A Multiple Dose Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-8189 in Participants With Bipolar I Disorder
Phase: PHASE1
Conditions: Bipolar I Disorder
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:           17-May-2024
NCT06273774
A Multiple Dose Clinical Study to Evaluate the 
Safety, Tolerability and Pharmacokinetics of 
MK-8189 in Participants with Bipolar I Disorder

PRODUCT: MK-8189
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PROTOCOL/AMENDMENT NO.: 020-02
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17-MAY-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 Multiple Dose Clinical Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of MK-8189 in Participants with Bipolar I Disorder
Protocol Number: 020-02
Compound Number: MK-8189
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):
IND
171279
Approval Date: 17 May 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 2
17-MAY-2024
This amendment allows for the evaluation of
more conservative dose regimens (Dose 
Regimens 2 and 3) even if Dose Regimen 1 is
generally well tolerated.
Amendment 1
29-FEB-2024
This amendment was primarily created to 
include assessments to monitor treatment-
emergent mania and depression and to add 
participant-level and study-level stopping rules.
Original Protocol
12-JAN-2024
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
This amendment allows for the evaluation of more conservative dose regimens (Dose 
Regimen 2 and Dose Regimen 3) even if Dose Regimen 1 is generally well tolerated.
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 4.1
Overall Design
The overall design allows for the 
evaluation of more conservative 
Dose Regimens, even if the more 
rapid titration or no titration is 
generally well tolerated.
To further inform optimal dose 
selection for Phase 3 trials.
Additional Changes
Section 1.1 
Synopsis
Increase sample size from 32 to 48
Allow for the enrollment of more 
conservative Dose Regimens to further 
inform on dose selection for Phase 3
Section 4.2 
Scientific Rationale for 
Study Design
Updated to include optimizing 
tolerability to explore a regimen 
with a titration. 
To further inform optimal dose 
selection for Phase 3
Section 8.10.6
Study 
Design/Dosing/Procedures 
Modifications Permitted 
Within Protocol 
Parameters
Allow for a panel to be repeated at 
the same Dose Regimen and allow 
for a more conservative non-
protocol-specified Dose Regimen to 
be evaluated.
Allow for the evaluation of additional 
more conservative Dose Regimens to 
further inform on dose selection for 
Phase 3.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.2.3
Ongoing Clinical Studies.............................................................................24
2.3
Benefit/Risk Assessment......................................................................................29
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................30
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................33
4.2.1
Rationale for Endpoints ...............................................................................33
4.2.1.1
Efficacy Endpoints.............................................................................33
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Pharmacokinetic Endpoints ...............................................................34
4.2.1.4
Pharmacodynamic Endpoints.............................................................34
4.2.1.5
Planned Exploratory Biomarker Research.........................................34
4.2.1.5.1
Planned Genetic Analysis ........................................................34
4.2.1.6
Future Biomedical Research..............................................................35
4.2.2
Rationale for the Use of Placebo .................................................................35
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................35
4.3
Justification for Dose...........................................................................................35
4.3.1
Starting Dose for This Study........................................................................35
4.3.2
Maximum Dose Exposure for This Study ...................................................36
4.4
Beginning and End-of-Study Definition ............................................................38
4.4.1
Clinical Criteria for Early Study Termination .............................................38
5
STUDY POPULATION ................................................................................................39
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................41
5.3
Lifestyle Considerations......................................................................................43
5.3.1
Meals and Dietary Restrictions....................................................................43
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5.3.1.1
Diet Restrictions.................................................................................43
5.3.1.2
Fruit Juice Restrictions ......................................................................43
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................44
5.3.2.1
Caffeine Restrictions..........................................................................44
5.3.2.2
Alcohol Restrictions...........................................................................44
5.3.2.3
Tobacco Restrictions..........................................................................44
5.3.3
Activity Restrictions ....................................................................................44
5.4
Screen Failures.....................................................................................................44
5.5
Participant Replacement Strategy......................................................................45
6
STUDY INTERVENTION............................................................................................46
6.1
Study Intervention(s) Administered...................................................................46
6.2
Preparation/Handling/Storage/Accountability .................................................48
6.2.1
Dose Preparation..........................................................................................48
6.2.2
Handling, Storage, and Accountability........................................................48
6.3
Measures to Minimize Bias: Randomization and Blinding..............................49
6.3.1
Intervention Assignment..............................................................................49
6.3.2
Stratification.................................................................................................49
6.3.3
Blinding........................................................................................................49
6.4
Study Intervention Compliance..........................................................................49
6.5
Concomitant Therapy..........................................................................................50
6.5.1
Rescue Medications and Supportive Care ...................................................51
6.6
Dose Modification (Dose Regimen Decisions) ...................................................51
6.6.1
Stopping Rules.............................................................................................52
6.6.1.1
Study Stopping Rules.........................................................................52
6.6.1.2
Individual Stopping Rules..................................................................52
6.7
Intervention After the End of the Study............................................................52
6.8
Clinical Supplies Disclosure................................................................................52
6.9
Standard Policies..................................................................................................53
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................54
7.1
Discontinuation of Study Intervention...............................................................54
7.2
Participant Withdrawal From the Study...........................................................55
7.3
Lost to Follow-up .................................................................................................55
8
STUDY ASSESSMENTS AND PROCEDURES........................................................56
8.1
Administrative and General Procedures ...........................................................56
8.1.1
Informed Consent.........................................................................................56
8.1.1.1
General Informed Consent.................................................................57
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................57
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8.1.2
Inclusion/Exclusion Criteria ........................................................................57
8.1.3
Participant Identification Card.....................................................................57
8.1.4
Medical History ...........................................................................................58
8.1.5
Prior and Concomitant Medications Review...............................................58
8.1.5.1
Prior Medications...............................................................................58
8.1.5.2
Concomitant Medications..................................................................58
8.1.6
Assignment of Screening Number...............................................................58
8.1.7
Assignment of Randomization Number.......................................................59
8.1.8
Study Intervention Administration ..............................................................59
8.1.8.1
Timing of Dose Administration.........................................................59
8.1.9
Discontinuation and Withdrawal .................................................................59
8.1.9.1
Withdrawal From Future Biomedical Research ................................59
8.1.10
Participant Blinding/Unblinding..................................................................60
8.1.11
Domiciling ...................................................................................................60
8.1.12
Calibration of Equipment.............................................................................61
8.2
Efficacy/Immunogenicity Assessments ..............................................................61
8.3
Safety Assessments...............................................................................................61
8.3.1
Physical Examinations.................................................................................61
8.3.2
Vital Signs....................................................................................................61
8.3.2.1
Resting Vital Signs ............................................................................62
8.3.2.2
Orthostatic Vital Signs.......................................................................62
8.3.3
Electrocardiograms ......................................................................................62
8.3.4
Clinical Safety Laboratory Assessments .....................................................64
8.3.5
Pregnancy Testing........................................................................................64
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................64
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................64
8.3.7
Rater Expectations and Training for Clinical Assessments.........................65
8.3.8
Monitoring of Extrapyramidal Symptoms...................................................65
8.3.9
Assessment of Neurological and Psychiatric Effects...................................65
8.3.10
Photograph of Rash......................................................................................66
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................66
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................66
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......68
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...69
8.4.4
Regulatory Reporting Requirements for SAE .............................................69
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................69
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................70
8.4.7
Events of Clinical Interest............................................................................70
8.5
Treatment of Overdose........................................................................................71
8.6
Pharmacokinetics.................................................................................................71
8.6.1
Blood Collection for Plasma MK-8189 .......................................................71
8.7
Pharmacodynamics..............................................................................................71
8.8
Biomarkers ...........................................................................................................71
8.8.1
Planned Genetic Analysis Sample Collection..............................................71
8.9
Future Biomedical Research Sample Collection...............................................72
8.10
Visit Requirements...............................................................................................72
8.10.1
Screening......................................................................................................72
8.10.2
Treatment Period Visit.................................................................................72
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................73
8.10.4
Poststudy......................................................................................................73
8.10.5
Procedures Based on Study Objectives: Timing of Procedure ....................73
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................74
9
KEY STATISTICAL CONSIDERATIONS ...............................................................76
9.1
Responsibility for Analyses.................................................................................76
9.2
Hypotheses/Estimation ........................................................................................76
9.3
Analysis Endpoints...............................................................................................76
9.3.1
Primary Endpoints .......................................................................................76
9.3.2
Exploratory Endpoints .................................................................................76
9.4
Analysis Populations............................................................................................76
9.4.1
All Participants As Treated Population........................................................76
9.4.2
Per-Protocol (PP) Population.......................................................................76
9.5
Statistical Methods...............................................................................................77
9.5.1
Statistical Methods for Pharmacokinetic Analyses......................................77
9.5.2
Statistical Methods for Safety Analyses ......................................................78
9.6
Interim Analyses ..................................................................................................78
9.7
Multiplicity ...........................................................................................................78
9.8
Sample Size and Power Calculations .................................................................79
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................80
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........80
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................80
10.1.2
Financial Disclosure.....................................................................................83
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10.1.3
Data Protection.............................................................................................84
10.1.3.1
Confidentiality of Data ......................................................................86
10.1.3.2
Confidentiality of Participant Records...............................................86
10.1.3.3
Confidentiality of IRB/IEC Information............................................86
10.1.4
Publication Policy........................................................................................86
10.1.5
Compliance with Study Registration and Results Posting Requirements ...87
10.1.6
Compliance with Law, Audit, and Debarment ............................................87
10.1.7
Data Quality Assurance ...............................................................................88
10.1.8
Source Documents .......................................................................................89
10.1.9
Study and Site Closure.................................................................................89
10.2
Appendix 2: Clinical Laboratory Tests..............................................................90
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................91
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................91
10.3.2
Definition of AE ..........................................................................................91
10.3.3
Definition of SAE ........................................................................................92
10.3.4
Additional Events Reported.........................................................................93
10.3.5
Recording AE and SAE ...............................................................................94
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................97
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................98
10.5
Appendix 5: Contraceptive Guidance................................................................99
10.5.1
Definitions....................................................................................................99
10.5.2
Contraceptive Requirements......................................................................100
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................101
10.7
Appendix 7: Country-specific Requirements..................................................105
10.8
Appendix 8: Blood Volume Tables...................................................................106
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................107
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...109
10.11 Appendix 11: General and Targeted Neurological Examinations ................110
10.11.1
The General Neurological Examination ....................................................110
10.11.1.1
Module 1 – Mental Status Examination...........................................110
10.11.1.2
Module 2 – Cranial Nerve Assessment............................................110
10.11.1.3
Module 3 – Motor System ...............................................................111
10.11.1.4
Module 4 – Reflexes ........................................................................112
10.11.1.5
Module 5 – Coordination and Gait ..................................................113
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10.11.1.6
Module 6 – Sensory .........................................................................114
10.11.2
The Targeted Neurological Examination...................................................114
10.11.2.1
Module 1 – Mental Status Examination...........................................114
10.11.2.2
Module 2 – Cranial Nerve Assessment............................................114
10.11.2.3
Module 3 – Motor System ...............................................................114
10.11.2.4
Module 5 – Coordination and Gait ..................................................115
10.11.2.5
Module 6 – Sensory .........................................................................115
10.12 Appendix 12: Abbreviations .............................................................................116
11
REFERENCES.............................................................................................................120
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................47
Table 2
Allocation of Participants to Treatment...........................................................49
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................67
Table 4
Pharmacokinetic (Blood) Collection Windows ...............................................73
Table 5
Protocol-required Safety Laboratory Assessments..........................................90
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................15
Figure 2
Study Design Diagram.....................................................................................32
 
