A Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants With Schizophrenia
Phase: PHASE1
Conditions: Schizophrenia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT05953740
Document Date:            08-Aug-2023
A Single Ascending Dose Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of the Long-Acting 
Injectable of MK-5720 in Participants with 
Schizophrenia

PRODUCT: MK-5720
1
PROTOCOL/AMENDMENT NO.: 001-02
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08-AUG-2023
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 Single Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants with 
Schizophrenia
Protocol Number: 001-02
Compound Number: MK-5720
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
N/A
EU CT
N/A
EudraCT
N/A
JAPIC-CT
N/A
WHO
N/A
UTN
N/A
IND
158448
Approval Date: 08 August 2023
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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
08-AUG-2023
Section 4.1 of the protocol was updated to 
include an oral run-in period with MK-8189 
prior to dosing MK-5720.
Amendment 1
16-JUN-2023
Section 9.5.2 of the protocol was updated to 
include language that was excluded 
unintentionally in the original protocol.
Original Protocol
06-JUN-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
Section 4.1 Overall Design was updated based on feedback from the FDA to include an oral 
run-in period with MK-8189 prior to dosing MK-5720.
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Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 4.1 Overall 
Design
This section was updated to include an oral run-in period with 
MK-8189 prior to dosing MK-5720. 
This change was made to address feedback from the FDA.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
The structure of the protocol has been updated.
To comply with current industry regulations and guidelines. This 
restructuring does not affect the clinical or regulatory integrity of the 
protocol. All other relevant changes and their primary reasons are included 
for completeness.
Throughout
Minor grammatical and typographical errors were corrected.
These were non-substantial editorial corrections.
Throughout
Period 1 and Period 2 were added throughout the protocol.
This change provides clarification on timing of events based on treatment 
period. 
Section 1 Protocol 
Summary
The estimated duration of the study was updated from 10 to 12
months.
The estimated duration of participation was updated from 16 to 17 
weeks. 
The change was made to accurately reflect the change in time requirements 
for the updated study design. 
Section 1.2 Schema
Table 1 and Figure 1 were updated to include Period 1 and Period 2. 
This change reflects the change of the study design on the dose escalation 
scheme and overall study design.
Section 1.3 Schedule 
of Activities
This section was split into two SoAs for each treatment period, Section 
1.3.1 for Period 1 and Section 1.3.2for Period 2.
This modification was made to simplify the SoA. 
Section 1.3.1 
Schedule of 
Activities: Period 1 
Oral Run-in with 
MK-8189
Section 1.3.1 contains information for the Screening Period, Washout 
Period, and the MK-8189 treatment period, and MK-8189 Washout
Period. 
This modification was made to accommodate the change in study design.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.3.2 
Schedule of 
Activities: Period 2 
MK-5720 Treatment
Section 1.3.2 was the previous SoA which has been modified to 
remove the Screening Period and related activities and Washout Period 
and related activities.
Footnote “a” was updated to remove details regarding the washout 
period and updated the duration of domiciling.
The row and footnote related to samples for genetic analysis were 
moved to Section 1.3.1.
These modifications were made to accommodate changes to study design and 
sort activities based on when they occur within the study.
Footnote “j” was updated to include windows for MRI exams to be 
completed.
This modification was made to provide clarification on what the windows 
were for collecting the MRI exams. 
Section 3 
Hypothesis, 
Objectives, and 
Endpoints
The following primary objective and endpoint was added:
Objective: To evaluate the safety and tolerability of multiple 
once-daily oral doses of MK-8189 in participants with 
schizophrenia.
Endpoint: Adverse events, Discontinuation due to adverse events
The following exploratory objective and endpoint was added:
Objective: To assess the pharmacokinetics of oral MK-8189 after 
multiple doses in participants with schizophrenia.
Endpoint: AUC0-24, Cmax, Tmax and C24
This modification was made to reflect the update to the study design.
The imaging exploratory objective and endpoint was reworded.
This modification was made to clarify that imaging will be done at multiple 
timepoints.
Section 4.2 Scientific 
Rationale for Study 
Design
Rationale for the Period 1 study design with MK-8189 was added.
Refer to Section 4.1 Rationale
Section 4.2.2 
Rationale for the Use 
of 
Comparator/Placebo
The following bolded text was added 
“Placebo will be used in this study to allow for an appropriate 
assessment of the safety data of oral MK-8189 and MK-5720 LAI 
and to maintain study blinding to reduce bias.”
Refer to Section 4.1 Rationale
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Section Number 
and Name
Description of Change
Brief Rationale
Section 4.3 
Justification for Dose
Rationale was added for the MK-8189 doses and duration of the run-in 
period.:
Refer to Section 4.1 Rationale
Section 4.3.2 
Maximum Dose 
Exposure for This 
Study
Table 4 was updated to include the projected steady state PK 
parameters following multiple oral doses of MK-8189 for the 48 mg 
dose. 
Refer to Section 4.1 Rationale
Section 4.2.2 
Rationale for Dose 
Interval and Study 
Design
Rationale for the oral run-in Period with MK-8189 was added. 
Refer to Section 4.1 Rationale
Section 5.1 Inclusion 
Criteria
The following criterion was added:
“Has regular bowel movements and, in the opinion of the investigator, 
no clinically significant diarrhea or constipation”.
This change was added based on oral MK-8189 being used. 
Section 5.2 
Exclusion Criteria
Exclusion criteria #15 and #16 were updated to include a note 
clarifying these criteria only apply to panels who are receiving 
imaging as described in PCL #1. 
This change was made based on feedback from one of the study investigators 
to help with enrollment of non-MRI panels.
Section 5.3.1.1 Diet 
Restrictions
This section was divided up into subsections to clarify restrictions for 
Period 1, Period 2, and all Periods. New restrictions were provided for 
MK-8189 in Period 1.
This modification provides clarification on diet restrictions based on new 
study intervention.
Section 5.5 
Participant 
Replacement 
Strategy
Clarification on replacement strategy to include both participant 
withdraw and discontinuation due to tolerability concerns was added.
The following text was removed: “The replacement participant may 
begin dosing at the subsequent dose level for that panel, based on 
investigator and Sponsor review and discussion.”
This modification expands the scope of using replacements for participants 
who withdraw or discontinue the study.
This modification was made to reflect the parallel study design and there are 
no subsequent dose level for a given panel.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 6.1 Study 
Intervention(s) 
Administered
Table 6 was updated with study intervention information for the oral 
run-in period with MK-8189 for all panels.
This change was made to reflect the new study intervention being added.
The following footnote was added to the table:
“Those who receive placebo in Period 1 will receive placebo in Period 
2. Those receiving MK-8189 in Period 1 will receive MK-5720 in 
Period 2.”
This modification was made to clarify on study intervention assignment for 
both periods.
Section 6.2.1 Dose 
Preparation
The following section was subdivided into MK-8189 and MK-5720 
and language was added for MK-8189.
This modification was made to provide clarification on how study 
intervention is to be prepared and guidance for MK-8189 dose preparation.
Section 6.3.1 
Intervention 
Assignment
Table 7 was updated to include the treatments for Period 1 and Period 
2.
This modification reflects the changes to the current treatment groups in the 
study based on the new study design.
Section 6.3.3 
Blinding
The MK-8189 was added to the following statement: 
“MK-8189, MK-5720 and placebo will be prepared and/or dispensed 
in a blinded fashion by an unblinded pharmacist or qualified study-site 
personnel.”
This modification was made to include MK-8189 in the blinding of study 
intervention.
Section 8.1.8 Study 
Intervention 
Administration
This section was subdivided into Period 1 and Period 2. New text was 
added for Period 1 for MK-8189 dosing.
This section was modified to provide guidance on how each study 
intervention is to be administered for each period.
Section 8.1.8.1 
Timing of Dose 
Administration
This section was subdivided into Period 1 and Period 2. Dosing 
instructions for MK-8189 in Period 1 was added. 
Refer to Section 8.1.8 rationale.
Section 9.3.1 
Primary Endpoints
Information regarding the analysis of safety and tolerability data for 
MK-8189 was added.
The SAP section was updated to align with new study design updates. 
Section 9.3.3 
Exploratory 
Endpoints
Information regarding the analysis of the PK endpoints for MK-8189 
in Period 1 was added. 
Refer to Section 9.3.1 rationale.
Section 9.4.1 All 
Participants as 
Treated Population
Updated to include two APaT populations for this study.
Refer to Section 9.3.1 rationale.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 9.5 
Statistical Methods
This section was updated to provide clarification on the statistical 
methods for data obtained in Period 1 and Period 2.
