocol is written with some flexibility to accommodate the inherent dynamic nature of 
Phase 1 clinical studies. Modifications to the dose, dosing regimen, and/or clinical or 
laboratory procedures currently outlined may be required to achieve the scientific goals of 
the study objectives and/or to ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.

Repeat of or decrease in the dose of the study intervention administered in any given 
study part and/or period

Entire period(s) may be omitted (applicable only for the highest dose level for a given 
participant)

For Part 2, decrease in the duration of study intervention administration (eg, number 
of days)

Adjustment of the dosing interval (eg, bid to qd or vice versa)

Lengthening of the washout period between doses

Addition of PK pause

Instructions to take study intervention with or without food or drink may also be 
modified based on newly available data

Modification of the PK sample processing and shipping details based on newly 
available data

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The PK sampling scheme currently outlined in the protocol may be modified during the study
based on newly available PK data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety and/or PK analyses. The total 
blood volume withdrawn from any single participant will not exceed the maximum allowable 
volume during their participation in the entire study (refer to the Central Laboratory Services 
Manual for approximate total blood volume to be drawn for each participant).
 
 
. Additional laboratory safety tests may be added to blood samples 
previously drawn to obtain additional safety information. These changes will not increase the 
number of study procedures for a given participant during their participation in the entire 
study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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9
KEY STATISTICAL CONSIDERATIONS
This section details the principal statistical analysis strategy and procedures for the study. If, 
after the study has begun, changes are made to the statistical analysis plan stated below, then 
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the Clinical Study Report.
9.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Department of the Sponsor.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
 
 
 
 
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse experiences, in addition to 
laboratory safety tests, ECGs, C-SSRS and vital signs.
 
9.3.2
Secondary Endpoints
 
9.3.3
Exploratory Endpoints
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9.4
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
9.4.1
All Participants As Treated Population
The All Participants as Treated Population consists of all participants who received at least 
one dose of treatment. This population will be used for assessments of safety and tolerability.
9.4.2
Per-Protocol (PP) Population
The Per-Protocol Population consists of the set of data generated by the subset of participants 
who comply with the protocol sufficiently to ensure that these data will be likely to exhibit 
the effects of treatment, according to the underlying scientific model. Compliance covers 
such considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data from at least one treatment will be included in the Per-Protocol dataset. This 
population will be used for the Pharmacokinetics and Pharmacodynamic analyses.
9.5
Statistical Methods
9.5.1
Statistical Methods for Safety Analyses
Incidence of AEs will be summarized. Summary statistics and plots will be generated for raw 
laboratory safety tests, ECGs, and vital signs as well as for change from baseline by 
treatment group, as deemed clinically appropriate. Depending on the safety parameter, the 
difference from baseline will either be computed on the original scale (raw change from 
baseline) or on the log scale and back-transformed for reporting (percent change from 
baseline). Responses to the C-SSRS will be listed.
QTC: counts will be provided by dose and time point for QTc values falling in the following 
ranges: ≤ 450, > 450, > 480 and > 500 msec. Counts will also be provided by dose and time 
point for QTc change from baseline values falling in the following ranges: < 30, ≥ 30 and ≥ 
60 msec. Means and 90% confidence intervals for QTc and QTc change from baseline will 
be provided for each dose by time point (Part 1).
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9.5.2
Statistical Methods for Pharmacodynamic Analyses
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5.3
Statistical Methods for Pharmacokinetic Analyses
 
 
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9.6
Interim Analyses
During the in-life portion of the trial, data will be reviewed 
 
 in an on-going basis to support decision-making. The aggregate summaries will 
be presented in an unblinded manner. No individual participant level results will be provided 
unless needed to assess patient safety. The sponsor study statistician and pharmacokineticist 
will be unblinded in order to perform the in-life analysis. There are no planned interim 
analyses to test any formal hypotheses.
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9.7
Multiplicity
 