CCI
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multiple Dose Clinical Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of MK-8189 in Participants with Bipolar I Disorder
Short Title: MK-8189 Study in Bipolar I Participants
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in male and female participants with bipolar I 
disorder:
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
multiple doses of MK-8189 in participants 
with bipolar I disorder, manic or mixed 
features
Adverse events
Adverse experiences leading to 
discontinuation of study intervention
Secondary Objectives
Secondary Endpoints
Not applicable
Not applicable
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Bipolar disorder
Population
Participants with Bipolar I Disorder
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5.5 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:
Up to approximately 48 adult participants with bipolar I disorder will be randomized such 
that 16 evaluable participants, in one dose regimen, complete the study as described in 
Section 9.
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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-8189
4 mg
12 mg
All dose 
levels
Oral
Dose 
Regimens 1, 2
and 3
Test Product
Placebo
Placebo
0 mg
All dose 
levels
Oral
Dose 
Regimens 1, 2 
and 3
Placebo
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
for approximately 10 weeks from the time 
the participant provides documented 
informed consent through the final contact. 
After a screening phase of up to 42 days
each participant will receive assigned 
intervention for approximately 14 days. 
After the end of treatment each participant 
will be followed for 14 days.
Study Governance Committees:
Executive Oversight Committee
No
External Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
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Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 12.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
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1.3
Schedule of Activities
Panels A, B, C
Study Period:
Screening/
Rescreeni
nga
Washout Interventi
on
Poststudy Notes
Scheduled Day
Up to -42
-5 to -1
Day 1 
Predose
1
2
3
4 5, 6
7
8
9 10
11 12 13 14
15, 16 17 +14 post 
last dose
Administrative/Study Procedures
Informed 
Consent
X
Sections 8.1.1.1
Informed 
Consent for FBR
X
Sections 8.1.1.2
Participant ID 
Card
X
X
Section 8.1.3
Inclusion/
Exclusion 
Criteria
X
X
Sections 5.1, 5.2
Based on IC/EC, only 
specific criteria will be 
reviewed prior to 
randomization.
Medical History
(includes 
psychiatric 
history and 
substance usage)
X
Substances: Drugs, alcohol, 
tobacco, and caffeine
Prior/
Concomitant 
Medication 
Review
X
------------
-----------
-
-
-
-
--
-
-
-
-
-
-
-
-
----
-
X
Sections 5.2, 6.5, 8.1.5
Washout from 
current 
antipsychotic 
therapy
X
Section 8.1.5.1
Assignment of 
Randomization 
Number
X
Section 8.1.7
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Panels A, B, C
Study Period:
Screening/
Rescreeni
nga
Washout Interventi
on
Poststudy Notes
Scheduled Day
Up to -42
-5 to -1
Day 1 
Predose
1
2
3
4 5, 6
7
8
9 10
11 12 13 14
15, 16 17 +14 post 
last dose
MK-
8189/Placebo 
Administration
X X X
X
X
X
X X
X
X
X
X
X
Section 8.1.8
Standard Mealsb
X
X
X
Sections 5.3.1, 5.3.2.1
Domicilingc
X
--
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
Section 8.1.11
Participants will be 
domiciled minimally from 
Day -1 through Day 14 72 
hours procedures are 
complete.
Safety Procedures
Full physical 
examination
X
X
X
X
Section 8.3.1
Day 1 predose: up to 24 
hours prior to dosing
Height
X
Weight
X
X
BMI to be taken only at 
Screening
Full 
Neurological 
Exam
X
X
Section 10.11.1
Targeted 
Neurological 
Exam
X
X
X
Section 10.11.2
Resting VS
(HR, BP)
X
X
X
X
X
X
X
X
Section 8.3.2
HR and BP will be taken in 
triplicate. 
Intervention days: predose.
Day 17: approximately the 
same time as Day 14 
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Panels A, B, C
Study Period:
Screening/
Rescreeni
nga
Washout Interventi
on
Poststudy Notes
Scheduled Day
Up to -42
-5 to -1
Day 1 
Predose
1
2
3
4 5, 6
7
8
9 10
11 12 13 14
15, 16 17 +14 post 
last dose
Orthostatic VS 
X
X
X
X
X
X
X
X
Section 8.3.2
Intervention days: predose.
Day 17: approximately the 
same time as Day 14  
Resting VS
(RR, T)
X
X
X
X
X
X
Section 8.3.2
Intervention days: predose
Day 17: approximately the 
same time as Day 14  
12-lead ECG 
X
X
X
X
X
X
X
X
Section 8.3.3
ECGs will be taken in 
triplicate.
Intervention days: predose.
Day 17: approximately the 
same time as Day 14 
Serum hCG 
(POCBP only)
X
X
Sections 5.1, 8.3.5, 10.2, 
10.5.
Urine or Serum 
hCG Pregnancy 
Testd
(POCBP only)
X
Sections 5.1, 8.3.5, 10.2, 10.5
Day 1 predose: up to 24h
(urine) or 72h (serum) prior 
to dosing.
Serum FSH
(PONCBP only)
X
Sections 10.2, 10.5
HIV, hepatitis B 
and C screen
(per site SOP)
X
Section 10.2
Drug screen
(per site SOP)
X
X
Day 1 predose: up to 72h 
prior to dose. 
Additional drug screens are 
conducted per site SOP.
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Panels A, B, C
Study Period:
Screening/
Rescreeni
nga
Washout Interventi
on
Poststudy Notes
Scheduled Day
Up to -42
-5 to -1
Day 1 
Predose
1
2
3
4 5, 6
7
8
9 10
11 12 13 14
15, 16 17 +14 post 
last dose
Laboratory 
Safety
(Hematology, 
Chemistry and 
Urinalysis)
X
X
X
X
X
X
Sections 8.3.4, 10.2
Day 1 predose: up to 72h
prior to dose
AE/SAE review
X
------------ ------------ -
-
-
-
--
-
-
-
-
-
-
-
-
------
-
X
C-SSRS 
Baseline
X
Section 8.3.6.1
C-SSRS Since 
Last Assessment 
X
X
X
X
X
X
X
Section 8.3.6.1
Day 1 predose: up to 24h 
prior to dose 
Intervention days: predose
Day 17: approximately the 
same time as Day 14
EPS Scales
(BARS, AIMS, 
SAS)
X
X
X
Section 8.3.8
Day 1 predose: up to 24h 
prior to dose 
Intervention days: within 3
hours after dose.
CGI-BP-S
X
X
X
X
Section 8.3.9
Day 1 predose: up to 24h 
prior to dose 
Day 7, 14: predose
YMRSe
X
X
X
X
Section 8.3.9
Day 1 predose: up to 24h
prior to dose
Day 7, 14: predose
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Panels A, B, C
Study Period:
Screening/
Rescreeni
nga
Washout Interventi
on
Poststudy Notes
Scheduled Day
Up to -42
-5 to -1
Day 1 
Predose
1
2
3
4 5, 6
7
8
9 10
11 12 13 14
15, 16 17 +14 post 
last dose
HAM-D17e
X
X
X
X
Section 8.3.9
Day 1 predose: up to 24h
prior to dose
Day 7, 14: predose
Pharmacokinetics
Blood for 
Plasma 
MK-8189 and/or 
Metabolites 
Assayf
X X 
X X
X
X
X
Section 8.6
Biomarkers
Blood for 
Genetic Analysis 
X
Section 8.8
The PGA sample should be 
obtained predose on Day 1 
but may be collected at the 
next scheduled blood draw, if 
needed.
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AE=adverse event; AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-BP-S: Clinical Global Impressions-Bipolar Version-
Severity of Illness; C-SSRS=Columbia-Suicide Severity Rating Scale; EC=exclusion criteria; ECG=electrocardiogram; EPS = Extrapyramidal Symptoms; FBR=future 
biomedical research; FSH=follicle-stimulating hormone; h=hour; HAM-D17=Hamilton Depression Rating Scale; hCG=human chorionic gonadotropin; IC=inclusion 
criteria; ID=identification; PGA=planned genetic analysis; POCBP=participant of childbearing potential; PONCBP=participant of nonchildbearing potential; SAS = 
Simpson-Angus Scale; SAE=serious adverse event; SOP=standard operating procedure; VS=vital signs; YMRS=Young Mania Rating Scale.
a
Rescreening is defined as a separate screening period. All activities conducted during Screening must be completed as part of Rescreening. See Section 8.10.1.
b
Meals should be given at approximately the same time on the days specified in the SoA. Breakfast will be given at ~ 1-hour postdose, lunch given at ~ 4-hours postdose, a 
snack given at ~ 8-hours postdose and dinner at ~ 12-hours postdose. All meals will follow the completion of all specified procedures at that timepoint.
c
Participants currently treated with antipsychotic therapy will be domiciled from Day -5 prior to Day 1 (to start washout period) and will remain in the CRU until 72 hours 
post the last dose on Day 14. Participants not currently being treated with antipsychotic therapy may be domiciled minimally starting on Day -1 through 72 hours post the 
last dose on Day 14. Participants may stay longer at PIs discretion.
d
In the event the urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required.
e
Additional assessment may be performed at the discretion of the investigator.
f
PK sampling timepoints are below for all Panels.
Day 1: Predose and 2, 6, 8, 10, 12, 16, 24 (Day 2) hours postdose
Day 8: Predose and 2, 6, 8, 10, 12, 16, 24 (Day 9) hours postdose
Day 14: Predose and 8, 12, 24 (Day 15), 36 (Day15), 48 (Day 16), 72 (Day 17) hours postdose
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2
INTRODUCTION
2.1
Study Rationale
MK-8189 is currently being evaluated in a Phase 2b study for the treatment of adults with 
Schizophrenia.  A signal for efficacy was previously observed in a Phase 2 POC study (P005) 
where participants were titrated from 4 mg QD of MK-8189 to 12 mg QD of MK-8189.  The 
Phase 2b study is currently evaluating safety and efficacy of MK-8189 when participants are 
titrated from 4 mg to 16 mg or 8 mg up to 24 mg QD. As there is substantial precedent for 
therapies effective in the treatment of schizophrenia to also be effective in the treatment of 
bipolar I disorder (i.e, olanzapine, risperidone, aripiprazole, quetiapine and cariprazine), MK-
8189 will also be evaluated for the treatment of bipolar I disorder. Furthermore, the target 
dose range for these indications is usually the same for both indications and in some cases the 
starting dose may be higher for bipolar I disorder.  A previous study (P011, Part 1) 
demonstrated that initiating dosing at the highest clinical dose in adult participants with 