Refer to Section 9.3.1 rationale.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................23
1.3.1
Schedule of Activities: Period 1 Oral Run in with MK-8189......................23
1.3.2
Schedule of Activities: Period 2 MK-5720 Treatment ................................28
2
INTRODUCTION..........................................................................................................31
2.1
Study Rationale....................................................................................................31
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.2.1
Preclinical Studies with MK-5720.....................................................32
2.2.2.2
Clinical Studies with MK-5720 and MK-8189..................................32
2.2.3
Completed Clinical Studies (MK-8189)......................................................34
2.2.3.1
Protocol 011 .......................................................................................34
2.2.3.2
Protocol 012.........................................................................................39
2.2.3.3
Protocol 016.......................................................................................40
2.3
Benefit/Risk Assessment......................................................................................42
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................44
4
STUDY DESIGN............................................................................................................46
4.1
Overall Design......................................................................................................46
4.2
Scientific Rationale for Study Design.................................................................48
4.2.1
Rationale for Endpoints ...............................................................................48
4.2.1.1
Efficacy Endpoints.............................................................................48
4.2.1.2
Safety Endpoints................................................................................48
4.2.1.3
Pharmacokinetic Endpoints ...............................................................50
4.2.1.4
Pharmacodynamic Endpoints.............................................................50
4.2.1.5
Planned Exploratory Biomarker Research.........................................50
4.2.1.5.1
Planned Genetic Analysis ........................................................50
4.2.1.6
Future Biomedical Research..............................................................51
4.2.2
Rationale for the Use of Comparator/Placebo .............................................51
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................51
4.3
Justification for Dose...........................................................................................51
4.3.1
Starting Dose for This Study........................................................................52
4.3.2
Maximum Dose Exposure for This Study ...................................................54
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4.3.3
Rationale for Dose Interval and Study Design ............................................58
4.4
Beginning and End-of-Study Definition ............................................................58
4.4.1
Clinical Criteria for Early Study Termination .............................................59
5
STUDY POPULATION ................................................................................................60
5.1
Inclusion Criteria.................................................................................................60
5.2
Exclusion Criteria................................................................................................62
5.3
Lifestyle Considerations......................................................................................66
5.3.1
Meals and Dietary Restrictions....................................................................66
5.3.1.1
Diet Restrictions.................................................................................66
5.3.1.2
Fruit Juice Restrictions ......................................................................66
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................66
5.3.2.1
Caffeine Restrictions..........................................................................66
5.3.2.2
Alcohol Restrictions...........................................................................67
5.3.2.3
Tobacco Restrictions..........................................................................67
5.3.3
Activity Restrictions ....................................................................................67
5.4
Screen Failures.....................................................................................................67
5.5
Participant Replacement Strategy......................................................................67
6
STUDY INTERVENTION............................................................................................68
6.1
Study Intervention(s) Administered...................................................................68
6.2
Preparation/Handling/Storage/Accountability .................................................74
6.2.1
Dose Preparation..........................................................................................74
6.2.2
Handling, Storage, and Accountability........................................................74
6.3
Measures to Minimize Bias: Randomization and Blinding..............................75
6.3.1
Intervention Assignment..............................................................................75
6.3.2
Stratification.................................................................................................75
6.3.3
Blinding........................................................................................................75
6.4
Study Intervention Compliance..........................................................................76
6.5
Concomitant Therapy..........................................................................................76
6.5.1
Rescue Medications and Supportive Care ...................................................77
6.6
Dose Modification (Escalation)...........................................................................78
6.6.1
Stopping Rules.............................................................................................79
6.7
Intervention After the End of the Study............................................................79
6.8
Clinical Supplies Disclosure................................................................................79
6.9
Standard Policies..................................................................................................80
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................81
7.1
Discontinuation of Study Intervention...............................................................81
7.2
Participant Withdrawal From the Study...........................................................81
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7.3
Lost to Follow-up .................................................................................................81
8
STUDY ASSESSMENTS AND PROCEDURES........................................................82
8.1
Administrative and General Procedures ...........................................................82
8.1.1
Informed Consent.........................................................................................82
8.1.1.1
General Informed Consent.................................................................83
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................83
8.1.2
Inclusion/Exclusion Criteria ........................................................................83
8.1.3
Participant Identification Card.....................................................................84
8.1.4
Medical History ...........................................................................................84
8.1.5
Prior and Concomitant Medications Review...............................................84
8.1.5.1
Prior Medications...............................................................................84
8.1.5.2
Concomitant Medications..................................................................84
8.1.6
Assignment of Screening Number...............................................................84
8.1.7
Assignment of Randomization Number.......................................................85
8.1.8
Study Intervention Administration ..............................................................85
8.1.8.1
Timing of Dose Administration.........................................................85
8.1.9
Discontinuation and Withdrawal .................................................................86
8.1.9.1
Withdrawal From Future Biomedical Research ................................86
8.1.10
Participant Blinding/Unblinding..................................................................86
8.1.11
Domiciling ...................................................................................................87
8.1.12
Calibration of Equipment.............................................................................87
8.2
Efficacy/Immunogenicity Assessments ..............................................................87
8.3
Safety Assessments...............................................................................................87
8.3.1
Physical Examinations.................................................................................88
8.3.2
Vital Signs....................................................................................................88
8.3.2.1
Resting Vital Signs ............................................................................88
8.3.2.2
Orthostatic Vital Signs.......................................................................89
8.3.3
Electrocardiograms ......................................................................................89
8.3.4
Clinical Safety Laboratory Assessments .....................................................90
8.3.5
Suicidal Ideation and Behavior Monitoring.................................................90
8.3.5.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................90
8.3.6
Monitoring for Extrapyramidal Symptoms..................................................91
8.3.7
Assessment of Neuropsychological Effects.................................................91
8.3.8
Photograph of Rash......................................................................................91
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................92
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................92
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......94
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...94
8.4.4
Regulatory Reporting Requirements for SAE .............................................94
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................95
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................95
8.4.7
Events of Clinical Interest............................................................................95
8.5
Treatment of Overdose........................................................................................96
8.6
Pharmacokinetics.................................................................................................96
8.6.1
Blood Collection for Plasma MK-5720 and MK-8189................................96
8.7
Pharmacodynamics..............................................................................................97
8.8
Biomarkers ...........................................................................................................97
8.8.1
Planned Genetic Analysis Sample Collection..............................................97
8.9
Future Biomedical Research Sample Collection...............................................97
8.10
Visit Requirements...............................................................................................97
8.10.1
Screening......................................................................................................97
8.10.2
Treatment Period Visit.................................................................................98
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................98
8.10.4
Poststudy......................................................................................................98
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......98
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................99
9
KEY STATISTICAL CONSIDERATIONS .............................................................101
9.1
Responsibility for Analyses...............................................................................101
9.2
Hypotheses/Estimation ......................................................................................101
9.3
Analysis Endpoints.............................................................................................101
9.3.1
Primary Endpoints .....................................................................................101
9.3.2
Secondary Endpoints .................................................................................101
9.3.3
Exploratory Endpoints ...............................................................................102
9.4
Analysis Populations..........................................................................................102
9.4.1
All Participants As Treated Population......................................................102
9.4.2
Per-Protocol (PP) Population.....................................................................102
9.5
Statistical Methods.............................................................................................103
9.5.1
Statistical Methods for Safety Analyses ....................................................103
9.5.2
Statistical Methods for Pharmacokinetic Analyses....................................103
9.6
Interim Analyses ................................................................................................105
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9.7
Multiplicity .........................................................................................................105
9.8
Sample Size and Power Calculations ...............................................................105
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................106
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......106
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................106
10.1.2
Financial Disclosure...................................................................................109
10.1.3
Data Protection...........................................................................................110
10.1.3.1
Confidentiality of Data ....................................................................110
10.1.3.2
Confidentiality of Participant Records.............................................110
10.1.3.3
Confidentiality of IRB/IEC Information..........................................111
10.1.4
Publication Policy......................................................................................111
10.1.5
Compliance with Study Registration and Results Posting Requirements .111
10.1.6
Compliance with Law, Audit, and Debarment ..........................................112
10.1.7
Data Quality Assurance .............................................................................112
10.1.8
Source Documents .....................................................................................113
10.1.9
Study and Site Closure...............................................................................114
10.2
Appendix 2: Clinical Laboratory Tests............................................................115
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................116
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................116
10.3.2
Definition of AE ........................................................................................116
10.3.3
Definition of SAE ......................................................................................117
10.3.4
Additional Events Reported.......................................................................118
10.3.5
Recording AE and SAE .............................................................................118
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................121
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................123
10.5
Appendix 5: Contraceptive Guidance..............................................................124
10.5.1
Definitions..................................................................................................124
10.5.2
Contraceptive Requirements......................................................................125
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................126
10.7
Appendix 7: Country-specific Requirements..................................................130
10.8
Appendix 8: Blood Volume Table ....................................................................131
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................132
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...134
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10.11 Appendix 11: General and Targeted Neurological Examinations ................135
10.11.1
The General Neurological Examination ....................................................135
10.11.1.1
Module 1 – Mental Status Examination...........................................135
10.11.1.2
Module 2 – Cranial Nerve Assessment............................................135
10.11.1.3
Module 3 – Motor System ...............................................................136
10.11.1.4
Module 4 – Reflexes ........................................................................137
10.11.1.5
Module 5 – Coordination and Gait ..................................................138
10.11.1.6
Module 6 – Sensory .........................................................................139
10.11.2
The Targeted Neurological Examination...................................................139
10.11.2.1
Module 1 – Mental Status Examination...........................................139
10.11.2.2
Module 2 – Cranial Nerve Assessment............................................139
10.11.2.3
Module 3 – Motor System ...............................................................139
10.11.2.4
Module 5 – Coordination and Gait ..................................................140
10.11.2.5
Module 6 – Sensory .........................................................................140
10.12 Appendix 12: Abbreviations .............................................................................141
11
REFERENCES.............................................................................................................146
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LIST OF TABLES
Table 1
Dose Escalation Scheme..............................................................................21
Table 2
Dose Escalation Criteria Based on PK Analysis..........................................50
Table 3
Pharmacokinetic Exposures of MK-5720 at NOAEL Doses.......................53
Table 4
Projected Steady-State Human PK Estimates of MK-8189 Following 
Multiple PO Administration of MK-8189 ...................................................54
Table 5
Predicted Human PK of MK-5720 and MK-8189 Following Single IM 
Administration .............................................................................................55
Table 6
Study Interventions......................................................................................69
Table 7
Allocation of Participants to Treatment.......................................................75
Table 8
Approved Oral Antipsychotic Medications .................................................78
Table 9
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................93
Table 10
Pharmacokinetic (Blood) Collection Windows ...........................................99
Table 11
Protocol-required Safety Laboratory Assessments....................................115
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LIST OF FIGURES
Figure 1
Overall Study Design...................................................................................22
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Single Ascending Dose Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants with 
Schizophrenia
Short Title: MK-5720 SAD Study
Acronym: Not applicable 
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants with schizophrenia.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
single-ascending doses of MK-5720 
long-acting injectable administered 
intramuscularly in participants with 
schizophrenia.
Adverse Events 
Study discontinuation due to adverse events
To assess the plasma pharmacokinetics of 
MK-5720 and MK-8189 following single
doses of MK-5720 long-acting injectable 
administered intramuscularly in participants 
with schizophrenia.
Plasma MK-5720 AUC0-last, AUC0-inf, 
Cmax, Tmax, CL/F, Vz/F and apparent 
terminal t1/2
Plasma MK-8189 AUC0-28d, AUC0-inf, 
Cmax, Tmax, C28d, CL/F, Vz/F and 
apparent terminal t1/2
To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-8189 
in participants with schizophrenia.
Adverse Events 
Study discontinuation due to adverse events
CCI
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Secondary Objective
Secondary Endpoints
To assess the plasma pharmacokinetics of 
MK-8189 following single doses of
MK-5720 long-acting injectable 
administered intramuscularly in participants 
with schizophrenia
 
To compare the effect of the site of 
administration of MK-5720 long-acting 
injectable on plasma pharmacokinetics of 
MK-5720 and MK-8189 following a single 
dose of MK-5720 long-acting injectable 
administered intramuscularly in the gluteal 
muscle relative to its administration in the 
deltoid muscle. 
Estimation: The effects of the site of 
administration on plasma pharmacokinetics 
of MK-5720 and MK-8189 following a 
single dose of MK-5720 long-acting 
injectable administered intramuscularly in 
the gluteal muscle will be estimated and 
compared to a single dose of MK-5720 
long-acting injectable administered 
intramuscularly in the deltoid muscle.
Plasma MK-8189 AUC0-28d, AUC0-inf, 
Cmax, Tmax, C28d, CL/F, Vz/F and 
apparent terminal t1/2
Plasma MK-5720 AUC0-last, AUC0-inf, 
Cmax, Tmax, CL/F, Vz/F and apparent 
terminal t1/2
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Schizophrenia
Population
Participants with schizophrenia or
schizoaffective disorder
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study.