9.8
Sample Size and Power Calculations
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and 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 and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
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healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
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 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
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.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. 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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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, frequently 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.
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 before transmission to the Sponsor.
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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.
10.1.4
Committees Structure
In this Phase 1 study, the number of events is anticipated to be low, which will diminish the 
statistical power and interpretation of the results. Therefore, a DMC will not be utilized.
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 ICMJE 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 trials Regulation 536/2014, 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, https://euclinicaltrials.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 trials 
Regulation 536/2014 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.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
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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, ICH 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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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.
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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 8 will be performed by the central laboratory.
Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response evaluation. 
If a local sample is required, it is important that the sample for central analysis is obtained at 
the same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the CRF.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is above the 
ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
(fasted)a
Calcium
Alkaline 
phosphatase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, nitrite, leukocyte esterase by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum (Screening Visit) OR urine (predose in each 
treatment period) hCG pregnancy test (as needed for POCBP)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
FSH (as needed in PONCBP only)
Breath alcohol test
Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids, and benzodiazepines) 
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
Genotyping for HLA-DQB1*06:02 allele 
All study-required laboratory assessments will be performed by a 
central laboratory
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human 
chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of 
normal; WBC=white blood cell; POCBP=participant of childbearing potential; 
PONCBP=participant of nonchildbearing potential
a For Panel B, no fasting requirement for safety laboratory blood collection on Day 4 of each 
period in Part 2.
The investigator (or medically qualified designee) 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
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
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 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 preexisting 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.
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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.
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition that 
has not worsened.
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
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 preexisting condition that has not 
worsened is not an SAE.) A preexisting 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.
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-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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.
10.3.4
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.
10.3.5
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 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.
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Assessment of intensity/toxicity
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 study intervention cause the AE?
The determination of the likelihood that the study intervention 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 study 
intervention and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the study intervention 
caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill 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 study intervention? 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 study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
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◦
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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention 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; (2) the study is a single-dose drug study; or (3) study 
intervention (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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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 study intervention or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the CRFs/worksheets by an investigator 
who is a qualified physician according to their 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
The investigator must review and provide an assessment of causality for each AE/SAE and 
document this in the medical notes.
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.
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The investigator may change their 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.
10.3.6
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 email 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.
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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: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
Premenarchal
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
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Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implanta,b
IUSa,c
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception a,b 
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception a,b