schizophrenia was generally well tolerated, suggesting titration is not necessary for good 
tolerability. As there is an expected benefit to reaching the target clinical dose as quickly as 
possible during a manic episode, this study will also evaluate a starting dose of 24 mg QD, 
the highest clinical dose, in participants with bipolar I disorder.  These data in conjunction 
with the Phase 2b data in schizophrenia participants will be used to support dose selection for 
Phase 3 trials.
2.2
Background
Refer to the IB for detailed background information on MK-8189.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8189 is a small molecule inhibitor of the PDE10A enzyme that is being developed for 
the treatment of schizophrenia and bipolar disorder. PDE10A is a member of the cyclic 
nucleotide phosphodiesterase family that functions to metabolically inactivate both cAMP 
and cGMP. PDE10A is highly expressed in the brain and has limited expression in peripheral 
tissues; in the brain, PDE10A is expressed at high levels in the medium spiny neurons of the 
striatum.  Functional imaging studies have revealed that bipolar disorder is associated with 
exaggerated dopamine signaling in the striatum, consistent with schizophrenia, suggesting 
that striatal dysfunction may be a common neurobiology underlying psychosis [Karcher, N. 
R., et al 2019].  Preclinical studies have generated substantial evidence to support the 
hypothesis that PDE10A inhibition is a novel therapeutic target that regulates striatal activity. 
In vitro and in vivo assays demonstrate that PDE10A inhibition activates the Dopamine D2 
receptor indirect pathway, similar to current antipsychotic medications, while also facilitating 
D1 receptor direct pathway and glutamatergic signaling in the striatum.  PDE10A-deficient 
mice show reduced exploratory behavior when placed in a novel environment and have a 
blunted response to the psychomotor activating effects of NMDA receptor antagonists, 
phencyclidine and MK-801. In addition, administration of selective PDE10A inhibitors 
decrease psychomotor activity, reverse deficits in prepulse inhibition, and inhibit conditioned 
avoidance responding in rodents, models that are predictive of antipsychotic activity in the 
clinic. PDE10A inhibitors are also efficacious in nonclinical assays that test cognitive 
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domains impaired in psychiatric disorders, models of negative symptoms and decrease body 
weight in diet-induced obese animals. As described in Section 2.1, a signal for efficacy in 
participants with schizophrenia has been observed and based on precedent with many other 
antipsychotics, it is expected that efficacy would also be expected in participants with bipolar 
I disorder.
Bipolar disorder is a chronic lifetime condition affecting 1-4% of the population globally.  
Bipolar I Disorder is characterized by the occurrence of at least one manic or mixed episode, 
interspersed with periods of full or partial remission. Second-generation anti-psychotics are 
indicated to treat acute manic or mixed features. Atypical antipsychotic monotherapy 
currently available are associated with tolerability issues e.g., weight gain, metabolic issues, 
EPS, sedation, and hyperprolactinemia that can lead to reduced treatment adherence or 
discontinuation of therapy. A recent meta-analysis estimated typical weight gain of 3.8 kg in 
drug-naïve patients after starting antipsychotic treatment in the first 3 months of treatment. 
Obese bipolar patients have a 10-year shorter life span due to the higher CVD risk and 
vascular age. As a result, there is still a significant unmet need in this patient population.
2.2.2
Preclinical and Clinical Studies
The nonclinical safety profile of MK-8189 was determined in a series of safety 
pharmacology studies, genetic toxicology studies, oral repeat-dose toxicity/tolerability 
studies in rats and rhesus non-human primates (NHPs), reproductive and developmental 
toxicity studies in rats and rabbits, and repeat-dose tolerability studies in wild-type TgRasH2 
mice. The pivotal nonclinical safety assessment studies, conducted in compliance with Good 
Laboratory Practice (GLP), support the use of MK-8189 in patients of ≥ 13 years old.
Preclinical and clinical study information can be found in the MK-8189 IB.
Four single-dose clinical studies (P001, P002, P004, P010) in healthy participants, a single 
dose study in healthy participants and participants with moderate hepatic impairment (P012), 
2 CYP3A DDI studies in healthy participants (P006, P015), and 4 multiple-dose clinical 
studies in healthy participants and participants with schizophrenia (P003, P007, P011, P016) 
have been completed with MK-8189.  One multiple-dose study in participants with 
Alzheimer’s disease has also been completed (P017).  Protocol 011 included elderly (>60 
years of age, n=12) participants with schizophrenia and healthy elderly (> 60 years of age, 
n=18) participants. Protocol 017 included 29 elderly participants (≥65 years of age) with 
Alzheimer’s disease. Please see IB for a summary of completed studies and Section 2.2.3 for 
a summary of ongoing studies.
Overall, across the completed studies, 259 participants have received at least one dose of 
MK-8189; 130 participants without schizophrenia, 107 participants with schizophrenia and 
22 participants with Alzheimer’s Disease.
Across completed and ongoing studies, MK-8189 was generally well tolerated up to 24 mg in 
healthy participants and up to 80 mg in participants with schizophrenia.  The most common 
treatment-related AEs (≥5%) following treatment of MK-8189 (n=259) across the 12 
completed Phase 1 studies which included, healthy participants (non-elderly and elderly), 
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participants with schizophrenia (non-elderly and elderly), elderly participants with 
Alzheimer’s disease and participants with hepatic impairment, were headache (11.6% vs 
Placebo 8.9%) somnolence (13.4%vs Placebo 12.7%), dystonia (6.6% vs Placebo 1.8%), 
decreased appetite (8.9% vs Placebo 7.1%), nausea (8.1% vs Placebo 7.1%), fatigue (5.8% vs 
Placebo 0%), dizziness (6.6% vs Placebo 5.4%), vomiting (5.4%vs Placebo 0% ), diarrhea 
(5.4% vs Placebo 1.8%), akathisia (6.9% vs Placebo 3.6%) and insomnia (5.8%vs Placebo 
1.8%).  Most AEs were mild to moderate in severity. There were no deaths and one 
treatment- related SAE across the Phase 1 studies; In P007, one participant discontinued due 
to a treatment-related SAE of increased psychosis which resulted in hospitalization.  The 
SAE occurred following treatment with the 36 mg dose.  The AE was considered severe and 
had a duration of 6 days. The SAE resolved following initiation of an antipsychotic and 
benzodiazepine.
Participants with schizophrenia (n=107) were only evaluated in multiple-dose studies.  The 
most commonly (≥ 5%) reported treatment-related AEs in participants with schizophrenia 
administered MK-8189 as monotherapy (n=75) or adjunct therapy (n= 32) were headache 
(16.8%), somnolence (15.0%), decreased appetite (12.1%), nausea (9.3%), dystonia (8.4%), 
akathisia (7.5%), dizziness (6.5%), vomiting (6.5%) and constipation (5.6%).  In comparison, 
the most commonly reported AEs in participants administered placebo (n=37) were 
somnolence (13.5%), headache (10.8%), anxiety (5.4%), decreased appetite (5.4%), dizziness 
(5.4%), nausea (5.4%) and rash (5.4%). There is no clear trend for a relationship between 
MK-8189 dose and specific AEs.
Of the 107 participants with schizophrenia that received MK-8189, 32 participants were 
administered MK-8189 in addition to their standard of care.  The MK-8189 dose was titrated 
from 2 mg to a maximum dose of MK-8189 24 mg.  The most common treatment-related 
AEs (reported by 2 or more participants) were headache (21.9%), decreased appetite 
(18.8%), somnolence (12.5%), vomiting (12.5%), akathisia (9.4%), diarrhea (9.4%), nausea 
(9.4%), tremor (9.4%), anxiety (6.3%), insomnia (6.3%), upper abdominal pain (6.3%), 
constipation (6.3%), dystonia (6.3%) and orthostatic hypotension (6.3%).  The common 
treatment-related AEs in the placebo group (n=10) were headache (20.0%) and somnolence 
(20.0%).
2.2.3
Ongoing Clinical Studies
Protocol 013
P013 was a multiple-dose clinical study to evaluate the safety, tolerability, and 
pharmacokinetics of MK-8189 in healthy Chinese participants. This study enrolled 
16 healthy Chinese male and female participants and were randomized to receive MK-8189 8 
mg or placebo (Days 1 to 3), MK-8189 12 mg or placebo (Days 4 to 6), MK-8189 16 mg or 
placebo (Days 7 to 9) and MK-8189 24 mg or placebo (Days 10 to 12). MK-8189 oral 
administration of titrated doses up to 24 mg was generally tolerated in healthy Chinese 
participants. No reports of serious adverse events (SAEs) or deaths were identified. All 
12 participants treated with MK-8189 reported 1 or more AEs and the investigator found at 
least 1 event related. These events were generally mild to moderate in severity and recovered 
without concomitant medication. All 12 participants had 1 or more AE considered related to 
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MK-8189 by the investigator. The most frequently reported (> n=1) treatment related AEs 
after MK-8189 were somnolence (n=10, 83.3%), insomnia (n=9, 75.0%), decreased appetite 
(n=5, 41.7%), nausea (n=4, 33.3%), dystonia (n=4, 33.3%), tremor (n=3, 25.0%), anxiety 
(n=3, 25%), blood bilirubin increased (n=2, 16.7%), akathisia (n=2, 16.7%), headache (n=2, 
16.7%) and hyperhidrosis (n=2, 16.7%). Of the 2 participants who discontinued the study, 1 
participant discontinued due to a treatment related AE of moderate delusions 
 