Type of Control
Placebo
CCI
CCI
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Study Blinding
Double-blind
Blinding Roles
Participants or Subjects 
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 12 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 64 participants will be randomized.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Panel A
MK-8189
4 mg
4 mg
Oral
Period 1
Test Product
Panel A
Placebo
0 mg
0 mg
Oral
Period 1
Placebo
Panel A
MK-5720
350 mg/mL
35 mg
IM
Period 2
Test Product
Panel A
Placebo
0 mg
0 mg
IM
Period 2 
Placebo
Panel B 
MK-8189
4 mg
8 mg
Oral
Period 1
Test Product
Panel B
Placebo
0 mg 
0 mg
Oral
Period 1
Placebo
Panel B
MK-5720
350 mg/mL
70 mg
IM
Period 2
Test Product
Panel B
Placebo
0 mg
0 mg
IM
Period 2
Placebo
Panel C
MK-8189
4 mg 
12 mg
16 mg
Oral
Period 1
Test Product
Panel C
Placebo
0 mg
0 mg
Oral
Period 1
Placebo
Panel C
MK-5720
350 mg/mL
140 mg
IM
Period 2
Test Product
Panel C
Placebo
0 mg
0 mg
IM
Period 2
Placebo
Panel D
MK-8189
12 mg
24 mg
Oral
Period 1
Test Product
Panel D
Placebo
0 mg
0 mg
Oral
Period 1
Placebo
Panel D
MK-5720
350 mg/mL
280 mg
IM
Period 2
Test Product
Panel D
Placebo
0 mg
0 mg
IM
Period 2
Placebo
Panel E
MK-8189
12 mg
48 mg
Oral
Period 1
Test Product
Panel E
Placebo
0 mg
0 mg
Oral
Period 1
Placebo
Panel E
MK-5720
350 mg/mL
≤560 mg
IM
Period 2
Test Product
Panel E
Placebo
0 mg
0 mg 
IM
Period 2
Placebo
Panel F
MK-8189
12 mg
48 mg
Oral
Period 1
Test Product
Panel F
Placebo
0 mg
0 mg
Oral
Period 1
Placebo
Panel F
MK-5720
350 mg/mL
≤560 mg
IM
Period 2
Test Product
Panel F
Placebo
0 mg
0 mg
IM
Period 2
Placebo
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Other current or former name(s) or alias(es) for study intervention(s) are as follows: Not 
applicable.
Total Number of Intervention Groups/Arms
6
Duration of Participation
Each participant will participate in the study 
for approximately 17 weeks from the time 
the participant provides documented 
informed consent through the final contact. 
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 12.
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1.2
Schema
The study design is depicted in [Table 1] and [Figure 1].
Table 1
Dose Escalation Scheme
Panelsa,b
MK-8189 Oral 
Run-In Dosec
(Period 1)
Dose Escalation of MK-5720
(Period 2)
A
4 mg
35 mgd
PK Breake
PK Breake
PK Breake
PK Breake
B
8 mg
70 mgd
C
≤16 mg
≤140 mgd
D
≤24 mg
≤280 
mgf,g
E
≤48 mg
≤560
mgf,g
F
≤48 mg
≤560 mgf,g
IM=intramuscular; LAI= long acting injectable; MRI=magnetic resonance imaging; PK=pharmacokinetics
Note: During Period 1, MK-8189 will be administered once daily for 7 days followed by a washout period of at least 72 hours prior to dosing MK-5720.
a
The suggested doses (with the exception of the starting dose) may be adjusted downward based on evaluation of safety, tolerability and PK data observed in previous 
intervention panels. Refer to Section 6.6 (Dose Modification) for the safety and PK data that will be reviewed prior to dose escalation.
b
Panels A to B, 6 participants will be randomized to receive MK-5720 and 2 participants to receive matching placebo. Panels C to F, 9 participants will be randomized to 
receive MK-5720 and 3 participants to receive matching placebo. Patients will be randomized according to a computer-generated allocation schedule.
c
The dose of MK-8189 during the oral run-in period may be adjusted downward based  on the corresponding dose of MK-5720 administered in  the panel to match steady 
state peak plasma exposures of MK-8189 from oral MK-8189 and MK-5720 IM injection.
d
MK-5720 LAI will be administered IM in the deltoid muscle 
e
There will be a PK break following Panel B, C, D, and E  
f
MK-5720 LAI will be administered IM in the deltoid, or the gluteal muscle based on PK from Panels A to C
g
MRI imaging shall be performed in panels at or 1 dose level below the highest dose of MK-5720 administered IM in the deltoid and gluteal muscle
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Figure 1
Overall Study Design
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1.3
Schedule of Activities
1.3.1
Schedule of Activities: Period 1 Oral Run in with MK-8189
All Panels
Study Period
Screening
Washout
and
Check-In
Intervention
Notes
Scheduled Day
Up to -35
-6
-2
1
2
3
4
5
6
7
8
9
10
Predose
Up to 24 h
Administrative 
Procedures
Informed Consent
X
Sec. 5.1, 8.1.1.1
Informed Consent 
for FBR
X
Sec 5.1, 8.1.1.2
Participant ID 
Card
X
Sec. 8.1.3
Inclusion and 
Exclusion Criteria
X
X
Sec. 5.1, 5.2, 8.1.5
Medical History 
(includes 
psychiatric 
history and 
substance abuse)
X
Substances: Drugs, alcohol, tobacco, 
and caffeine
Sec. 8.1.4
Prior and 
Concomitant 
Medication 
Review
X-------------------------------------------------------------------------------------------------------------X
Sec. 5.2, 6.5, 8.1.5
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All Panels
Study Period
Screening
Washout
and
Check-In
Intervention
Notes
Scheduled Day
Up to -35
-6
-2
1
2
3
4
5
6
7
8
9
10
Predose
Up to 24 h
Assignment of 
Screening 
Number
X
Sec. 8.1.6
Washout from 
current 
antipsychotic 
therapy
X
X
Medication discontinued at least 5 days 
or at least 3 half-lives (whichever is 
longer) prior to Day -1
Sec. 8.1.5
Assignment of 
Randomization 
Number
X
Sec. 5.5, 8.1.7
MK-8189 or 
Placebo 
Administration
X
X
X
X
X
X
X
Sec. 8.1.8
Washout from 
MK-8189
X
X
X
Section 4.1
Standard Meals
X----------------------------------------------------------------------------------------------------------X
Sec. 5.3.1
Domicilinga
X----------------------------------------------------------------------------------------------------------X
Sec. 8.1.11
Safety Procedures
Full physical 
examination
X
X
Sec. 8.3.1, 8.10.5
Height
X
Sec. 8.3.1
Weightb
X
X
BMI to be taken only at Screening
Sec. 8.3.1
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All Panels
Study Period
Screening
Washout
and
Check-In
Intervention
Notes
Scheduled Day
Up to -35
-6
-2
1
2
3
4
5
6
7
8
9
10
Predose
Up to 24 h
Full neurological 
examc
X
Sec. 8.3.7, Appendix 11
Targeted 
neurological 
examc
X
X
X
X
X
Sec. 8.3.7, Appendix 11
Orthostatic VS 
(HR and BP)d,f,g
X
X
X
X
X
X
X
X
Sec. 8.3.2.2, 8.10.5
Vital Signs (HR, 
BP)d,f,g
X
X
X
X
X
X
X
X
Sec. 8.3.2., 8.10.5
Vital Signs (RR, 
temperature) d,e,f
X
X
X
X
X
X
X
X
Sec. 8.3.2.1, 8.10.5
12-lead ECG d,f,g
X
X
X
X
X
X
X
X
Sec. 8.3.3, 8.10.5
HIV, hepatitis B 
and C screen 
X
Per site SOP
Sec. 5.2, 8.3.4, Appendices 2 and 8
UDS
X
X
To be completed at screening and upon 
admission
Sec. 5.2, 8.3.4, Appendix 2
Hematology g  
X
X
X 
Sec. 8.3.4, 8.10.5, Appendices 2 and 8
Urinalysis g,h
X
X
X
Sec. 8.3.4, 8.10.5, Appendix 2
Chemistry g,h
X
X
X
Sec. 8.3.4, 8.10.5, Appendices 2 and 8
AE/SAE review
X----------------------------------------------------------------------------------------------------------------X
Sec. 8.4, Appendix 3
BPRS g
X
X
X
Sec. 5.1, 8.3.7, 8.10.5
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All Panels
Study Period
Screening
Washout
and
Check-In
Intervention
Notes
Scheduled Day
Up to -35
-6
-2
1
2
3
4
5
6
7
8
9
10
Predose
Up to 24 h
C-SSRS Baseline 
Version
X
Sec. 5.2, 8.3.5, 8.10.5
C-SSRS Since 
Last Assessment 
Version
X
X
X
X
X 
Sec. 8.3.5, 8.10.5
BARS g,i
X
X
X
X
X
Sec. 8.3.6, 8.10.5
AIMS g,i
X
X
X
X
X
Sec. 8.3.6, 8.10.5
SAS g,i
X
X
X
X
X
Sec. 8.3.6, 8.10.5
Pharmacokinetics
Blood for Plasma 
MK-8189 Assayj
X
X
X
X
X
X
Sec. 8.6.1, 8.10.5, Appendix 8
Biomarkers
Blood for Genetic 
Analysisk
X
Collect predose from enrolled 
participants in Period 1 only.
Sec. 8.8.1, Appendix 8, Study 
Operations Manual
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AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BDS=blood drug screen; BP=blood pressure; BPRS=Brief 
Psychiatric Rating Scale; C-SSRS=Columbia Suicide Severity Rating Scale; CRU=clinical research unit; DNA=deoxyribonucleic acid; EC=exclusion criteria; 
ECG=electrocardiogram; FBR=future biomedical research; HIV=human immunodeficiency virus; HR=heart rate; IC=inclusion criteria; ID=identification;; 
PK=pharmacokinetic; RR=respiratory rate; SAE=serious adverse event; SAS=Simpson Angus Scale; SOP=standard operating procedure; UDS=urine drug screen; VS=vital 
signs 
Note: Day 10 (or last day of MK-8189 washout) corresponds with Day -1 in Period 2.
a.
Participants currently treated with antipsychotic therapy will be domiciled from Day -6 prior to dosing on Day 1 in Period 1 (to start washout period) and will remain in 
the CRU until 28 days postdose in Period 2. Participants not currently being treated with antipsychotic therapy may be domiciled minimally starting on Day -2. 
Participants may stay longer at investigator’s discretion.
b.
After Day 1, assessments should be completed at the same time of day in relation to MK-8189 administration.
c.
Targeted neurological exam can occur at any time on Day 1 as long as the other neurological exams (general and targeted) can occur at the same time of day for the 
remained of the study.
d.
Day 1 Safety Assessments
1.
Predose: VS assessments (HR and BP) and ECG will be completed in triplicate (postdose assessments will be single measurements), RR and orthostatic VS 
(HR and BP) will be single measurements.
2.
Up to 24 hours: VS assessments (including orthostatic VS) (HR, BP, RR) will be collected at 2-, 6-, and 12-hour postdose in single measurements. 
e.
Temperature will be assessed at Screening and Predose Day 1 only and will require single measurements.
f.
Vitals and ECG on Days 2, 4 will be taken only for Panel E and F if the daily MK-8189 oral dose exceeds 24 mg corresponding to MK-5720 dose greater than 280 mg..
g.
The assessment can be done at any time during the day however an attempt should be made for consistent timing across days and periods.
h.