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception.      .
b
IUS is a progestin-releasing IUD.
Note:
Tubal occlusion includes tubal ligation
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: 12-Lead Electrocardiogram Evaluation Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
RHYTHM
Sinus Tachycardia
>110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
>1 beat
≥3 beats
Ventricular Premature Complex
All
≥3 beats
Ectopic Atrial Rhythm
All
All
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; or 
PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intraventricular Conduction 
Delay
QRS ≥130 ms
QRS ≥130 ms + Increase of ≥10 ms
QTc (B or F)
Male/Female
QTc ≥450ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P. Mitrale or 
P. Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus Strain 
Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Nonspecific ST-T Changes (In 
2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; 
mm=millimeter; ms=milliseconds,; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using 
Fredericia formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1.
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10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol-specified laboratory value is outside the parameter(s) outlined in the 
inclusion/exclusion criteria (including repeats if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
-
The participant may be excluded from the study.
-
The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
-
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
-
The abnormal test may be repeated (refer to items below for continuation of 
algorithm for repeated values).
◦
If the repeat test value is within the normal range, the participant may enter the 
study.
◦
If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.10 Appendix 10: General and Targeted Neurological Examinations
The General and Targeted Neurological Examination will be performed at the time points 
specified in the SoA (Section 1.3).
Note to the investigator: If at any time abnormalities are observed in the General or Targeted 
Neurological Exams, the investigator should do additional examinations as needed based on 
medical judgment.
10.10.1
The General Neurological Examination
The General Neurological Examination includes all of the modules listed below and is 
intended to be a general screening examination.
10.10.1.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention).
B. Thought Processes and Language (generally assess logic, relevance, organization, and 
coherence of participant’s use of language throughout the interview).
C. Orientation (time, place, person).
D. Attention/Concentration.
Ask the participant to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite 
months backwards or spell a 5 unique letter word (eg, “WORLD”) backwards.
Note: To avoid learning effects, switch between tests throughout the study.
E. Memory (test registration of 3 objects; then test immediate recall 5 minutes later).
Grade: NORMAL or IMPAIRED and describe abnormality (for each, A to E, above). 
Normal performance on Serial 7’s is getting to 65 with no more than 1 error.
10.10.1.2
Module 2 – Cranial Nerve Assessment
A. II – Visual Fields and acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus).
Observe for nystagmus during eye movements, increased nystagmus at the end of gaze or 
other oculomotor changes (mild nystagmus at extremes of gaze is normal). Note direction 
of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test [eg, by rubbing fingers 
on each side of participant’s head or by whispering numbers])
G. IX – Gag reflex
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H. X – Swallow
I.
XI – Shoulder shrug
J.
Tongue Protrusion (midline)
Score: left and right (except for G, H, J)
Grade: NORMAL or IMPAIRED and describe abnormality
10.10.1.3
Module 3 – Motor System
A. Muscle Tone
1. Ask the participant to relax.
Flex and extend the participant’s elbows and knees (bilaterally).
There is a small, continuous resistance to passive movement.
Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score: left and right
Grade: NORMAL, INCREASED or DECREASED
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
Test proximal limb strength by having the participant flex and extend the knees and 
elbows against your resistance.
Test bilaterally and compare one side to the other.
Score: left and right
Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
Test distal limb strength by having the participant conduct dorsiflexion and plantar 
flexion of the participant’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally, and compare one side to the other.
Score: left and right
Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
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C. Pronator Drift
Ask the participant to hold both arms straight forward with, palms up and eyes closed for 
≈10 to 15 seconds as tolerated; watch for how well the arm position is maintained.
Instruct the participant to keep both arms still while you tap them briskly downward. The 
participant should normally be able to maintain extension and supination. Inability to 
maintain extension and supination (and drift into pronation) indicates an upper motor 
neuron deficit.
Score: left and right
Grade: NORMAL or IMPAIRED and describe abnormality
10.10.1.4
Module 4 – Reflexes
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at investigator's discretion (eg, elbow, 
wrist, or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED, or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
10.10.1.5
Module 5 – Coordination and Gait
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the participant to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the participant will be 
asked to strike their hand on the thigh, raise the hand, turn it over and then strike the 
back of the hand down on the same place. (This test is impaired in cerebellar disease, 
extra pyramidal disease and upper motor neuron weakness.)
B. Point-to-Point Movements
1. Ask the participant to touch your index finger and their nose alternately several times. 
Move your finger about as the volunteer performs this task.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the point-to-point testing is disturbed, the participant will be asked to 
place one heel on the opposite knee and then run it down the shin to the big toe. 
Repeat this for both sides. (Impaired tests indicate cerebellar disease.)
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C. Romberg
1. Ask the participant to stand with both feet together and eyes closed for 20 to 30 
seconds without support.