 after MK-8189 8 mg. Another participant discontinued due to other reason (no 
longer wanted to take the study drug) and is described below.
Five participants reported dystonia (n=4 after MK-8189 and n=1 after placebo), an ECI: 
• One participant experienced dystonia (mild, related) after MK-8189 8 mg. 
 
 
 
 
 
• One participant experienced occlusal muscle dystonia (mild) after placebo.
 
 
 
• One participant experienced dystonia (mild, related) after the last dose of MK-8189 16 mg. 
 
 
• One participant experienced dystonia (mild, related) and akathisia (mild, related) after 
MK-8189 8 mg.
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
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• One participant experienced dystonia (mild, related) after MK-8189 8 mg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• One participant reported suicidal ideation (mild) after MK-8189 24 mg. 
 
 
 
 
 
The investigator considered the suicidal 
ideation related to study intervention as the participant had not reported previous suicidal 
thoughts. There were no clinically meaningful trends for study-intervention related changes 
in the vital sign measurements, physical examination assessments, or other observations 
related to safety in this study.
Protocol 014
Preliminary unblinded safety data are available from P014, a randomized, placebo-
controlled, parallel-group, multisite, double-blind, multiple panel study of MK-8189 in 
participants with schizophrenia to support efforts to de-risk the potential for MK-8189 to 
prolong QT as required by ICH E14, Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential For Non-Antiarrhythmic Drugs -Scientific Guideline. The study 
is clinically complete. Panel A enrolled 11 participants who were randomized to receive MK-
8189 48 mg (Day 1), MK-8189 60 (Day 2) (n=8) or matched placebo (n=3). Panel A-1 
PPD
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enrolled 10 participants who were randomized to receive MK-8189 48 mg (Day 1), MK-8189 
80 mg (Day 2) (n=8), or placebo (n=2).  Panel C enrolled 32 participants who were 
randomized to receive MK-8189 48 mg (Days 1 to 2) MK-8189 80 mg (Day 3) (n=20) or 
placebo (n=12). Across all panels MK-8189 was generally well tolerated. No SAEs or deaths 
occurred were reported.
In Panel A, of the 11 participants included in the safety analysis, 27.3% (3/11) experienced 1 
or more AEs during the study; 37.5% (3/8) after MK-8189 and 0% (0/3) after placebo. Three 
participants reported AEs after MK-8189 48 mg and 2 after 60 mg. All AEs were of mild 
intensity and no AE was reported by more than one participant. Treatment related AEs 
following MK-8189 administration included discomfort, somnolence, tremor and 
restlessness. There were no discontinuations due to AEs.
In Panel A-1, of the 10 participants included in the safety analysis, 50.0% (5/10) experienced 
1 or more AEs during the study; 62.5% (5/8) after MK 8189 and 0% (0/2) after placebo. All 
AEs during the treatment period were of mild intensity. The most frequently (reported by >1 
participant) AE for MK 8189 was somnolence (37.5%, n=3) which was considered 
treatment-related in all participants. Other treatment-related AEs reported by one participant 
each were asthenia, feeling jittery, akathisia, and anxiety. The AE of akathisia began 
following the 80 mg dose, no treatment was provided, and the AE lasted for approximately  
weeks. There were no discontinuations due to AEs.
In Panel C, of the 32 participants included in the safety analysis, AEs were reported by 
50.0% (16/32) of participants; 50.0% (10/20) after MK 8189 and 50.0% (6/12) after placebo. 
Seven participants reported AEs for MK-8189 48 mg and 6 for 80 mg n Panel C. AEs were 
mild to moderate in intensity. The most frequently (reported by >1 participant) AEs after 
MK-8189 were headache (15.0%, n=3) and dizziness (10.0%, n=2). No AEs were reported 
by >1 participant after placebo. Treatment- related AEs were reported by 30.0% (6/20) of 
participants after MK-8189 and 25.0% (4/12) of participants after placebo. The most 
frequently (reported by >1 participant) study intervention-related AEs after MK 8189 were 
headache and dizziness (10.0%, n=2). No study intervention-related AEs were reported by >1 
participant after placebo. The other treatment-related AEs following MK-8189 (reported by 1 
participant each) included skin irritation, nausea, vomiting, fatigue, muscle twitching, 
dystonia, oromandibular dystonia, parosmia, somnolence and anxiety. Of the 32 participants 
randomized in Panel C, 30 completed dosing per protocol; one participant discontinued due 
to an AE (dystonia described below) and one participant withdrew consent.
Two participants experienced dystonia: One participant experienced moderate oromandibular 
dystonia 
 which began 4 hours following their first 48 mg dose 
of MK-8189. The participant withdrew consent due to this AE and the participant was treated 
. A second participant also experienced mild dystonia 
approximately 7 hours following their first dose of MK-8189. 
 
 
 the 
participant completed study treatment pre protocol.
P
P
D
PPD
PPD
PPD
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Protocol 019
P019 is a randomized, double-blind, active- and placebo-controlled, 3-way crossover 
evaluating the effect of a supratherapeutic dose of MK-8189 on the QTc interval study in 
participants with schizophrenia. This study is ongoing and blinded. Approximately 
45 participants have been enrolled and no deaths reported. The treatment-related AEs 
reported in more than 1 participant and available in the database are akathisia (n=3), 
dizziness (n=3), vomiting (n=3), dyskinesia (n=2), dystonia (n=2), feeling hot and cold 
(n=2), headache (n=2), nausea (n=2) and parkinsonian-like tremor (n=2). The patient 
remained blinded.
One SAE of anaphylaxis was reported which is considered related to study drug by the 
investigator. After approximately 6 hours after MK-8189 48mg or placebo, the participant
reported nausea, vomiting, dizziness, and lightheadedness. 
 
 
 
 
 
 
 
 
 The participant was discontinued from the study.
There have been 6 discontinuations due to AEs (including the participant who experienced 
the SAE). The AEs that lead to discontinuation were akathisia (n=2), dystonia, ALT/AST 
increased and dyskinesia. Overall, MK-8189 doses titrated up to 80 mg are well tolerated in 
this study.
Protocol 008
P008 is an ongoing Phase 2B randomized, double-blind, placebo- and active controlled trial 
of the efficacy and safety of MK-8189 in adult participants 18 to 55 years of age who are 
experiencing an acute episode of schizophrenia according to DSM-V™criteria. A total of 
488 participants from approximately 80 sites across the USA, Europe and Asia will be 
recruited into this trial. Recruitment was initiated in December 2020. Treatment duration will 
be for a period of 12 weeks and includes a 6-week acute treatment period followed by a 
6-week extension period. Eligible participants will be randomized to receive one of five 
treatment sequences with target doses of MK-8189 (8 mg, 16 mg, and 24 mg QD), 
risperidone (6 mg QD), or placebo. Placebo completers at 6 weeks will be allocated to 
receive MK-8189 24 mg for the remainder of the trial. The MK-8189 8 mg treatment arm is 
no longer enrolling new participants. The determination of the minimally efficacious dose is 
planned to be established without completion of the current MK-8189 8 mg treatment arm.
This trial is being conducted in a hospital/acute care setting followed by an outpatient setting.
PPD
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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.
The following objectives will be evaluated in male and female participants with bipolar I 
disorder:
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
multiple doses of MK-8189 in participants 
with bipolar I disorder, manic or mixed 
features
Adverse events
Adverse experiences leading to 
discontinuation of study intervention
Secondary Objectives
Secondary Endpoints
Not applicable
Not applicable
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the PK profile of MK-8189 in 
participants
Cmax, AUC0-24, Tmax, t1/2, C24, Vz/F, 
CL/F
To evaluate the safety and tolerability of 
multiple doses of MK-8189
VS, ECG, Laboratory safety values, 
C-SSRS, BARS, SAS, AIMS, CGI-BP-S, 
YMRS, HAM-D17
Objective: 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, double-blind, placebo-controlled, multiple dose study to evaluate the 
safety and tolerability of MK-8189 in participants with stable bipolar I disorder. The study 
will evaluate up to 3 dose regimens within 3 Panels (Panels A, B and C). The intent will be 
for ~16 participants to complete at least one of the 3 specified dose regimens.
Panel A will enroll an initial cohort of 8 participants and receive 24 mg MK-8189 QD (2 x 
12 mg tablet) for 14 days (Dose Regimen 1) or placebo (3:1). If Dose Regimen 1/placebo is 
generally well tolerated based on AE reporting, an additional 8 participants will be enrolled 
to receive Dose Regimen 1/placebo and the decision to also enroll Panel B or Panel C in 
parallel with Panel A will be determined to further explore optimal tolerability. If Dose 
Regimen 1/placebo is not considered to be generally well tolerated following the initial 8 
participants, then 8 participants will be enrolled in Panel B or Panel C.
Panel B will receive 16 mg MK-8189 (1 x 12 mg tablet and 1 x 4 mg tablet) QD Days 1 to 3 
and 24 mg MK-8189 (2 x 12 mg tablets) QD Days 4 to 14 (Dose Regimen 2) or placebo 
(3:1). If Dose Regimen 2/placebo is generally well tolerated based on AE reporting, an 
additional 8 participants will receive Dose Regimen 2/placebo in Panel B and the decision to 
also enroll Panel C in parallel with Panel B will be determined. If Dose Regimen 2/placebo is 
not well tolerated, an initial cohort of 8 participants will be enrolled in Panel C.
Panel C will receive 8 mg MK-8189 (2 x 4 mg) Day 1, 16 mg MK-8189 (1 x 12 mg tablet 
and 1 x 4 mg tablet) Day 2 and 24 mg MK-8189 (2 x 12 mg tablet) QD Days 3 to 14 (Dose 
Regimen 3) or placebo (3:1). If Dose Regimen 3/placebo is generally well tolerated based on 
AE reporting, an additional 8 participants will be enrolled in Panel C. If Dose Regimen 
3/placebo is not well tolerated, no additional participants will be enrolled in Panel C and an 
alternate more conservative regimen may be evaluated per Section 8.10.6.
In Panels A, B and C, participants randomized to placebo will receive the same number of 
tablets matching the MK-8189 tablet strengths in the active group. See Study Design 
Diagram (Figure 2) below for the dose regimen decision tree.
If applicable, participants will be washed off their current antipsychotic therapy. The washout 
may start with a down titration of the antipsychotic treatment during the screening phase per 
direction of the investigator. Participants should not receive antipsychotics for at least 5 days 
or 3 half-lives (whichever is longer) prior to Day 1. For longer half-life antipsychotics (eg, 
aripiprazole and brexpiprazole), if deemed appropriate by the investigator, a participant may 
stop treatment (ie, cessation of atypical antipsychotic therapy) as an outpatient, but should be 
confined to the clinical research unit within a week of stopping treatment and minimally 
beginning on Day -5. Antipsychotic SOC may be restarted following the assessments that 
occur 72-hours following the last dose of study drug. At the investigator’s discretion, the 
participant may be domiciled for a longer duration i.e., participants may be domiciled prior to 
Day -5 or for a longer period following end of study treatment while SOC is restarted.
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Where applicable (Dose Regimen 2 or 3), titration to the next dose level within a regimen 
will occur per the investigator’s medical discretion based on the tolerability of study 
intervention within an individual participant. If the investigator deems it necessary, dose 
titration within an individual may be paused temporarily for the duration of any tolerability 
issues (i.e, AEs) and resumed when deemed appropriate. Any changes to the dose regimen 
will not prolong an individual’s participation in the trial and therefore it is acknowledged that 
failure to adhere to the protocol-defined dose regimen may result in some participants not 
reaching the escalation targets. Participants may be down-titrated by the investigator at any 
time without consultation of the Sponsor in the case of safety or tolerability issues.
Regardless of the state of the dose escalation of each participant it is important to keep 
participants in the study as the data collected at all doses is valuable for the purposes of 
defining a clinical tolerability margin. Any changes to the protocol specified treatment 
regimen will be documented in a Protocol Clarification Letter.
Figure 2
Study Design Diagram
Following completion of 14 days of dosing in at least 6 participants, a decision to enroll an 
additional 8 participants in the current panel and enroll participants in a more conservative
dose regimen (per Figure 2) will be made jointly by the investigator(s) and Sponsor. Dose 
regimen decisions will be based on the review of adverse event data. The Dose Regimen 
selected will be documented in a Protocol Clarification Letter.
Because this is a Phase 1 assessment of MK-8189 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. 
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Refer to Section 8.10.6 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
As described in Section 2.1, MK-8189 24 mg QD without titration was well tolerated in 
participants with schizophrenia and this study will explore the tolerability of this regimen in 
participants with Bipolar I disorder. An initial cohort of 8 participants will first be evaluated, 
such that if this regimen without titration is not well tolerated or if tolerability could be 
optimized, a regimen with titration can be explored as described in Figure 2. The adaptive 
nature of the study will minimize the number of participants exposed while identifying the 
optimal regimen to evaluate in Phase 3 trial in Bipolar participants. A matched placebo-
control will be included to reduce bias with regards to the patient reporting and investigator 
assessment of AEs.
Dose regimen decisions will be based on AEs as acute tolerability (eg EPS and vomiting) is 
the concern. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Not Applicable.
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of neurological exams, physical exams, ECGs, 
VS, and laboratory safety tests. The C-SSRS will be administered to monitor mood and 
suicidal ideation and behavior in all trial participants (see Section 4.2.3.). In addition, scales 
will be included to evaluate EPS and general well-being. As EPS are associated with 
antipsychotics and have been observed in the MK-8189 clinical program, the BARS, AIMS 
and SAS will be used to quantify any EPS observed in the study. The BARS is an akathisia 
rating scale with objective and subjective measures and an overall rating from 0 to 5. A score 
of 0 presents no evidence for akathisia, a score of 3 is moderate akathisia and a score of 5 is 
severe akathisia. The AIMS evaluates 12 items and uses a 5-point scale to assess abnormal 
movement in 3 areas (orofacial, extremities, trunk). The SAS evaluates 10 items and uses a 
5-point scale to measure symptoms of parkinsonism or parkinsonian side effects (including 
rigidity, tremor, akinesia, and salivation). Participants with severe EPS symptoms will be 
discontinued if not attenuated with dose reduction, dose titration and/or medical 
management.
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The CGI-S scale is a rating system commonly used in clinical research and practice to 
evaluate the overall severity of illness and impairment in individuals with psychiatric 
conditions. The CGI-BP-S is a modified version of the CGI-S to be used specifically in 
patients with bipolar disorder. The CGI-BP-S scale consists of a range of severity ratings 
from 1 (normal, not ill) to 7 (very severely ill). The scale includes a severity assessment of 
mania, depression and overall bipolar illness.
The YMRS is an 11-item scale that assesses manic symptoms based on the patient’s clinical 
observation during the interview. The 11 items are elevated mood, increased motor activity-
energy, sexual interest, sleep, irritability, rate and amount of speech, language-thought 
disorder, content, disruptive-aggressive behavior, appearance, and insight. The severity of the 
abnormality is rated on a 5-point (0 to 4) or 9-point (0-8) scale; scoring between listed points 
is encouraged. Possible scores range from 0-60.
The Hamilton Depression Rating Scale (HAM-D) is a widely used clinical assessment tool to 
measure the severity of depression. The HAM-D17 consists of 17 items or questions that 
assess various symptoms associated with depression. These items cover a range of symptoms 
including depressed mood, guilt feelings, suicidal ideation, insomnia, agitation, and so on. 
Each item is scored based on the severity and frequency of the symptom. The scoring is 
typically done on a 3- or 5-point scale, with higher scores indicating more severe symptoms.
4.2.1.3
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189. Therefore, individual 
plasma concentration and actual sample collection times of MK-8189 will be used to derive 
the PK parameter values AUC0-24, Cmax, Tmax, C24, CL/F, Vz/F, and apparent t1/2.
4.2.1.4
Pharmacodynamic Endpoints
Not Applicable.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
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.
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.
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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.
4.2.1.6
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
As the safety and tolerability profile is under continued evaluation, a placebo-control will be 
included in this trial to ensure objective assessment of AEs.
4.2.3
Rationale 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
As this is a Phase 1 assessment of MK-8189 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 8.10.6.
4.3.1
Starting Dose for This Study
Doses of 16 mg and 24 mg dose of MK-8189 are currently being evaluated in a Phase 2B 
trial in participants with schizophrenia. In Phase 2B doses are currently titrated to the target 
dose. For the treatment of a manic episode of bipolar, it is important to reach the target 
clinical dose as soon as possible, thus, the starting dose in this trial will be 24 mg. This 
starting dose has been previously evaluated in participants with schizophrenia and found to 
be well tolerated (P011). No participants discontinued due to treatment-related AEs.  The 
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majority of AEs were mild and no AEs were severe. AEs considered related to treatment 
included somnolence (n=2), hypertonia (n=1), decreased appetite (n=1), musculoskeletal 
stiffness (n=1) and increased ALT (n=1). No AEs of akathisia or dystonia were reported.  
Furthermore, in another study (P014), participants received starting doses of 48 mg MK-8189 
and escalated to 60 mg or 80 mg MK-8189 and these doses were found to be generally well 
tolerated. Based on these data, titration does not appear to be required for good tolerability, 
however, this will be confirmed in the bipolar I population.
4.3.2
Maximum Dose Exposure for This Study
The current trial will evaluate doses up to and including 24 mg and there is significant 
clinical experience at or above this dose in the Phase 1 program and the 24 mg dose is 
currently being evaluated in the Phase 2b study. 
As described in Section 2.2.2 and 2.2.3, previous and ongoing clinical studies have 
demonstrated that MK-8189 has been generally well tolerated following 48 mg QD for
3 days in participants with schizophrenia (P007, Panel D following titration from 8 mg to 
48 mg over 12 days) and up to 80 mg in participants with schizophrenia (P014, Panel C 
following titration from 48 mg to 80 mg over 2 days). In P007, the observed steady-state 
Cmax and AUC0-24hr following the 48 mg dose on Day 15 was
*hr. 
Based on data from the chronic toxicology studies, the exposure multiple at the 48 mg dose 
for AUC0-24hr would be 
 based on the 6-month rat study and
fold based on the 
9-month monkey study. Brief summaries of the chronic toxicology studies supporting dose 
escalation are provided below: In the 6-month rat study, doses of 0, 25, 100 and 750 
mg/kg/day were evaluated. Two high-dose (750 mg/kg/day) female rats were found dead 
(Week 13 and Week 24) with acute tubular necrosis (with and without tubular 
mineralization). Therefore, the 100 mg/kg/day dose was considered the no observed adverse 
effect level (NOAEL) for this study (AUC0- 24hr = 
 