Hematology, chemistry, urinalysis can be use for predose labs in Period 2 as long as they are obtained 24 hours prior to dosing MK-5720.
i.
Additional BARS, AIMS, and SAS assessments should be conducted, as soon as reasonably possible, when there are observed or reported complaints of dystonia 
and/or akathisia
j.
PK Timepoints for MK-8189
1.
Day 1: predose, 2, 6, 8, 10, 12, and 16 hours postdose
2.
Day 2: 24-hour postdose relative to D1 dose administration
3.
Day 7: predose, 2, 6, 8, 10, 12, 16 hours postdose
4.
Day 8: 24 hours postdose for D7 dose administration
5.
Day 9: 48 hours postdose for D7dose administration
6.
Day 10: 72 hours postdose for D7 dose administration
k.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that 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 (or their legally acceptable representative) provides documented informed consent for FBR. 
If the planned genetic analyses are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
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1.3.2
Schedule of Activities: Period 2 MK-5720 Treatment 
All Panels
Study Period
Intervention
P
o
Notes
Scheduled Day
1
2
3
5
6
7
8
9
10
12
13
14
15
16
17
19
20
22
29
36
43 
50
56
Poststudy
Pre-Dose
Up to 24 h hours
Administrative Procedures
Prior and Concomitant Medication 
Review
X------------------------------------------------------------------------------------------------X
Sec. 5.2, 6.5, 8.1.5
MK-5720 or Placebo 
Administration
X
Sec. 8.1.8
Standard Meals
X----------------------------------------------------------------------------------------X
Sec. 5.3.1
Domicilinga
X----------------------------------------------------------------------------------------X
Sec. 8.1.11
Outpatient Visits
X
X
Xb
Safety Procedures
Full physical examination
X
X
X
Sec. 8.3.1, 8.10.5
Height
Sec. 8.3.1
Weightc
X
X
X
Sec. 8.3.1
Full neurological examd
X
X
X
Sec. 8.3.7, Appendix 
11
Targeted neurological examd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.3.7, Appendix 
11
Orthostatic VS (HR and BP)e,f
X
X
X X
X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.3.2.2, 8.10.5
Vital Signs (HR, BP) e,f
X
X
X X
X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.3.2., 8.10.5
Vital Signs (RR, temperature) e,f
X
X
X X
X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.3.2.1, 8.10.5
12-lead ECGe,g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.3.3, 8.10.5
Hematologyg
X
X
X
X
Sec. 8.3.4, 8.10.5, 
Appendices 2 and 8
Urinalysisg
X
X
X
X
Sec. 8.3.4, 8.10.5, 
Appendix 2
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All Panels
Study Period
Intervention
P
o
Notes
Scheduled Day
1
2
3
5
6
7
8
9
10
12
13
14
15
16
17
19
20
22
29
36
43 
50
56
Poststudy
Pre-Dose
Up to 24 h hours
Chemistryg
X
X
X
X
Sec. 8.3.4, 8.10.5, 
Appendices 2 and 8
AE/SAE review
X------------------------------------------------------------------------------------------------------X
Sec. 8.4, Appendix 3
BPRSg
X
X
Sec. 5.1, 8.3.7, 
8.10.5
C-SSRS Since Last Assessment 
Version
X
X
X
X
X
X
X
Sec. 8.3.5, 8.10.5
BARS g,h
X
X
X
X
X
X
X
Sec. 8.3.6, 8.10.5
AIMS g,h
X
X
X
X
X
X
X
Sec. 8.3.6, 8.10.5
SAS g,h
X
X
X
X
X
X
X
Sec. 8.3.6, 8.10.5
MRIi,j,
X
X
X
X
Refer to Site Imaging 
Manual
Pharmacokinetics
Blood for Plasma MK-5720, 
MK-8189, and or Metabolites 
Assayj
X
X
X X
X X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.6.1, 8.10.5, 
Appendix 8
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All Panels
Study Period
Intervention
P
o
Notes
Scheduled Day
1
2
3
5
6
7
8
9
10
12
13
14
15
16
17
19
20
22
29
36
43 
50
56
Poststudy
Pre-Dose
Up to 24 h hours
AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BDS=blood drug screen; BP=blood pressure; BPRS=Brief 
Psychiatric Rating Scale; C-SSRS=Columbia Suicide Severity Rating Scale; CRU=clinical research unit; DNA=deoxyribonucleic acid; EC=exclusion criteria; 
ECG=electrocardiogram; FBR=future biomedical research; HIV=human immunodeficiency virus; HR=heart rate; IC=inclusion criteria; ID=identification; LAI=long acting 
injectable; MRI=magnetic resonance imaging; PK=pharmacokinetic; RR=respiratory rate; SAE=serious adverse event; SAS=Simpson Angus Scale; SOP=standard 
operating procedure; UDS=urine drug screen; VS=vital signs 
Note: Day -1 in Period 2 corresponds to Day 10 in Period 1 (or last day of the MK-8189 washout period).
a.
Participants currently treated with antipsychotic therapy will be domiciled from Day -6 prior to dosing on Day 1in Period 1 (to start washout period) and will remain in 
the CRU until 28 days postdose in Period 2. P Participants may stay longer at investigator’s discretion.
b.
Poststudy follow-up visit will occur 14 ± 2 days after the last study procedure has occurred.
c.
After Day 1, assessments should be completed at the same time of day in relation to MK-5720 administration.
d.
Targeted neurological exam can occur at any time on Day 1 as long as the other neurological exams (general and targeted) can occur at the same time of day for the 
remained of the study.
e.
Day 1 Safety Assessments
1.
Predose: VS assessments (HR and BP) and ECG will be completed in triplicate (postdose assessments will be single measurements), RR and orthostatic VS 
(HR and BP) will be single measurements.
2.
Up to 24 hours: VS assessments (including orthostatic VS) (HR, BP, RR) will be collected at 2-, 6-, and 12-hour postdose in single measurements.
f.
Temperature will be assessed at Predose and Day 56 only and will require single measurements.
g.
The assessment can be done at any time during the day however an attempt should be made for consistent timing across days and periods.
h.
Additional BARS, AIMS, and SAS assessments should be conducted, as soon as reasonably possible, when there are observed or reported complaints of dystonia 
and/or akathisia.
i.
Imaging (MRI) will occur in 2 panels at or 1 dose level below the highest dose of MK-5720 LAI administered in the deltoid and gluteal muscles.
j.
Imaging will occur on Day 1 and Day 14 within 6 to 12 hours postdose in the panels that receive the MK-5720 LAI in the deltoid and gluteal muscle and additionally 
on Day 7, and Day 19 in half of the number of participants in the panel (~ 6 participants) that receive the LAI injection in the deltoid muscle.
1.
Windows for completion of MRIs: Day 1 (4-12 hrs); Day 7 (+/-1 Day); Day 14 and 19 (+/-2 days)
k.
PK Sample Timepoints: Predose, 0.5, 1, 2, 4, 6, 24, 48, 96, 120, 144, 168, 192, 216, 264, 288, 312, 336, 360, 384, 432, 456, 504, 672, 840, 1008, 1176, and 1320 hours 
postdose.
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2
INTRODUCTION
2.1
Study Rationale
MK-5720 is a novel ester carbamate acetal prodrug of the PDE10A inhibitor MK-8189 and is 
being developed as a LAI formulation of MK-8189 for the QM treatment of schizophrenia. 
The primary bioconversion pathway involves systemic esterase-mediated hydrolysis of
MK-5720 to the metabolite, MK-8189. MK-8189 is a potent and highly selective competitive 
inhibitor of PDE10A that is being developed as an orally administered, novel therapeutic for 
the treatment of schizophrenia. MK-5720 and its metabolite, MK-8189, are not considered
compounds with a high potential for risk of harm to schizophrenic participants based on 
preclinical safety data available for MK-5720 and the clinical safety experience gathered 
across multiple clinical studies conducted with oral MK-8189 to date. No dose-limiting
toxicities were observed in the 1-month rat and rhesus toxicity studies with MK-5720 and 
substantial preclinical safety margins were obtained over initial human doses. Preclinical 
studies with MK-5720 as well as clinical safety experience observed with MK-8189 in 
schizophrenic patients to date support the study of MK-5720 in participants with 
schizophrenia for the FIH study.
This study constitutes the first administration of MK-5720 to humans. The main objective of 
this FIH study is to evaluate the safety, tolerability, and PK of MK-5720 LAI after 
administration of single-IM doses in adult participants with schizophrenia. Since the
developmental and reproductive toxicological data for MK-5720 has not been generated at 
this stage, the potential effect of MK-5720 in reproductive healthy women is unknown. As a 
result, only healthy men and PONCBP, ages 18 to 60 years of age inclusive, who meet the
inclusion criteria are eligible to participate in the study. Data from this study will be used to 
guide the selection of doses and dosing regimens for upcoming clinical studies in patients 
with schizophrenia.
The number of participants in each panel (n=8 to 12, allocated n=6 to 9 to 
MK-8189/MK-5720 and n=2 to 3 to placebo) was chosen for this early Phase 1 study to
balance scientific requirements for statistical significance with the study’s objectives 
regarding the ethical use of human participants in a clinical study.
Details regarding specific benefits and risks for participants in this clinical study may be 
found in the accompanying IB and ICF documents.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-5720.
2.2.1
Pharmaceutical and Therapeutic Background
MK-5720 is a novel ester carbamate acetal prodrug of the PDE10A inhibitor, MK-8189 and 
is being developed as a LAI formulation of MK-8189 for the QM treatment of schizophrenia. 
MK-8189 is a potent and selective inhibitor of PDE10A that is being developed as a novel
therapeutic for the treatment of schizophrenia. The PDE10A enzyme metabolically 
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inactivates the ubiquitous second messengers, cAMP and cGMP [Bender, A. T. and Beavo, J. 
A. 2006] and is highly expressed in the target nucleus of the corticostriatal pathway, the 
striatum [Seeger, T. F., et al 2003].
Preclinical pharmacology studies demonstrate that PDE10A inhibition increases 
cAMP/cGMP signaling in pathways that have been associated with underlying pathology 
(glutamate) as well as clinically validated therapeutics (dopamine D2 receptor antagonists) 
for schizophrenia. Enhanced signaling in these pathways is hypothesized to restore 
behavioral inhibition that is impaired in schizophrenia [Grauer, S. M., et al 2009] [Schmidt, C. 
J., et al 2008]. PDE10A inhibitors may potentially be an alternative treatment as monotherapy
and/or adjunct treatment in schizophrenia patients who have inadequate response to first line
AAP or SGA treatment.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Preclinical Studies with MK-5720
MK-5720
Refer to the IB for detailed preclinical information on MK-5720.
2.2.2.2
Clinical Studies with MK-5720 and MK-8189
MK-5720
There have been no clinical studies conducted with MK-5720. 
MK-8189
Preclinical and clinical study information can be found in the MK-8189 IB.