Be prepared to catch the participant if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the participant to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.10.1.6
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
D. Vibration: tuning fork vibration detection in hands, feet bilaterally.
E. Position sense: perception of thumb and toe movement, bilaterally.
F. Stereognosis: (identify common objects placed in hand, [eg, coin, key, etc]).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
10.10.2
The Targeted Neurological Examination
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
10.10.2.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention)
10.10.2.2
Module 2 – Cranial Nerve Assessment
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
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10.10.2.3
Module 3 – Motor System
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL or IMPAIRED and describe abnormality
10.10.2.4
Module 5 – Coordination and Gait
D. Gait
1. Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.10.2.5
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
10.11 Appendix 11: List of Caffeine Products and Caffeine Content
This list is not inclusive; many products contain caffeine, including over-the-counter 
medications, weight loss products, mineral and herbal supplements, etc. Please check the 
labels of any concomitant therapies and/or supplements for caffeine content.
Product
Serving Size
(in fluid ounces [oz] and milliliters 
[mL])
Caffeine 
(mg)
Coffee
Brewed
8 oz. (237 mL)
95-200 mg
Brewed, decaffeinated
8 oz. (237 mL)
2-12 mg
Brewed, single-serve varieties
8 oz. (237 mL)
75-150 mg
Brewed, single-serve 
varieties, decaffeinated
8 oz. (237 mL)
2-4 mg
Espresso, restaurant-style
1 oz. (30 mL)
47-75 mg
Espresso, restaurant-style, 
decaffeinated
1 oz. (30 mL)
0-15 mg
Instant
8 oz. (237 mL)
27-173 mg
Instant, decaffeinated
8 oz. (237 mL)
2-12 mg
Specialty drink (latte or 
mocha)
8 oz. (237 mL)
63-175 mg
Tea
Brewed tea
Black tea
8 oz. (237 mL)
14-70 mg
Black tea, decaffeinated
8 oz. (237 mL)
0-12 mg
Green tea
8 oz. (237 mL)
24-45 mg
Iced tea
Instant, prepared with water
8 oz. (237 mL)
11-47 mg
Ready-to-drink, bottled
8 oz. (237 mL)
5-40 mg
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Product
Serving Size
(in fluid ounces [oz] and milliliters 
[mL])
Caffeine 
(mg)
Soft Drinks
A&W Root Beer
12 oz. (355 mL)
0 mg
Barq's Root Beer
12 oz. (355 mL)
16-18 mg
Coca-Cola
12 oz. (355 mL)
23-35 mg
Diet Coke
12 oz. (355 mL)
23-47 mg
Diet Pepsi
12 oz. (355 mL)
27-37 mg
Dr. Pepper, regular and diet
12 oz. (355 mL)
36-42 mg
Mountain Dew, regular and 
diet
12 oz. (355 mL)
42-55 mg
Mug Root Beer, regular and 
diet
12 oz. (355 mL)
0 mg
7UP
12 oz. (355 mL)
0 mg
Pepsi
12 oz. (355 mL)
32-39 mg
Sierra Mist, regular and diet
12 oz. (355 mL)
0 mg
Sprite, regular and diet
12 oz. (355 mL)
0 mg
Energy Drinks
Amp, regular or sugar-free
8 oz. (237 mL)
71-74 mg
5-Hour Energy shot
2 oz. (60 mL)
200-207 mg
Full Throttle, regular or 
sugar-free
8 oz. (237 mL)
70-100 mg
Red Bull, regular or sugar-
free
8.4 oz. (248mL)
75-80 mg
Rockstar, regular or sugar-
free
8 oz. (237 mL)
79-80 mg
Other Products
Chocolate chips, semisweet
1 cup (168 grams)
104 mg
Dark chocolate-coated coffee 
beans
28 pieces
336 mg
Energy mints
2 mints
95-200 mg
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24h
area under the curve from time 0 to 24 hours
AUC0-inf
area under the curve from time 0 to infinity
BDS
blood drug screen
BICR
blinded independent central review
bid
twice daily
BLA
Biologics License Application
BLOQ
below limits of quantification
BMI
body mass index
BP
blood pressure
BT
body temperature
C2h
concentration at 2 hours
C6h
concentration at 6 hours
C8h
concentration at 8 hours
C18h
concentration at 18 hours
C21h
Concentration at 21 hours
C24h
concentration at 24 hours
CAC
Clinical Adjudication Committee
CCU
Cardiac care unit
CG
Cockcroft-Gault
CI
confidence interval
CL/F
oral clearance
Cmax
maximum plasma concentration
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Abbreviation
Expanded Term
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
CNS
central nervous system
COVID-19
coronavirus disease of 2019
CRF
Case Report Form
CRU
clinical research unit
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTA
Clinical Trial Application
CTFG
Clinical Trial Facilitation Group
CTMS
Clinical Trial Management System
CV
cardiovascular
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection
EDS
excessive daytime sleepiness
EEG
electroencephalogram
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EMG
electromyogram
EOC
Executive Oversight Committee
EOG
Electro-oculogram
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPCR
G protein-coupled receptor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HLA-DQB1
human leukocyte antigen DQ Beta 1
HR
heart rate
HRT
hormone replacement therapy
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
IC20
20% inhibitory concentration
IC50
half-maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
ID
identification
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Abbreviation
Expanded Term
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
JRCT
Japan Registry of Clinical Trials
KSS
Karolinska Sleepiness Scale
LAM
lactational amenorrhea method
LFT
liver function test
LSEQ
Leeds Sleep Evaluation Questionnaire
MAD
maximum administered dose
MWT
Maintenance of wakefulness test
N1
sleep stage 1
N2
sleep stage 2
N3
sleep stage 3
NCS
not clinically significant
NDA
New Drug Application
NE
neurological examination
NOAEL
no observed adverse effect level
NR
normal range
NT1
narcolepsy type 1
OR
objective response
OX1R
orexin 1 receptor
OX2R
orexin 2 receptor
PBO
placebo
PCL
Protocol Clarification Letter
PD
pharmacodynamic(s)
PE
physical examination
pEFD
preliminary embryo-fetal developmental
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Abbreviation
Expanded Term
PK
pharmacokinetic
PN
protocol number
po
orally
POCBP
participant of childbearing potential
PONCBP
participant of nonchildbearing potential
PP
per-protocol
PR
pulse rate
PSG
polysomnography
q3h
every 3 hours
q6h
every 6 hours
q8h
every 8 hours
REM
rapid eye movement
RNA
ribonucleic acid
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SR
semirecumbent
SUSAR
suspected unexpected serious adverse reaction
Tmax
time to maximum plasma concentration
t1/2
half life
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Abbreviation
Expanded Term
UDS
urine drug screen
ULN
upper limit of normal
US
United States (of America)
UTN
Universal Trial Number
Vd
volume of distribution
VS
vital signs
Vz/F
apparent volume of distribution
WBC
white blood cell
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11
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