 at the 48 mg dose. In 
the 9-month monkey study, doses of 0, 30/10/3, 150 or 600/300 mg/kg/day of MK-8189 were 
administered. Renal tubular degeneration was observed in the high-dose group (600/300 
mg/kg/day). The NOAEL for target organ toxicity is 150 mg/kg/day 
 
, providing 
 over the supratherapeutic exposure of
 at the 48 mg 
dose.
The effects of MK-8189 on measures of cardiac conduction and repolarization were assessed 
in both in vitro (hERG current [Ikr] evaluation) and in vivo (anesthetized guinea pigs and 
conscious telemetered monkey models). MK-8189 inhibited hERG current with an IC50 
value of 
 providing a margin of
fold to the steady-state unbound Cmax in humans 
at 48 mg 
 In an anesthetized guinea pig study, MK-8189 had no effects on HR 
and ECG parameters. Average peak plasma concentrations of MK-8189 measured during the 
20-min infusions of 10, 30 and 60 mg/kg were 
 and 
, respectively. Thus, the 
NOEL/NOAEL in this study was
, providing an exposure margin of 
fold 
relative to the observed steady-state supratherapeutic Cmax of 
μM. In a telemetry study 
in monkeys, single oral doses of 2, 5, and 20 mg/kg were evaluated and test article-related 
dose-independent increases in HR, blood pressure (BP) and the rate-corrected QT interval 
were observed. In a second study at lower oral doses of 0.03, 0.1 and 0.3 mg/kg, there were 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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no test article-related effects. Thus, the no-observed effect level was a single-oral dose of 
0.3 mg/kg providing exposure margins of 
fold of the observed steady-state
supratherapeutic Cmax. A number of studies were conducted to determine the underlying 
cause (see MK-8189 IB for additional details). The general conclusion from these studies 
was that increases in HR, BP and QT interval likely occur due to a stress induced release of 
epinephrine subsequent to PDE10A target engagement in conscious rhesus monkeys and 
therefore, these changes in QT, HR and BP are not relevant to humans. Therefore, clinical 
and preclinical data support dose escalation to 24 mg in the current study and provide 
margins up to exposures associated with a supratherapeutic steady-state dose of 48 mg.
Furthermore, a concentration-QTc analysis was conducted in P007 and as shown in 
there is no evidence for a relationship between concentration and QTc at MK 8189 exposures 
achieved with the 48 mg dose. Though healthy participants only received doses up to 24 mg 
in P007, a concentration-QT effect would be driven by inhibition of hERG and independent 
of disease state.
CCI
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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 
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, 
pharmacodynamic, efficacy, or biologic data 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. Participants must meet diagnostic criteria for bipolar I disorder, manic or mixed features 
according to the Diagnostic and statistical manual of Mental Disorders TR (DSM-5 TR) 
and considered to be in a non-acute phase of their illness based on the following:
• Clinical interview
• No psychiatric hospitalization with the previous 90 days
• No changes in psychotropic medication within the last 60 days
• No increase in level of psychiatric care due to worsening of symptoms of bipolar I
disorder for 90 days prior to screening.
• CGI-BP-S Overall Illness Score of ≤ 3 at Screening
• YMRS ≤10
• HAM-D17 ≤10
2. Has a history of receiving and tolerating antipsychotic medication within the usual dose 
range employed for bipolar I disorder.
3. Be in good health based on medical history, physical examination, VS measurements, 
and ECGs performed before randomization. Note: The mean QTcF-duration must be 
≤450 msec. Repeat 12-lead safety ECGs may be performed in participants whose 
parameters are, per investigator discretion, minimally outside the designated range.
4. Be in good health based on laboratory safety tests obtained at the screening visit.
Appendix 2 provides a table of laboratory safety tests to be performed. Appendix 10
provides an algorithm for the assessment of out-of-range laboratory values.
5. Participants BMI is between 18 and 40 kg/m2, inclusive. See Section 8.3.1 for criteria on 
rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
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6. If currently taking an antipsychotic, participant is able to discontinue the use of all 
antipsychotic medication at least 5 days or 3 half-lives (whichever is longer) prior to 
Day 1 and the duration of the study.
7. Able to swallow tablets and comply with the dosage regimen.
8. Has a stable living situation in which the participant or a contact person can be reached 
by the investigator if there is a need for follow up.
Demographics
9. Is an individual of any sex/gender, from 18 years to 60 years of age inclusive, at the time 
of providing the informed consent.
10. 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
•
Is a POCBP and:
-
Uses an acceptable contraceptive method, 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 14 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 8.3.5.
-
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
11. The participant (or legally acceptable representative) has provided documented informed 
consent. for the study. The participant (or legally acceptable representative) may also 
provide consent for FBR. However, the participant may participate in the study without 
participating in FBR.
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Additional Categories
12. Willing to comply with the study restrictions (see Section 5.3 for a complete summary of 
study restrictions).
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. 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 2 months or suicidal behavior in the past 6 months.
2. Has any clinically significant abnormal laboratory, VS, physical examination, or 12-lead 
safety ECG findings at screening or changes from baseline that may interfere with the 
interpretation of PK or safety parameters or, in the opinion of the investigator, would 
make the participant inappropriate for entry into this study.
3. Has untreated or uncompensated endocrine, GI, cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, genitourinary, or major neurological (including stroke 
and chronic seizures) abnormalities or diseases. 
4. Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than those 
specified in Inclusion Criterion No. 1
5. 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.
6. Has evidence or history of mental retardation, borderline personality disorder, or organic 
brain syndrome.
7. Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia
8. Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse. 
9. Has a DSM-5 TR defined substance use disorder (excluding nicotine and caffeine) within 
3 months of screening.
10. Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures.
11. 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.
12. 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.
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13. 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.
14. Does not tolerate venipuncture or have difficulty for collecting blood samples.
15. Inability to tolerate oral medication or swallow tablets.
Prior/Concomitant Therapy
16. Has received or is currently receiving treatment with clozapine for any length of time. 
17. Has received treatment with monoamine oxidase inhibitors within 3 months of screening 
or cariprazine within 2 months of screening.
18. Subjects who have had a dose of depot antipsychotics within 12 months of screening.
19. Is unable to refrain from the use of co-medication that is a moderate or strong inhibitor or 
inducer of CYP3A or moderate or strong inducer of CYP2C9 beginning approximately 
2 weeks or 5 half-lives, whichever is longer, prior to administration of the initial dose of 
trial drug and throughout the trial. (see Section 6.5).
20. Has received any vaccine starting from 30 days prior to study intervention or is scheduled 
to receive any vaccine through 30 days following study intervention.  There may be 
certain vaccines that are permitted (see Section 6.5).
Prior/Concurrent Clinical Study Experience
21. 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.
Other Exclusions
22. Is a smoker that does not agree to follow the smoking restrictions as defined by the CRU
23. Consumes greater than 3 servings of alcoholic beverages (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. Participants who consume 4 servings of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
24. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
25. A regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 2 years. Participants must have a negative drug screen (with 
the exception of cannabis and/or prescribed concomitant medications permitted at the 
discretion of the PI and Sponsor) prior to randomization.
26. The investigator has any concern regarding safe participation in the study or for any other 
reason the investigator considers the participant inappropriate for participation in the 
study.
27. Has been in incarceration or imprisonment within 3 months prior to screening.
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28. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for laboratory safety evaluations are specified in Appendix 2.
On Full PK Sampling Days (Days 1, 8 and 14)
Participants will fast from all food and drinks, except water, for at least 8 hours prior to study 
drug administration until 1-hour postdose. Participants will fast from all food and drinks 
except water between study drug administration and the first scheduled meal. Meals and 
snack(s) will be provided by the investigator at time points indicated in the Schedule of 
Activities. Participants will fast from all food and drinks except water between meals and 
snacks. The caloric content and composition of meals will be the same on each full PK 
sampling day in each panel (for this study the meal content should be consistent within a 
given clinical site). After the 24-hour postdose procedures have been completed, subsequent 
meals and snacks will be unrestricted in caloric content, composition and timing.
Study intervention administration will need to be taken with water. Water will be restricted 1 
hour and 1 hour after study intervention administration.
On All Other Days
Participants will fast from all food and drinks, except water, for at least 8 hours prior to study 
drug administration. Water will be unrestricted in timing. Meals and snacks will be 
unrestricted in caloric content, composition and timing.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study and until the poststudy visit.
On full PK sampling days, participants will refrain from the consumption of all fruit juices 24 
hours prior to and 24 hours after study drug administration.
On all other days during the study, the consumption of all 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 will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits.
On full PK sampling days, participants will be permitted to consume approximately 2 units 
of caffeinated beverages or xanthine-containing products only between 1 hour and 2 hours 
postdose. Otherwise, participants will refrain from consumption of such products 8 hours 
prior to study drug administration until the last PK assessment is complete.
On all other days, caffeinated beverages or xanthine-containing products will be limited to no 
more than 6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before the prestudy and 
poststudy visits. During the in-house period, consumption of alcohol is not allowed. At all 
other times, alcohol consumption is limited to no more than approximately 3 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.
5.3.3
Activity Restrictions
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 until the poststudy visit.
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 8.10.1.
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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.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
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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.
Global clinical supply complaints and/or temperature excursions are to be reported to the 
Clinical Complaints Intake mailbox, via email to clinical.complaints.intake@MSD.com, 
within 1 business day of awareness.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
Country-specific requirements are noted in Appendix 7.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Active
Experimental MK-8189
Drug
Tablet
4 mg
12 mg
All dose 
levels
Oral
Dose 
Regimens 1, 
2 and 3
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
All dose 
levels
Oral
Dose 
Regimens 1, 
2 and 3
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
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 2 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.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. 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 2.
Table 2
Allocation of Participants to Treatment
Panel A
Days 1 to 14
MK-8189
n=12
24 mg QD
Placebo
n=4
Placebo QD
Panel B
Days 1 to 3
Days 4 to 14
MK-8189
n=12
16 mg QD
24 mg QD
Placebo
n=4
Placebo QD
Placebo QD
Panel C
Day 1
Day 2
Days 3 to 14
MK-8189
n=12
8 mg QD
16 mg QD
24 mg QD
Placebo
n=4
Placebo QD
Placebo QD
Placebo QD
The suggested doses may be adjusted downward based on evaluation of safety, tolerability and/or pharmacokinetic 
data observed in previous treatment periods/panels.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. MK-8189 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.
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.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
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 
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dosing by a member of the study-site staff other than the person administering the study 
intervention. Study-site personnel perform a mouth check to ensure that the study 
intervention was ingested.
6.5
Concomitant Therapy
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination 
during the ongoing study (i.e., after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates 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.
Moderate to strong inhibitors or inducers of CYP3A and moderate to strong inducers of 
CYP2C9 are not allowed as MK-8189 is being metabolized by these CYP enzymes and 
coadministration of inhibitors or inducers may potentially alter the metabolism and PK of 
MK-8189. See also Section 6.5.1 on rescue medication. 
Paracetamol/acetaminophen (up to 4 g per day) and ibuprofen (up to 1.2g per day) and 
antacids (eg, magnesium hydroxide) may be used for minor ailments without prior 
consultation with the Sponsor.
•
With the exception of antipsychotics, upon agreement with the sponsor, participants may 
continue treatment with their prescribed therapy for bipolar I disorder (See inclusion 
criteria no. 1) as well as comorbid conditions related to their primary diagnosis, including 
but not limited to depression, anxiety, insomnia. During the trial, the prescribed dose and 
regimen of medication must be stable for at least 3 months prior to screening and there 
are no expected changes in co-medication during the study.
•
In addition, medications to treat mild chronic conditions such as hypothyroidism, 
diabetes, high blood pressure, chronic respiratory conditions or other medical conditions 
are allowed during the study.  For permitted medications, the prescribed dose and 
regimen of medication must be stable for at least 2 months prior to screening and there 
are no expected changes in co-medication during the study. See also Section 6.5.1 on 
rescue medication.
•
Vaccines used in the event of a disease outbreak or pandemic are allowed. However, 
while prioritizing standard clinical care, efforts should be made not to administer 
nonstudy vaccines within 30 days) of study intervention start.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
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6.5.1
Rescue Medications and Supportive Care
CRUs will be staffed with medically trained personnel with appropriate access to full-service 
acute care hospitals to facilitate rapid institution of medical intervention.
For the treatment of EPS, such as acute dystonia, all participants may be treated with an 
anticholinergic (e.g. benztropine, diphenhydramine, hydroxyzine). If the symptoms are 
unresponsive to anticholinergic treatment or not recommended based on a participant’s 
medical history/concomitant medication, a benzodiazepine can be used.
In case the participant presents with signs of akathisia without signs of dystonia, the 
participant can be treated with a β-adrenergic blocker. If symptoms do not disappear with the 
β-adrenergic blocker, treatment with an anticholinergic may be used.  An anticholinergic may 
be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred
treatment based on a participant’s medical history and/or concomitant medication.
If a participant’s symptoms of bipolar disorder worsen to the extent such that addition (or, if 
applicable, increase in dose) of a mood stabilizer, antipsychotic or antidepressant is required, 
they will discontinue treatment per stopping rules in Section 6.6.1.
6.6
Dose Modification (Dose Regimen Decisions)
All dose-regimen decisions (i.e. initiation of a Panel with a lower starting dose or 
continuation of enrollment within a dose regimen) 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, Translational Medicine Therapeutic Area Lead or designee. 
The Sponsor safety review team will obtain input from the investigator regarding his/her 
evaluation of safety and tolerability from the previous dosing period and his/her 
recommendation to initiate the next panel as described in Figure 2.
Dose regimen decisions will be based on AEs as acute tolerability (e.g. EPS and vomiting)
after 14 days of dosing.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
moving to a dose regimen with a higher starting dose or continuation with the current dose 
regimen, the next planned dose regimen may be followed per section 4.1 or altered such that 
participants:
•
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),
•
Receive the same or lower dose as a divided dose, or
•
Dosing may be stopped.
Participant discontinuation criteria are outlined in Section 7.
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6.6.1
Stopping Rules
6.6.1.1
Study 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.
•
Three or more MK-8189 treated participants per Panel (Dosing Regimen) meet any of the 
criteria listed under 6.6.1.2 and the clinical investigator judges the event to be related to 
MK-8189.
6.6.1.2
Individual Stopping Rules
Administration of study intervention will be stopped for a participant if they meet any of the 
following criteria for exacerbation of symptoms:
•
Requires, per clinical judgement of the investigator, the addition (or, if applicable, 
increase in dose) of a mood stabilizer, antipsychotic or antidepressant
•
YMRS total score of ≥15
•
HAM-D17 total score ≥15
•
CGI-BP-S total score ≥4
•
Hospitalization for worsening of symptoms
•
Active suicidal ideation or homicidal ideation or suicidal behavior
Note: all events listed above are considered as Event of Clinical Interest and require reporting 
to the Sponsor within 24 hours (see Section 8.4.7).
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
The emergency unblinding call center will use the intervention allocation 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.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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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 interrupts study intervention administration for more than 2 consecutive 
days or has 4 cumulative missed doses.
•
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 severe EPS symptoms which are not attenuated with medical 
management or dose modification.
•
The participant has a positive drug screen (with the exception of prescribed medications 
permitted and/or cannabis at the discretion of the PI and Sponsor) 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.
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7.2
Participant Withdrawal From the Study
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
A participant must be withdrawn from the study if:
•
The participant or participant’s legally acceptable representative withdraws consent from 
the study.
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 8.1.9.1. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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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 or assent, when applicable, be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
•
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 
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.
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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, age of majority requirements or 
health), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent from the participant (or their legally acceptable representative) 
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 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 
the participant provides documented informed consent or assent (as applicable). At the time 
of intervention allocation 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.
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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 3 months before first dose of study intervention.
Use of any prescription or nonprescription medication during the washout period should first 
be discussed between the investigator and Sponsor unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult.  Note: medications permitted under Section 6.5 of the protocol do not need to be 
discussed prior to use.
Washout from Antipsychotics:
All participants will be washed out from their antipsychotic medication prior to Day 1 The 
washout may start with a down titration of the antipsychotic treatment during the screening 
phase.
Participants may restart their antipsychotic therapy following completion of the 72 hour post 
last dose study procedures.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication (start/stop time and reason for 
therapy), 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 allocation. 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 8.10.1. 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.
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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
Study intervention(s) will be administered by the investigator and/or study staff. All doses of 
study drug administration will be taken with approximately 240 mL of water. Site staff will 
ensure the participant has swallowed study treatment. Details on water and dietary 
restrictions are outlined in Section 5.3.1.
8.1.8.1
Timing of Dose Administration
Participants will be dosed according to the SoA (Section 1.3). MK-8189 study administration 
will be in the AM at approximately the same time each day (within a 30 minute window) and 
after an 8-hour overnight fast.
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 8.10.4 to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
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 
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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, they will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. The emergency unblinding call center will 
provide the investigator or medically qualified designee the requested information 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.
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
Participants currently treated with antipsychotic mediations will be domiciled in the CRU 
from Day -5 prior to Day 1of the treatment period (to start the washout of current 
antipsychotic mediation) and will remain in the CRU until 72 hours post the last dose of 
study intervention on Day 14. Participants not currently being treated with antipsychotic 
medication may be domiciled starting on Day -1. At the discretion of the investigator, 
participants may be requested to remain in the CRU longer.
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Participants may be permitted to leave the unit, for urgent or emergency situations only, 
during the domiciling period at the discretion of the investigator after discussion with the 
Sponsor. The decision how to monitor the participant will be at the discretion of the 
investigator after discussion with the Sponsor.
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. The total amount of blood/tissue 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 Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Complete physical examinations will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. At prespecified 
timepoints noted in the SoA (Section 1.3). Height and weight will also be measured and 
recorded.
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 weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed at 
prespecified timepoints noted in the SoA (Section 1.3).
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8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
BP and HR measurements will be assessed in a supine position with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
Participants should be resting in a quiet setting without distractions in a supine position for at 
least 10 minutes before having VS measurements obtained. Supine 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.
Triplicate HR and BP will be obtained at least 1 to 2 minutes apart at all timepoints.  Day 1 
predose triplicate measurements will be within 3 hours prior to dosing. The mean of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed).
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants at a given study site.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained per the SoA (Section 
1.3). Participants should be supine for at least 10 minutes and then stand upright for 
approximately 2 minutes before measurement of orthostatic VS.
8.3.3
Electrocardiograms
•
Triplicate 12-lead ECG 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, RR, and 
QTc intervals. Refer to Appendix 9 for evaluation and potentially significant findings.
•
At each time point, 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.
•
Day 1 predose ECG triplicate measurements will be within 3 hours prior to dosing. The 
mean of these measurements will be used as the baseline to calculate change from 
baseline for safety evaluations (and for rechecks, if needed).
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.
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Participants should be resting in the supine for at least 10 minutes before each ECG 
measurement.
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.
During each treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with mean predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the mean QTc interval increase from baseline for any postdose 
time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc interval is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
During each treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The mean value of the QTc 
interval from the 3 ECGs will represent the value at that time point. If the mean QTc interval 
is ≥500 msec, 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 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.
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8.3.4
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 Operations Manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
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.
8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
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.
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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 
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.
8.3.7
Rater Expectations and Training for Clinical Assessments
For this study, potential raters of clinical and psychiatric assessments (BARS [Section 8.3.8], 
SAS [Section 8.3.8], AIMS [Section 8.3.8] and CGI-BP-S [8.3.9], YMRS [8.3.9] and HAM-
D17 [8.3.9]), will be identified based on review of their reported credentials against target 
minimum credentials for education, prior experience with the study populations and direct, 
hands-on experience with study-specific or similar assessments. Persons whose credentials 
meet or exceed those targets will then be considered ‘qualified’ as raters in this trial. It is
recommended that the same rater conducts the same assessments throughout the study for a
given participant, where feasible.
8.3.8
Monitoring of Extrapyramidal Symptoms
The investigator or qualified designee will complete the BARS, AIMS and SAS at times 
specified in the SoA.
8.3.9
Assessment of Neurological and Psychiatric Effects
A general (full) Neurological Exam will be conducted by a medically quailed investigator at 
the Screening and Baseline visits. A targeted Neurological Exam will be conducted by a 
medically quailed investigator at times specified in the SoA.
The General and Targeted Neurological Exams are contained in Appendix 11.
CGI-BP-S, YMRS and HAM-D17 will be performed only at times specified in the SoA.
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8.3.10
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.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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 allocation, 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 allocation 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.
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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and 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 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 3
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
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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
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
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.
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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 allocated 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.
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.
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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable
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.*
*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. Severe EPS or EPS leading to study intervention discontinuation
4. Treatment-emergent adverse event of new or worsening tardive dyskinesia
5. QTcF interval >500 msec
6. Suicidal or homicidal ideation, suicidal behavior.
7. Requires, per clinical judgement of the investigator, the addition (or, if applicable, 
increase in dose) of a mood stabilizer, antipsychotic or antidepressant to treat worsening 
of bipolar symptoms
8. YMRS total score ≥15
9. HAM-D17 total score ≥15
10. CGI-BP-S total score ≥4
11. Hospitalization for worsening of symptoms
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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 any 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/pharmacodynamics 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.
8.6.1
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations Manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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 for Genetic Analysis
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.
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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
All sample collections for study-specific assessments shown in the SoA are described within
the main Informed Consent.
If the participant has provided documented informed consent for FBR, leftover samples will 
be used for FBR. The following specimens will be included for FBR:
•
Leftover samples listed in Section 8.8.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Within approximately 6 weeks before intervention allocation/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 allocation/randomization if there are Day -1 
procedures planned per protocol.
8.10.2
Treatment Period Visit
Refer to the Schedule of Activities (Section 1.3).
Participants must be washed out from any antipsychotic therapy for at least 5 days or cover at 
least 3 half-lives of the drug (whichever is longer) prior to Day 1. Participants will report to 
the CRU on Day -5 to start their washout period. However, if participants are not currently 
being treated with antipsychotic medications and therefore do not require a washout, they 
may be domiciled on Day -1.
On treatment days, participants will be dosed once daily with MK-8189 or placebo and have 
procedures completed per the SoA. Participants will remain in the unit through 72 hours post 
the last dose and completion of all procedures and will be discharged at the discretion of the 
investigator.
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Participants will resume the use of their own antipsychotic medication after the completion
of the last PK sample collection (72 hr postdose). 
8.10.3
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 an official memo. 
8.10.4
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.
8.10.5
Procedures Based on Study Objectives: Timing of Procedure
At any postdose time point, the blood sample for MK-8189 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. All Vital Signs assessments should be prior to or at least 10 
minutes after a PK draw.
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 4.
Table 4
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
0 to <1 h
+/- 5 min
1 to ≤24 h
+/- 15 min
24 to 72h
+/- 2 hr