Summary of Completed Phase 1 Clinical Studies
Three single-dose clinical studies (P001, P002, and P004) 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 participants with schizophrenia and healthy participants (P003, P007, P011, and 
P016) have been completed with MK-8189. P011 included elderly (>60 years of age, n=12) 
participants with schizophrenia and healthy elderly (>60 years of age, n=18) participants. 
Overall, across the completed studies, 231 participants have received at least one dose of 
MK-8189; 124 participants without schizophrenia and 107 participants with schizophrenia. 
Overview of MK-8189 Pharmacokinetics
 
 
 Median Tmax of MK-8189 as monotherapy ranged from 10 to 24 hours with a
t1/2 of approximately 10.9 hours.
 
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MK-8189 is a CYP3A substrate and in a DDI study (P006), the coadministration of extended 
release 240-mg diltiazem, a moderate CYP3A inhibitor, increased MK-8189 AUC and Cmax 
by approximately 2-fold and 1.27-fold, respectively. Additionally, a subsequent DDI study 
(P015) demonstrated that coadministration of itraconazole, a strong CYP3A inhibitor, 
increased MK-8189 AUC and Cmax by approximately 1.2-fold and 1.16-fold, respectively, 
and these results were generally consistent with the results observed in the diltiazem study. 
Collectively, these results confirm that MK-8189 is a CYP3A substrate.
 
Overview of MK-8189 Safety Profile
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=231) across the completed 
Phase 1 studies which included, healthy participants (nonelderly and elderly), participants 
with schizophrenia (nonelderly and elderly) and participants with hepatic impairment, were 
headache (13.0%) somnolence (13.4%), dystonia (10.4%), decreased appetite (9.5%), nausea 
(8.7%), fatigue (5.6%), dizziness (6.5%), vomiting (6.1%), diarrhea (4.8%), akathisia (6.1%), 
anxiety (5.2%) and insomnia (5.2%). Most AEs were mild to moderate in severity. There 
were no deaths; however, there was 1 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 reported 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.
In a Phase 2 POC trial (P005), MK-8189 was generally well tolerated by the 90 participants 
who received at least 1 dose of the once daily MK-8189 (titrated every 3 days from 4 mg to 
8 mg and 12 mg, as tolerated). Participants were dosed after they were able to taper off 
psychotropic medications. AEs that occurred in ≥5% of participants in the MK-8189 
intervention group and had greater incidence than placebo were diarrhea, nausea, vomiting, 
decreased appetite, akathisia, dystonia, headache, sedation, somnolence, anxiety, and 
insomnia. No deaths were reported in the P005 study. No SAEs were reported for 
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participants on MK-8189. Eight participants (8.9%) had an AE of dystonia and 2 participants 
(2.2%) had an AE of oromandibular dystonia. Detailed PK and safety information from 
individual completed studies are summarized in the IB.
2.2.3
Completed Clinical Studies (MK-8189)
2.2.3.1
Protocol 011
P011 was a Phase 1 multiple-dose randomized, double-blind, placebo-controlled, 
multicenter, 2-part study. Part 1 (Panels A/B/C) evaluated the safety and tolerability of 
different titration regimens or initiating MK-8189 treatment without titration in participants
≤60 years of age with schizophrenia. Part 2 (Panels D/E/F/G) evaluated the multiple-dose 
safety, tolerability, and PK of MK-8189 in elderly participants with schizophrenia (Panel D 
and Panel E) and healthy elderly participants (Panel F and Panel G) between 61 and 80 years 
of age (inclusive). Panel E and Panel G were to explore the safety and tolerability at different 
titration regimens and were only to be initiated after a safety and tolerability review from 
Panel D and Panel F, respectively.
Part 1 Panel A: Participants with schizophrenia. Intervention MK-8189 16 mg/placebo 
(Days 1 to 3), 24 mg/placebo (Days 4 to 10).
Overall, multiple oral doses of MK-8189 titrated from 16 to 24 mg were generally well 
tolerated in participants with schizophrenia. Of the 8 participants included in the safety 
analysis in Panel A, 6 (75%) experienced 1 or more AEs during the study; 5 participants 
(83.3%) after MK-8189 and 1 participant (50%) after placebo. All AEs were mild or 
moderate in intensity and resolved prior to the end of the study. No participants were 
discontinued from the study intervention due to an AE.
Five participants (62.5%) reported 1 or more AEs that the investigator considered study 
intervention related; 4 participants (66.7%) after MK-8189 and 1 participant (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
decreased appetite (n=1 [16.7%] following MK-8189 24 mg and n=1 [50.0%] following 
placebo), dystonia (n=2 [33.3%] following MK-8189 16 mg), and somnolence (n=2 [33.3%] 
following MK-8189 16 mg).
Dystonia and new or worsening tardive dyskinesia per protocol were defined as ECIs. There 
were 2 (33.3%) participants administered MK-8189 who experienced a nonserious ECI. One 
participant, who prior to the study was being treated with benztropine to prevent EPS, 
experienced mild intermittent bilateral dystonia of the upper extremities after MK-8189 
16 mg. The investigator treated the participant with benztropine 1 mg and symptoms resolved 
after 2 days. The participant had also experienced moderate somnolence (3-day duration; 
related to MK-8189) which resulted in this participant remaining at the 16-mg dose for all 7 
days of dosing. This participant was also taking a sedating antihistamine, hydroxyzine, for 
the duration of the AE. One participant had moderate dystonia of the tongue, lips, facial 
muscles, and left hand after MK-8189 16 mg. The investigator treated the participant with 
benztropine 1 mg and symptoms resolved after 22 hours. The participant was titrated to 
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MK-8189 24 mg per protocol and completed the study without recurrence of dystonia. The 
investigator considered both events related to study intervention. 
Part 1 Panel B: Participants with schizophrenia. Intervention MK-8189 24 mg/placebo 
(Days 1 to 7).
Overall, multiple oral doses of MK-8189 24 mg were generally well tolerated in participants 
with schizophrenia. Of the 18 participants included in the safety analysis in Panel B,10 
(55.6%) experienced 1 or more AEs during the study; 9 participants (64.3%) after MK-8189 
and 1 participant (25%) after placebo. All AEs were mild or moderate in intensity. One 
participant had a moderate ligament sprain continuing at the end of the study. The 
investigator considered the event not related to study intervention. All other AEs resolved 
prior to the end of the study.
Five (35.7%) participants administered MK-8189 24 mg reported 1 or more AEs that the 
investigator considered study intervention related. The most commonly (>1 participants) 
reported study intervention related AE was somnolence (n=2, [14.3%] following treatment 
with MK-8189 24 mg).
One (7.1%) MK-8189 treated participant, who had a history of gastroesophageal reflux 
disease, discontinued intervention due to mild vomiting following administration of 
MK-8189 24 mg. The investigator treated the participant with ondansetron 4 mg and 
symptoms resolved after 3 days. This participant also reported nausea on Day 2. The 
investigator considered both AEs not related to intervention. One (7.1%) participant had a 
mild AE of increased ALT (116 IU/L; NR: 7 to 52 IU/L) following treatment of MK-8189 
24 mg that the investigator considered related to study intervention. This participant had 
mildly elevated screening (61 IU/L) and predose (98 IU/L) values of ALT which continued 
to increase during the study. The AE was reported on the last day of study intervention and 
resolved in ~ 2 weeks. Alkaline phosphatase followed a similar pattern. AST was normal at 
screening and predose but the participant experienced an elevation throughout the study. 
Bilirubin remained within normal range throughout the study.
Part 1 Panel C: Not initiated.
Part 2 Panel D: Elderly participants with schizophrenia. Intervention MK-8189
8 mg/placebo (Days 1 to 3), 16 mg/placebo (Days 4 to 6), 24 mg/placebo (Day 7 to 13).
Overall, multiple oral doses of MK-8189 titrated from 8 mg to 24 mg were generally well 
tolerated in elderly participants with schizophrenia. Of the 16 participants included in the 
safety analysis in Panel D, 10 (62.5%) experienced 1 or more AEs during the study; 7 
participants (58.3%) after MK-8189 and 3 participants (75%) after placebo. The majority of 
AEs were mild or moderate in severity; an AE of severe intensity is discussed below. One 
participant (8.3%) in the MK-8189 intervention group had a mild skin disorder (verbatim 
term: small bump on the left side of the forehead) not resolved at the end of study. The AE 
was reported following the last dose of study intervention (MK-8189 24 mg) and the 
investigator considered this event not related to study intervention. All other AEs resolved 
prior to the end of the study. 
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Six participants (37.5%) reported 1 or more AEs that the investigator considered study 
intervention related; 4 participants (33.3%) after MK-8189 and 2 participants (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
somnolence (n=2 [16.7%] following MK-8189 8 mg, and 24 mg and n=1 [25%] following 
placebo), dystonia (n=1 [8.3%] following MK-8189 8 mg and n=1 [25.0%] following 
placebo) and restlessness (n=2 [16.7%] following MK-8189 8 mg and 16 mg).
One participant (8.3%) in the MK-8189 intervention group experienced an AE of severe 
intensity (somnolence) and a nonserious related ECI (dystonia). On Day 1 following 
administration of the MK-8189 8-mg-dose, the participant experienced severe somnolence 
which resolved after 3 days with continued dosing. No action was taken regarding study 
intervention. On Day 3 following the 8-mg-dose, this participant experienced moderate 
bilateral upper extremity dystonia. The event lasted for 3 days and resolved with
cyclobenzaprine 10 mg. This participant also reported moderate akathisia beginning on Day 
3 with a duration of 3 weeks. This same participant did not receive the Day 6 dose (MK-8189 
16 mg) due to moderate AEs of conjunctivitis (3-day duration) and a maculo-papular rash 
(4-day duration). The investigator considered all AEs related to study intervention. The 
participant did not titrate to the MK-8189 24-mg-dose and was dosed with 16 mg on Day 7. 
The participant withdrew consent on Day 8 and discontinued from study intervention. Three 
participants (n=2 [16.7%] following MK-8189 and n=1 [25.0%] following placebo) were 
discontinued from study intervention due to an AE. One participant discontinued intervention 
due to moderate pain that the investigator did not consider related to study medication. The 
AE started on Day 3 following administration of MK-8189 8 mg and resolved after ~ 1.5 
weeks. The subject discontinued prior to the 16-mg intervention administration on Day 5. 
One participant discontinued intervention due to moderate restlessness after administration of 
MK-8189 16 mg (Day 3). This participant also experienced moderate dyskinesia (verbatim: 
involuntary movement of lower extremities) (Day 6). Both AEs resolved after 23 hours with 
no action taken. The investigator considered both AEs related to study intervention. One 
participant discontinued intervention due to mild dystonia (described below) after 
administration of placebo.
Two participants (n=1 [8.3%] following MK-8189 and n=1 [50.0%] following placebo) 
reported ECIs. One participant experienced moderate dystonia following treatment with 
MK-8189 8 mg and is described above. One participant had mild dystonia of the throat after 
placebo study intervention (Day 3) which initially responded to treatment with benztropine
but then recurred. The event resulted in discontinuation from study intervention and resolved 
after 2 weeks. The investigator considered the event related to study intervention.
One participant (25.0%) in the placebo treatment group had 2 laboratory AEs: mild decreased 
eGFR on 2 occasions. One reported on Day 4 with a duration of 4 days. The other reported 
after the last dose of study intervention along with a mild increased blood glucose. The 
increased blood glucose resolved in 2 weeks; however, the decreased eGFR lasted 
approximately 1.25 months and was considered recovered/resolved with sequelae. The 
participant had a screening eGFR value of 55 mL/min/1.73 m2(NR: >59) with a creatinine of 
1.23 mg/dL (NR: 0.76 to 1.27). The eGFR was low at screening but within 10% of the lower 
limit of normal permitted by the protocol. The participant had a medical history of diabetes 
and hypertension. The investigator felt the eGFR decreases were due to the poorly controlled 
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diabetes, hypertension, and reluctance to hydrate. All AEs were considered not related to 
study intervention.
Part 2 Panel E: Not initiated
Part 2 Panel F: Healthy elderly participants. Intervention MK-8189 8 mg/placebo (Days 1 to 
3), 16 mg/placebo (Days 4 to 6), 24 mg/placebo (Day 7 to 13).
Overall, multiple-oral doses of MK-8189 titrated from 8 to 24 mg were generally well 
tolerated in healthy elderly participants. Of the 6 participants included in the safety analysis 
for Panel F, 4 of 5 participants administered MK-8189 (80%) experienced 1 or more AEs 
during the study. The 1 participant that received placebo did not report an AE. All AEs were 
mild or moderate in intensity and all but 1 AE resolved prior to the end of the study as 
described below.
Three (60%) participants after MK-8189 reported 1 or more AEs that the investigator 
considered study intervention related. No specific related AEs were reported in more than 1 
participant.
One participant (20%) administered MK-8189 discontinued from study intervention due to an 
AE of moderate nausea after administration of MK-8189 24 mg. This participant had
multiple AEs throughout the course of the study. Following treatment with MK-8189 8 mg, 
the participant had an AE of mild decreased appetite (~ 1-week duration) considered related 
by the investigator. Following the third dose of MK-8189 24 mg, this participant reported 
AEs of moderate dizziness (~ 8-hour duration), moderate nausea (5-day duration; reason for 
discontinuation), mild vomiting on 2 occasions (1- and 2-minute durations), mild dyspepsia 
(3.5-hour duration), and mild ongoing hyponatremia (133 mmol/L on Day 10 and 130
mmol/L at discharge [NR 135 to 146 mmol/L]). The investigator considered all AEs after 
MK-8189 24 mg related to study intervention. This participant also had mild diarrhea 
(considered unrelated to study intervention) beginning on Day 6 (16 mg) with a duration of 
5 days which may have contributed to the hyponatremia. The participant also experienced a 
mild macule (verbatim: asymptomatic macular erythematous lesions on upper left chest) on 
Day 5 which was considered unrelated to treatment.
One participant reported moderate involuntary muscle contractions (3.5-hour duration) along 
with moderate EPS (~ 2-week duration) following MK-8189 16 mg (Day 5). The participant 
also experienced a second episode of moderate involuntary muscle contractions on Day 6 
(~ 2-week duration). Following the participant’s first MK-8189 24-mg dose and due to the 
ongoing EPS, the participant did not feel comfortable continuing at the 24-mg dose and was 
down-titrated to 16 mg for the duration of the study. The EPS was characterized by 
intermittent internal and visible tremor, intermittent stiffness and intermittent cogwheeling. 
The participant was given benztropine as needed until these AEs resolved. This participant 
also reported mild salivary hypersecretion (2-hour duration) following MK-8189 16 mg
(Day 10). The investigator considered all AEs related to study intervention.
Part 2 Panel G: Healthy elderly participants. Intervention MK-8189 16 mg/placebo (Days 1 
to 3), 24 mg/placebo (Days 7 to 13).
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Overall, multiple oral doses of MK-8189 titrated from 16 to 24 mg in healthy elderly may be 
less well tolerated than initiating titration of MK-8189 at a dose of 8 mg. Of the
15 participants included in the safety analysis for Panel G, 12 (80%) experienced 1 or more 
AEs during the study; 11 participants (84.6%) after MK-8189 and 1 participant (50%) after 
placebo. The majority of AEs were mild or moderate in intensity; AEs of severe intensity are 
described below. All AEs resolved prior to the end of the study.
Ten participants (66.7%) reported 1 or more AEs that the investigator considered study 
intervention related; 9 participants (69.2%) after MK-8189 and 1 participant (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
somnolence (n=4 [30.8%] following MK-8189 16 mg), akathisia (n=3 [23.1%] following
MK-8189 16 mg [n=2] and 24 mg [n=1]), tremor (n=3 [23.1%] following MK-8189 24 mg), 
myalgia (n=2 [15.4%] following MK-8189 16 mg and 24 mg), headache (n=2 [15.4%] 
following MK-8189 24 mg), hypertonia (n=1 [7.7%] following MK-8189 24 mg and n=1 
[50%] placebo), and oromandibular dystonia (n=2 [15.4%] following MK-8189 16 mg and 
24 mg).
Three participants (23.1%) administered MK-8189 experienced 1 AE of severe intensity. 
One participant experienced severe somnolence on Day 1 (MK-8189 16 mg) which resolved 
after 8.75 hours. The participant also reported mild akathisia (3-hour duration), mild
dyspepsia (3-hour duration) and restlessness (~ 1-week duration) also on Day 1 and an AE of 
mild tremor (4-day duration) on Day 5 (MK-8189 24 mg). One participant experienced 
severe somnolence on Day 1 (MK-8189 16 mg) which resolved after 10 hours. This 
participant had no other reported AEs. The investigator considered all AEs for both 
participants related to study intervention. No action was taken with study intervention for 
these 2 participants. One participant experienced a severe hypnagogic hallucination after 
MK-8189 24 mg (discussed below).
Three (23.1%) participants administered MK-8189 discontinued study intervention due to an 
AE. One participant discontinued due to a severe hypnagogic hallucination on Day 8. This 
participant experienced mild akathisia (20-hour duration) and moderate headache (8-hour 
duration) on Day 7 after MK-8189 24 mg. The participant was treated with benztropine 1 mg 
as needed for the akathisia. Overnight, prior to the Day 8 24-mg administration, the 
participant experienced moderate tactile hallucination (5-minute duration), moderate 
hyperhidrosis (5-hour duration) and mild palpitations (2-minute duration). Early morning 
upon waking on Day 8, the participant experienced a severe hypnagogic hallucination 
(5-minute duration). The participant did not receive the Day 8 dose due to these AEs. Later 
that day (Day 8), the participant experienced moderate tactile hallucination (15-minute
duration), moderate hyperhidrosis (15-minute duration), mild hypertonia (5-day duration) 
and moderate sinus tachycardia (39-minute duration). Since similar AEs reoccurred on 
Day 8, the participant decided not to continue dosing due to the possibility of a reoccurrence 
of the hypnagogic hallucination. This participant also reported a mild ECI of oromandibular 
dystonia (30-minute duration) on Day 1 (MK-8189 16 mg) and a mild headache on Day 10 
(MK-8189 24 mg). The investigator considered all AEs related to study intervention except
the mild headache on Day 10. One participant discontinued intervention due to mild akathisia 
following Day 3 administration of MK-8189 16 mg. The investigator treated the participant 
with benztropine 1 mg and symptoms resolved after 2 days. The investigator considered the 
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AE related to study intervention. This participant also reported mild fatigue (6-day duration) 
and moderate wheezing (2-day duration) 8 days following intervention discontinuation. The 
investigator considered these AEs not related to study intervention. One participant 
discontinued intervention due to moderate ECI of oromandibular dystonia of the jaw on Day 
4 following administration of MK-8189 24 mg. The investigator treated the participant with 
benztropine 1 mg and symptoms resolved after 6.5 hours. The participant also reported 
moderate anxiety (~ 11-hour duration; treated with lorazepam 1 mg), mild myalgia 
(14.5-hour duration; treated with ibuprofen 800 mg) and mild apathy (23-hour duration) on 
Day 4. The investigator considered all Day 4 AEs related to study intervention. Prior to the 
Day 4 AEs, the participant experienced on Day 2 moderate apathy (2-day duration), mild 
dysphonia (6-day duration), mild involuntary muscle contractions (verbatim: fasciculation, 
2-day duration) and mild parosmia (~ 1-week duration), all considered related to intervention 
by the investigator. On Day 3, the participant experienced mild back pain (3-day duration; 
treated with paracetamol 1000 mg), salivary hypersecretion (3-day duration) and mild muscle
tightness of the legs (10.5-hour duration). The only AE considered related to intervention on
Day 3 by the investigator was the salivary hypersecretion.
One participant (7.7%) had a mild laboratory AE of decreased eGFR on Day 12 after 
MK-8189 24 mg which was not considered related to study intervention. The decreased
eGFR lasted around 1.5 months and was considered recovered/resolved with sequelae by the 
investigator. The participant had a normal screening eGFR value of 75 mL/min/1.73 m2
(NR:>59) with a creatinine value of 0.81 mg/dL (NR: 0.76 to 1.27). The eGFR fluctuated
between 65 and 75 mL/min/1.73 m2throughout the study but was never below the NR until 
Day 12 (eGFR value of 58 mL/min/1.73 m2; creatinine value of 1.01 mg/dL). The participant 
had a history of hypertension, and the investigator felt the eGFR decrease was related to their 
baseline hypertension. The investigator referred the participant to their PCP for further
treatment of hypertension (participant was prescribed lisinopril by the PCP).
Across all Panels, there were no dose-related trends for increases in specific AEs. There were 
no clinically meaningful trends for MK-8189-treatment related changes in safety laboratory
values, VS, including orthostatic VS, ECGs, or physical exams. There were no SAEs nor 
deaths reported and no participant reported suicidal ideation or behavior per the C-SSRS.
2.2.3.2
Protocol 012
P012 was an open-label, single-dose Phase 1 study to evaluate the safety, tolerability, and PK 
in participants with hepatic impairment and matched healthy participants.
Overall, MK-8189 4 mg was generally well tolerated in the moderate hepatic impairment and 
healthy participants in the study. No deaths nor SAEs nor ECIs were reported. No participant 
discontinued from the study due to an AE. Of the 14 participants included in the safety
analysis, 4 (28.6%) experienced 1 or more AEs during the study: 4 (57.1%) in the moderate 
hepatic impairment group and none in the healthy participants group. Ten (71.4%) 
participants did not report an AE. All AEs were mild in intensity and all AEs resolved by the 
end of the study. The most frequently (>1 participant) reported AE amongst the moderately 
hepatic impaired participants was vomiting (n=2/7; 28.6%). One participant vomited on Day
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1, ~ 5 hours after dosing and another participant on Day 3. All other AEs were reported by 1 
participant only.