Study Intervention Administration: +/- 30 minutes.
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Predose and Postdose Procedures
•
Predose standard safety evaluations should be prior to the scheduled timepoint: 
•
VS and ECG within 3 hours
•
laboratory safety tests within 72 hours,
•
physical examination within 24 hours
•
EPS scales, CSSR-S and CGI-BP-S, YMRS and HAM-D17 within 24 hours.
•
Postdose standard safety evaluations: VS and ECG:
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8189 in humans, 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 a panel to further understand tolerability of a Dose Regimen.
•
Repeat of a panel with a more conservative dose titration than the prespecified Dose 
Regimens.
•
Repeat of or decrease in the dose of the study intervention administered in any given 
period/panel.
•
Entire period(s) or panel(s) may be omitted.
•
Decrease in the duration of study intervention administration (eg, number of days).
•
Adjustment of the dosing interval (eg, divided doses <bid to qd, qd to bid, tid, or vice 
versa>).
•
Remove a planned PK pause if agreed by Sponsor and investigator if no further increases 
in total daily dose.
•
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/pharmacodynamic sample processing and shipping details based 
on newly available data.
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The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic 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, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
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 his/her 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
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 of the study are stated in Section 3 of the protocol.
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Safety:
Clinical assessment of AEs and participant discontinuation due to AEs.
9.3.2
Exploratory Endpoints
Safety: 
12-lead ECGs, vital signs, laboratory safety tests.
EPS assessments (AIMS, BARS, SAS), CSSRS, CGI-BP-S, YMRS, and HAM D17. 
Pharmacokinetics:
MK-8189 AUC24, Cmax, C24, CL/F, Vz/F, Tmax and half life.
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 
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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 pharmacokinetics analyses.
9.5
Statistical Methods
9.5.1
Statistical Methods for Pharmacokinetic Analyses
Model-based PK summary
For each panel, separately for each PK parameter, individual values of AUC0-24, Cmax, and 
C24 at each day (dose may be confounded with day) will be natural log-transformed and 
evaluated with a linear mixed effects model containing a fixed effect for day, and a random 
effect for subject. Kenward and Roger's method will be used to calculate the denominator 
degrees of freedom for the fixed effects. Ninety-five percent confidence intervals (CIs) for 
the least squares (LS) means for each day will be constructed on the natural log scale and 
will reference the t-distribution. Exponentiating the LS means, and lower and upper limits of 
these CIs will yield estimates for the population geometric means (GM) and 95% CIs about 
the GMs on the original scale.
A sample code for each panel is as follows:
proc mixed data=adpp; by panel parameter; 
class subjid day;
model lnpk= day/ddfm=kr; 
random subjid;
lsmeans day/alpha=0.05 cl; run;
Descriptive Statistics
For each panel, individual values will be listed for each PK parameter (AUC24,  Cmax, C24, 
CL/F, Vz/F, and halflife), and the following (non-model-based) descriptive statistics will be 
provided: N (number of participants with non-missing data), arithmetic mean, standard 
deviation, arithmetic percent coefficient of variation (CV, calculated as 100 × standard 
deviation/arithmetic mean), median, minimum, maximum, geometric mean, and geometric 
percent CV (calculated as 100 × sqrt( exp(s2) − 1), where s2 is the observed variance on the 
natural log-scale).  Median, maximum and minimum will be provided for Tmax.
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9.5.2
Statistical Methods for Safety Analyses
Primary: 
Safety and tolerability will be assessed by clinical review of AEs.
The overall safety endpoints include the number of participants with at least one AE, drug-
related AE, serious AE, serious, drug-related AE, who discontinue from study intervention 
due to an AE, or with an AE resulting in death.
The safety evaluation will include a summary by treatment group of the number and 
percentage of participants with each type of AE.
Exploratory:
Safety and tolerability will also be assessed by clinical review of other relevant parameters, 
including laboratory test results, vital signs, and ECG measurements.
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).
To explore changes in extrapyramidal symptomology, summary statistics will be generated 
for BARS, AIMS, SAS as well as for change from baseline.  The difference from baseline 
will be computed on the original scale (raw change from baseline).  Responses to the C-
SSRS will be listed.  The C-SSRS will be used to systematically and prospectively ascertain 
and document the occurrence of suicidal events (i.e., ideation and behavior).  Summary 
statistics for changes in baseline for CGI-BP-S will be provided.
Changes from baseline in YMRS total scores, HAM D17 total scores, and HAM D6 will be 
summarized. The 6-item HAM D6 is a subset of the HAM D17.  It consists of 6 items 
(depressed mood, work and activities, somatic symptoms general, feelings of guilt, anxiety 
psychic, and retardation); these items are summed to obtain the HAM-D6 total score.
9.6
Interim Analyses
During the in-life portion of the trial, descriptive summary level results (safety (labs, VS, 
ECGs)) may be prepared as needed to support decision-making meetings such as dose 
escalation meetings. The aggregate summaries will be presented in an unblinded manner. 
There are no planned interim analyses to test any formal hypotheses.
9.7
Multiplicity
Since there are no pre-specified hypotheses, no adjustments for multiplicity are needed.
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9.8
Sample Size and Power Calculations
A study with sample size of 12 on active and 4 on placebo in each panel is considered 
adequate to address the study objectives around safety and pharmacokinetics.
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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), and 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 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 
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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.
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.
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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.
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.
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IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators 
(or the sponsoring institution) in a fair manner for the work performed in support of MSD 
trials. MSD does not pay incentives to enroll participants in its trials. However, when 
enrollment is particularly challenging, additional payments may be made to compensate for 
the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring 
physicians for time spent on 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 
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 their 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.
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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 their 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 their 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.
Pursuant to Union law (Clinical Trials Directive 2001/20/EC and Clinical Trials Regulation 
536/2014), the Investigator is responsible for pseudonymizing and assigning a key-
code/patient ID to each study subject.  In addition, the Investigator is required by Union law 
to store the Key (linking the Patient ID to the full name of the study subject) at the site in the 
EU/EEA throughout the course of the study and for a designated period of time thereafter.  
Finally, the study site is only permitted to share pseudonymized study subject personal data 
with the Sponsor.  
The European Data Protection Board, in its Recommendations 01/2020 on measures that 
supplement transfer tools to ensure compliance with the EU level of protection of personal 
data (“Recommendations”), states in Paragraph 85 that pseudonymization (of study subject) 
personal data under the conditions described above constitutes an effective supplemental 
measure.  
Organizational measures are contractually imposed on third party vendors wherever possible, 
to ensure that Personal Data are protected by industry-best practices against accidental 
destruction or loss (physical/logical) which include regular backup procedures, Firewalls, and 
disaster recovery plans.
In support of Corporate Policy 1 Information Risk Management, on a Sponsor-wide basis all 
supplier relationships, both IT and non-IT related, are strongly encouraged to meet the 
Sponsor’s Supplier Information Risk Management Standard.  To protect the confidentiality, 
availability and integrity of Sponsor information, conformity to information risk 
requirements by supplier personnel, hardware and software may be measured, analyzed and 
appropriate corrective/preventive actions taken as necessary. Based on the supplier criticality, 
additional activities (e.g., on-site reviews, integrated business continuity exercises) may be 
required to ensure the cyber-resiliency of the supplier on an on-going basis.
The Sponsor has implemented (Corporate Policy 13.1 Information Security Standards 
Handbook) an organization-wide process to assign user access rights based on the whether 
the employee/contractor has a legitimate need to utilize a database in order to carry out 
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his/her job; manager approval is required when granting user access rights (beyond those 
sites or databases intended for all employees/contractors); and a process is in place for an 
annual review by each manager of the user access rights currently in place.  Organizational 
measures, also contractually imposed on third party vendors, to prevent data processing 
systems from being used by unauthorized persons include i) user identification and 
authentication procedures (e.g., special characters, minimum length, regular change of 
password), and ii) automatic blocking (e.g., password or timeout).
The Sponsor utilizes a database called “InForm”, operated by Oracle, for the storage of its 
study subject clinical trial data. InForm is a role-based system and only authorized users can 
see the data. Sites may only see the data they have entered.  Access by Sponsor users is 
restricted to only those associated with a specific clinical trial. 
Study sites are provided with a password to access the database.  Access to InForm requires 
https (Secure Socket Layer) with a FIPS 140-2 compliant algorithm to connect to the 
application via the study site’s web browser.  Once logged into the system, the connection 
between the database, located in Ashburn, Virginia, USA, and the site, is encrypted.  The 
Sponsor also stores the name and access credentials of the Investigators and other site staff 
(Study Coordinators) who record patient data into InForm.  Such study staff personal data is 
not pseudonymized.  Note, such encryption during transmission may not meet all conditions 
imposed by the EDPB in its Recommendations for this encryption, on its own, to constitute 
an effective supplemental measure.
Data, whether concerning a study subject or site staff, stored in the InForm database is 
encrypted.  Note, such encryption may not meet all conditions imposed by the EDPB in its 
Recommendations for this encryption, on its own, to constitute an effective supplemental 
measure.  
Whenever possible, organization wide measures are imposed on third party vendors to 
prevent unauthorized persons from gaining access to the data processing systems available on 
premises and in facilities (including databases, application servers and related hardware), 
where Personal Data are processed, include i) Access control system (ID reader, chip), ii) key 
management, card-keys procedures, and iii) on-site security personnel and alarm system.
InForm is a HIPAA Part 11 capable system.  Any data entered/changed or deleted will be 
associated with a viewable audit trail.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20).  Pursuant to organization-wide 
requirements, the Sponsor periodically conducts audits of the vendors providing IT services, 
including Oracle, the vendor supporting the InForm database.  The most recent audit of 
Oracle and its operations of InForm occurred in May 2020.  Finally, Oracle has obtained ISO 
27001 certification for the various databases it offers to third parties as a service, including 
the InForm database.   
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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.
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
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.
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10.1.5
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 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.6
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.
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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.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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.
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10.1.8
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.
10.1.9
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 5 will be performed by the local laboratory.
•
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.
•
Participants should fast approximately 8 hours prior to all chemistry laboratory 
collections. If the individual comes to the screening visit and is not fasting, a recheck 
may be needed at the discretion of the investigator. The participant will be asked to return 
at a later time for the safety laboratory collection.
Table 5
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
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 
(fasting)
Calcium
Alkaline 
phosphatase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, <bilirubin, urobilinogen, nitrite, leukocyte 
esterase> by dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
Other Screening Tests
FSH (as needed in PONCBP only)
Urine/blood alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)
Serology (HIV antibody, HbsAg, and hepatitis C virus antibody)
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; 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
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.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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.
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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.
-
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.
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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.
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).
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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?
◦
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.)
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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.
•
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.
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•
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.
•
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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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 contraceptive implant a
IUS a
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
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 b
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception 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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicidec
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
IUS is a progestin releasing IUD
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit
ovulation
c
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction) c
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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.
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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 their 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.
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. 
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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 
(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.
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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.
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: Blood Volume Tables
Panels A, B, C
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/Test
Laboratory Safety Tests
(including FSH/hCG and 
drug screen)
1
4
1
6
12
72
HIV/Hepatitis Screen (at 
the discretion of the 
investigator)
1
1
4.5
4.5
Blood for Planned 
Genetic Analysis
1
1
8.5
8.5
Blood for MK-8189
23
23
4
92
Total Blood Volume per Participanta
177 mL
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more than 
50 mL in total) may be obtained.
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10.9
Appendix 9: 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
QTc >450 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
Female
QTc >450 ms
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, PR=pulse rate; 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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10.10 Appendix 10: 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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10.11 Appendix 11: 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.
10.11.1
The General Neurological Examination
The General Neurological Examination includes all of the modules listed below and is 
intended to be a general screening examination.
10.11.1.1
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.
10.11.1.2
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
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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
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
10.11.1.3
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
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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
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
10.11.1.4
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
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10.11.1.5
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.)
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
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10.11.1.6
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)
10.11.2
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:
10.11.2.1
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)
10.11.2.2
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
10.11.2.3
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
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10.11.2.4
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
10.11.2.5
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
AAP
atypical antipsychotics
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
BARS
Barnes Akathisia Rating Scale
bid
twice daily
BMI
body mass index
BP
blood pressure
CCU
Cardiac care unit
CI
confidence interval
CGI-BP-S
Clinical Global Impression-Bipolar Version-Severity of Illness
Cmax
maximum plasma concentration
CNS
central nervous system
CL/F
Apparent clearance
CR
complete response
CRF
Case Report Form
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTFG
Clinical Trial Facilitation Group
CVD
cardiovascular
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
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Abbreviation
Expanded Term
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
EMA
European Medicines Agency
EPS
extrapyramidal symptoms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GI
gastrointestinal
HAM-D17
Hamilton Depression Rating Scale
HbsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
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
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug
IRB
Institutional Review Board
08W3NY