Intervention-related AEs were reported by 2 of 14 (14.3%) participants as detailed below. Six 
AEs (2 of 7 [28.6%] participants with moderate hepatic impairment) were considered 
intervention-related by the investigator: One participant developed mild AEs of vomiting,
~ 5 hours after dosing (1 episode, 1 minute), muscle spasm (10 minutes), and hot flush
(40 minutes). One participant had mild AE of headache (19.5 hours) on Day 1, followed by 
anxiety (30 minutes) and affect lability (30 minutes) on Day 2.
No clinically meaningful trends were observed as a function of study intervention for 
laboratory safety tests, VS, or ECGs.
2.2.3.3
Protocol 016
P016 was a randomized, placebo-controlled, parallel-group, single-site, double-blind, 
multiple-ascending dose study of MK-8189 in healthy participants. Up to approximately 
25 healthy participants were planned to be enrolled to ensure 20 participants completed the 
study. Participants were randomized to receive single rising doses of MK-8189 or placebo on
Days 1 through 6 (Day 1=8 mg, Day 2=16 mg, Day 3=24 mg, Days 4, and 5=48 mg, and 
Day 6=72 mg). Participants were domiciled from Day -2 until Day 9.
Adverse Events: In general, MK-8189 up to doses of 24 mg was well tolerated in healthy 
male and female participants in the study. The rapid titration regimen above 24 mg was not 
generally well tolerated due to central nervous system and gastrointestinal AEs.
Of the 12 participants included in the safety analysis, 100.0% (n=12/12) experienced 1 or 
more AEs during the study. In general, more AEs were observed with higher doses of
MK-8189, and all participants receiving placebo reported AEs; 28.6% (n=2/7) for MK-8189 
8 mg (Day 1), 57.1% (n=4/7) for 16 mg (Day 2), 42.9% (n=3/7) for 24 mg (Day 3), 100.0%
(n=6/6) for 48 mg (Days 4 and 5), 100% (n=4/4) for 72 mg (Day 6), and 100.0% (n=5/5) for 
placebo. Most AEs were mild or moderate in intensity; one AE of akathisia was rated severe. 
All but 1 unrelated AE of leukocyturia resolved by study completion. There were no deaths 
nor other SAEs.
Three participants receiving MK-8189 discontinued study intervention due to AEs that were 
considered related to study intervention by the investigator: One participant experienced a 
moderate AE of vomiting (duration 23.17 hours) following administration of the second
48-mg dose and was not titrated further by decision of the investigator. This participant also 
experienced mild nausea (2 days) following the second dose of 48 mg. One participant 
experienced a moderate AE of anxiety (duration 9.92 hours) following administration of the 
second 48-mg dose and was not titrated further by decision of the investigator. This 
participant also experienced moderate vomiting (duration 10 minutes) following the second 
dose of 48 mg. One participant discontinued study intervention following the 24-mg dose due 
to severe akathisia that started 23.5 hours after dosing (duration 22.5 hours) and was treated 
with 3 doses of 10-mg propranolol hydrochloride. This participant also experienced moderate 
affect lability which began after the 16-mg dose (duration 4 days) and a few days later
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(Day 9) mild affect lability with a duration of 3.43 weeks, as well as mild restlessness which 
started after the 24-mg-dose (duration 3 days).
One participant receiving placebo had a dose reduction when still blinded (from 48 mg on 
Day 4 to 24 mg MK-8189/placebo on Days 5 and 6) due to AEs of mild restlessness and 
moderate somnolence, both assessed by the investigator as related to study intervention, that 
started on Day 4 and lasted 40 minutes and 7 hours, respectively.
AEs reported by >1 participant treated with MK-8189 or placebo were: nausea (MK-8189: 
71.4%, placebo: 40.0%); decreased appetite (MK-8189: 71.4%, placebo: 20.0%); insomnia
(MK-8189: 57.1%); headache (MK-8189: 42.9%, placebo: 40.0%); nightmare (MK-8189: 
42.9%, placebo: 20.0%); diarrhea and pyuria (MK-8189: 42.9% each); restlessness
(MK-8189: 28.6%, placebo: 20.0%); vomiting, eructation, increased systolic BP, hematuria, 
and leukocyturia (MK-8189: 28.6% each); dizziness and somnolence (placebo: 40.0% each). 
AEs in the system organ classes of gastrointestinal disorders, metabolism and nutrition
disorders, and psychiatric disorders were most frequently reported, by 6 participants each.
A total of 83.3% (n=10/12) participants reported AEs that were considered related to study 
intervention by the investigator. In general, more AEs were observed with higher doses of 
MK-8189; 14.3% (n=1/7) for MK-8189 8 mg, 42.9% (n=3/7) for 16 mg, 28.6% (n=2/7) for
24 mg, 83.3% (n=5/6) for 48 mg, 100% (n=4/4) for 72 mg, and 60.0% (n=3/5) for placebo. 
Study-intervention-related AEs reported by >1 participant treated with MK-8189 or placebo 
were: nausea (MK-8189: 71.4%, placebo: 40.0%); decreased appetite (MK-8189: 71.4%, 
placebo: 20.0%); insomnia (MK-8189: 57.1%); headache (MK-8189: 42.9%, 
placebo:40.0%); nightmare (MK-8189: 42.9%, placebo: 20.0%); diarrhea (MK-8189: 
42.9%); restlessness (MK-8189: 28.6%, placebo: 20.0%); vomiting, eructation, increased 
systolic BP (MK-8189: 28.6% each); dizziness and somnolence (placebo: 40.0% each).
Dystonia was an ECI. One participant experienced an AE of dystonia in the legs 
approximately 14 hours after receiving MK-8189 72 mg on Day 6 with a duration of 17 
minutes. Earlier in the day (~ 6-hours postdose), this participant experienced intermittent 
tremors in the legs (duration 40 minutes) and 10 minutes later also muscle twitches in the 
right leg (duration 7.67 hours). All AEs were of mild intensity, considered related to study 
intervention and resolved without intervention. Although not considered dystonia, the 
following dystonic-like reactions were also observed. One participant receiving MK-8189 
experienced AEs of intermittent muscle tightness in the arms on Day 2 ~ 30-minutes predose 
(ie, 23.5 hours after the 8-mg dose) (duration 3 hours), muscle spasms in the right hand on 
Day 2 44 minutes after the 16-mg dose (duration 1 minute) and blepharospasm on Day 4
after the first 48-mg dose (duration 3 days). The participant also experienced orofacial 
dyskinesia on Day 2 predose. All AEs were of mild intensity, considered related to study 
intervention and resolved without intervention. This participant discontinued study 
medication after the second dose of MK-8189 48 mg due to an AE of vomiting. One 
participant receiving placebo experienced mild muscle spasms in the calves on Day 7 with a 
duration of 5 days. This participant also developed moderate intermittent akathisia on Day 7 
with a duration of 5 days that was treated with 60-mg propranolol hydrochloride on Days 7 to
11. Both events were considered related to study intervention and resolved. Two other 
participants randomized to MK-8189 received propranolol hydrochloride to treat AEs. One 
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participant to treat severe akathisia (see above). Another participant received a single dose of 
10-mg propranolol hydrochloride on Day 7 to treat an acute stress disorder of moderate 
intensity that started 33 hours after the last dose (72 mg on Day 6) and resolved in 4 hours. 
The AE was not considered related to study intervention.
Laboratory Safety Tests and Physical Examination: Overall there were no clinically 
meaningful trends observed as a function of study intervention for laboratory safety tests and 
physical examination. Although there were some AEs reported related to laboratory safety 
tests, none of these were considered related to study intervention.
12-lead ECGs and Semi-automated Holter ECGs: 12-lead ECGs were collected from Day
1 to Day 6 24 hours with Day 1 predose as baseline. Semi-automated Holter ECGs were 
collected on Days 1, 3, and 6 (up to 72-hours postdose) with time-matched baseline. QTcF 
categorical analyses were performed for the Holter ECGs only.
QTcF: Mean change from time-matched baseline for QTcF from the semi-automated Holter 
ECGs was similar for MK-8189 and placebo. A similar pattern was observed for the 12-lead
ECGs. All QTcF values during the study were ≤450 msec (Holter). All changes in QTcF from 
time-matched baseline (Holter) were <30 msec, except for 1 participant receiving MK-8189
8 mg who had an increase >30 msec and ≤60 msec on Day 1 8 hours (actual increase: 33 
msec, time-matched baseline value: 395 msec) and 14 hours (actual increase: 40 msec, time-
matched baseline value 391 msec). This participant continued dosing up to 72 mg without 
any further QTcF increases of >30 msec.
12-lead ECG parameters were generally similar for MK-8189 and placebo. However, mean 
change from baseline for ventricular rate was higher for MK-8189 than for placebo at higher 
doses (starting on Day 5 10 hours) up to 72 hours after the 72-mg dose, which was also 
present on the Holter ECGs on Day 6. The rationale for the ventricular/heart rate increase is 
unknown.
Mean change from time-matched baseline for resting systolic and diastolic BP was generally 
similar for MK-8189 and placebo. It was numerically higher from Day 6 6 hours onwards,
and Day 6 14 hours onwards, respectively.
Orthostatic Hypotension: One participant (MK-8189 48 mg) experienced orthostatic 
hypotension (ie, a decrease of ≥20 mmHg between standing and semi-recumbent systolic BP
or decrease of ≥10 mmHg between standing and semi-recumbent diastolic BP). All events
were asymptomatic, and no occurrences were considered AEs.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine.
No clinical studies with MK-5720 have been conducted to date. The conduct of the proposed 
clinical first-in-human study described in the clinical protocol is supported by the safety 
profile of MK-5720 established in the preclinical toxicological studies and that of its 
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metabolite, MK-8189 in clinical studies. Furthermore, there is no evidence of mutagenicity 
or genotoxicity in a standard core battery of genetic toxicity assays conducted with MK-5720 
and MK-8189.
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 participants with schizophrenia.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
single-ascending doses of MK-5720 
long-acting injectable administered 
intramuscularly in participants with 
schizophrenia.
Adverse Events 
Study discontinuation due to adverse events
To assess the plasma pharmacokinetics of 
MK-5720 and MK-8189 following single
doses of MK-5720 long-acting injectable 
administered intramuscularly in participants 
with schizophrenia.
Plasma MK-5720 AUC0-last, AUC0-inf, 
Cmax, Tmax, CL/F, Vz/F and apparent 
terminal t1/2
Plasma MK-8189 AUC0-28d, AUC0-inf, 
Cmax, Tmax, C28d, CL/F, Vz/F and 
apparent terminal t1/2
To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-8189 
in participants with schizophrenia.
Adverse Events 
Study discontinuation due to adverse events
Secondary Objectives
Secondary Endpoints
To assess the plasma pharmacokinetics of 
MK-8189 following single doses of
MK-5720 long-acting injectable 
administered intramuscularly in participants 
with schizophrenia
 
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To compare the effect of the site of 
administration of MK-5720 long-acting 
injectable on plasma pharmacokinetics of 
MK-5720 and MK-8189 following a single 
dose of MK-5720 long-acting injectable 
administered intramuscularly in the gluteal 
muscle relative to its administration in the 
deltoid muscle. 