PRODUCT: MK-8189
118
PROTOCOL/AMENDMENT NO.: 020-02
MK-8189-020-02 FINAL PROTOCOL
17-MAY-2024
Abbreviation
Expanded Term
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
JRCT
Japan Registry of Clinical Trials
LAM
lactational amenorrhea method
MOA
Mechanism of Action
mRNA
messenger RNA
NCS
not clinically significant
NDA
New Drug Application
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
OR
objective response
PANSS
Positive and Negative Syndrome Scale
PCL
Protocol Clarification Letter
PDE10A
phosphodiesterase 10A
PK
pharmacokinetic
po
orally
POC
Proof of Concept
POCBP
Person of childbearing potential
PONCBP
Person of nonchildbearing potential
PP
per-protocol
PR
partial response
PRO
patient-reported outcome
QD
once daily
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAS
Simpson Angus Scale
SD
standard deviation
08W3NY

PRODUCT: MK-8189
119
PROTOCOL/AMENDMENT NO.: 020-02
MK-8189-020-02 FINAL PROTOCOL
17-MAY-2024
Abbreviation
Expanded Term
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
Tmax
time to maximum plasma concentration
t½
half life
UDS
urine drug screen
ULN
upper limit of normal
UTN
Universal Trial Number
Vz/F
Apparent volume of distribution
VS
vital signs
WBC
white blood cell
YMRS
Young Mania Rating Scale
08W3NY

PRODUCT: MK-8189
120
PROTOCOL/AMENDMENT NO.: 020-02
MK-8189-020-02 FINAL PROTOCOL
17-MAY-2024
11
REFERENCES
[Karcher, N. R., et al 
2019]
Karcher NR, Rogers BP, Woodward ND. 
Functional connectivity of the striatum in 
schizophrenia and psychotic bipolar disorder. 
Biol Psychiatry Cogn Neurosci Neuroimaging. 
2019;4:956-65.
[08F4P9]
08W3NY