Estimation: The effects of the site of 
administration on plasma pharmacokinetics 
of MK-5720 and MK-8189 following a 
single dose of MK-5720 long-acting 
injectable administered intramuscularly in 
the gluteal muscle will be estimated and 
compared to a single dose of MK-5720 
long-acting injectable administered 
intramuscularly in the deltoid muscle.
Plasma MK-8189 AUC0-28d, AUC0-inf, 
Cmax, Tmax, C28d, CL/F, Vz/F and 
apparent terminal t1/2
Plasma MK-5720 AUC0-last, AUC0-inf, 
Cmax, Tmax, CL/F, Vz/F and apparent 
terminal t1/2
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Objective: To characterize the morphology 
of the injection site depot over time, using 
direct visualization of the depot. 
Depot volume and surface area, measured at 
multiple time points via segmentation of the 
intramuscular depot on T2-weighted 
magnetic resonance imaging, after a single 
dose of MK-5720 long-acting injectable 
administered intramuscularly in both the 
deltoid and gluteal muscles.
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
Objective: To assess the pharmacokinetics 
of oral MK-8189 following multiple doses 
of MK-8189 in participants with 
schizophrenia.
AUC0-24, Cmax, Tmax, terminal t1/2, and 
C24 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, multisite, double blind, single ascending dose, 
parallel group study of MK-5720 in participants with schizophrenia to be conducted in 
conformance with GCP. The primary objective of the study is to assess the safety, 
tolerability, and to characterize the PK of single rising doses of MK-5720 administered IM
and to evaluate the safety and tolerability of multiple once-daily oral doses of MK-8189 in 
participants with schizophrenia.
MK-5720-001 clinical study will consist of 6 panels (A, B, C, D, E, and F) and two treatment 
periods, Periods 1 and 2. Period 1 will include an oral tolerability run-in period with 
participants receiving once-daily administration of MK-8189 (or corresponding placebo) for 
7 days followed by a washout period of at least 72 hours prior to initiation of Period 2. 
Participants will receive rising single dose IM injection of MK-5720 (or corresponding 
placebo) in Period 2. The dose of MK-8189 (or placebo) used in Period 1 will vary based on 
each panel as mentioned in [Table 1]. Approximately 8 participants (n=6 for 
MK-8189/MK-5720 and n=2 for placebo) will be in Panels A and B and approximately 12 
participants (n=9 for MK-8189/MK-5720 and n=3 for placebo) in Panels C through F. Each 
panel will sequentially receive single rising IM doses of MK-5720 and the corresponding 
dose of oral MK-8189 as mentioned in Table 1. Each participant will be assigned to 1 of 6
panels and will participate in both treatment periods. Participants will be randomized to 
receive a single IM injection of MK-5720 or placebo and oral MK-8189 or placebo in a 
blinded fashion. Panels A through C will investigate IM doses of MK-5720 in the deltoid 
muscle while Panels D through F will investigate IM doses in the deltoid or gluteal muscle 
based on PK data obtained from Panels A to C. Since patient preference for injection sites 
differ between geographic regions, the effect of the site of administration of MK-5720 LAI 
on plasma PK of MK-5720 and MK-8189 following a single dose of MK-5720 LAI 
administered IM in the gluteal muscle relative to administration in the deltoid muscle will be 
compared. Currently, the literature on this topic is sparse, but the published data show 
discrepancies in the elimination half-life, peak plasma concentration, and absorption rate that 
are dependent on the site of injection. Hence, both PK and safety of MK-5720 LAI will be 
compared between both IM sites of administration at the highest well tolerated dose of 
MK-5720 to potentially offer the choice of administration into either the deltoid or gluteal 
muscle to meet patient and physician preference in future clinical studies. MK-5720 LAI will 
be administered as a suspension for injection for doses up to ≤560 mg that will be 
administered IM using the appropriate needle size/gauge based on the participant’s BMI and 
site of LAI administration.
MRI exam will be incorporated in 2 panels at or 1 dose level below the highest dose of 
MK-5720 LAI that are administered IM in the deltoid and gluteal muscles to visualize the 
injection site depot using multislice spin-echo T2-weighted and assess the location of the 
depot in the muscle and to quantify drug depot characteristics, including volume and surface 
area over time. This information will be utilized to better understand any differences in PK
between patients and to build models to better predict human PK from preclinical animal 
models in subsequent clinical studies.  
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Decision to dose participants with MK-5720 in any given panel will be based on 
demonstrating acceptable tolerability in individual participants with oral MK-8189 from the 
oral tolerability run-in period and based on key safety variables including AEs, VS, 12-lead 
ECGs, laboratory safety tests, neurological and physical examinations, and C-SSRS. The 
decision for a participant to proceed to Period 2 will be a joint decision between the PI and 
the Sponsor. Dose escalation decisions for MK-5720 will be based on key safety variables 
including AEs, VS, 12-lead ECGs, laboratory safety tests, neurological and physical 
examinations, C-SSRS, and local and systemic reactions assessed in Period 2. The decision 
to proceed to the next higher dose level will be based upon acceptable safety of MK-5720 at 
the previous dose. When available, plasma PK data will be reviewed to aid dose escalation 
decisions. For dose escalation to Panel B, the decision to proceed will be based on 14 days of 
safety and tolerability data from Panel A. 
 
 Plasma 
concentrations of MK-5720 from the preceding panels will be determined at the allocated PK 
breaks to ensure that the NOAEL AUC exposure limits are not exceeded at the doses in the 
subsequent panels. Similarly, plasma concentrations of MK-8189 from the preceding panels 
will also be determined at the allocated PK breaks to ensure that MK-8189 exposures do not 
exceed exposures observed with oral MK-8189 at doses that are generally well tolerated in 
participants with schizophrenia. Dose escalation decisions for Panels C through F will be 
informed by safety, tolerability, and PK data from all patients in the prior panel through 28 
days postdose. 
If applicable, participants will be washed off their current antipsychotic therapy prior to 
MK-8189 dose administration in Period 1. The washout may start with a down titration of the 
antipsychotic treatment during the screening phase per direction of the investigator. If 
participants are not currently receiving antipsychotic therapy, they may be domiciled as late 
as Day -2 prior to dosing administration in Period 1. All participants will be domiciled from 
the initial washout period prior to dosing MK-8189 in Period 1 and until 28 days postdose for 
monitoring of safety, tolerability, and intensive PK sampling in Period 2. At the discretion of 
the investigator, the participants may be domiciled for a longer duration if further observation 
is required. Participants will return to the clinic for outpatient procedures as outlined in 
Section 1.3.2 (SoA).
Because this is a Phase 1 assessment of MK-5720 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.10.6 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.
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4.2
Scientific Rationale for Study Design
The study design selected is deemed optimal for the initial evaluation of safety, tolerability, 
and PK of MK-5720 in schizophrenic patients. 
This is the first instance of administration of MK-5720 to humans with the study aimed to 
evaluate the safety and tolerability of MK-5720 and characterize the PK profile of MK-5720 
as single ascending doses in participants with schizophrenia with the protocol specifically 
designed in a manner to ensure the safety of the participant. The study incorporates an oral 
tolerability run-in period with MK-8189 to demonstrate and establish acceptable tolerability 
with MK-8189 in individual participants prior to administration of MK-5720 IM injection 
given the inability to reduce daily exposure levels of MK-8189 once MK-5720 injection is 
administered to participants. Data from the study will be instrumental in guiding dose 
selection and dosing regimen for future clinical studies. Since the developmental and 
reproductive toxicological data for MK-5720 has not been generated at this stage, the 
potential effect of MK-5720 in reproductive healthy women is unknown and hence, only 
adult men and PONCBP, ages 18 to 60 years of age inclusive, who meet the inclusion criteria 
are eligible to participate in the study.
The protocol has been designed in a manner to ensure the safety of clinical study participants. 
In all preclinical studies the bioconversion of prodrug MK-5720 to MK-8189 is rapid and 
generally similar between monkey and human but found to be more rapid in rat. Following 
IV administration of MK-5720 in rats and monkeys, the plasma concentration of MK-5720 
was undetectable at timepoints beyond 15 minutes postdose. Additionally, the exposure of 
MK- 5720 was less than 1% of the MK-8189 exposure (AUC0-inf) seen after IM 
administration of MK-5720 in monkeys. The rapid bioconversion prevented determination of 
t1/2 of MK-5720. Given MK-5720 is approximately 650-fold less potent compared to 
MK-8189 based on in vitro binding assays and that the bioconversion of MK-5720 in humans
is anticipated to be rapid, concentrations are expected to be well below pharmacologically 
active concentrations and therefore, the main pharmacological activity expected in the clinic 
is as a result of the MK-8189 metabolite. Both, prodrug and MK-8189 concentrations will be 
actively monitored in the clinic.
Furthermore, the structure of this study is designed based upon the projected PK of MK-8189 
derived from MK-5720 LAI, that is estimated to have a t1/2 of ~ 10 days in humans. This 
study will collect PK samples for 55 days postdose to ensure MK-8189 washout of at 
approximately 5 half-lives.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
No efficacy endpoints will be evaluated in this study.
4.2.1.2
Safety Endpoints
No treatment related findings were identified in the GLP 1-month single dose IM toxicity 
studies with 3-month recovery period conducted with MK-5720 in rats and NHPs. The 
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NOAELs were the highest dose tested, 510 mg/kg in rats 
 
 
for MK-5720.
Clinical pathology changes were not considered toxicologically meaningful, given the small 
magnitude and transient nature, and were attributed to an inflammatory response associated 
with MK-5720 histomorphology changes in the injection sites noted in rats at ≥30 mg/kg 
 
 
 In both species these findings 
resolved after a 3-month recovery period. Histological findings at the injection sites in rats 
and NHPs were consistent with those typically observed following administration of a long-
acting formulation that produces an extended-release depot [Paquette SM, et al 2014].
Because studies in preclinical species are not always predictive of what may occur in 
humans, the safety and tolerability of MK-5720 will be assessed throughout the study by 
monitoring participants frequently for clinical AEs as well as through the conduct of 
neurological exams, physical exams, ECGs, VS, and laboratory safety tests (chemistry, 
hematology, urinalysis). The timing of the safety endpoints has been planned to ensure 
adequate safety monitoring throughout the treatment period also taking into consideration the 
range of potential half-life predictions of MK-8189 from the MK-5720 LAI. Key safety data 
such as VS, 12-lead ECGs, lab safety tests and physical/neurological examinations will be 
reviewed for up to at least 14-days postdose for Panel A prior to dose escalation to Panel B 
and up to 28-days postdose prior to dose escalation to the next higher dose level in all other 
treatment periods. The C-SSRS will be administered to monitor mood and suicidal ideation 
and behavior in all trial participants (see Section 4.2). 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).
The BPRS rating scale will be used to measure psychiatric symptoms such as depression, 
anxiety, hallucinations, and unusual behavior in a range of psychotic and affective symptoms 
in participants with schizophrenia. The BPRS has been used in clinical research as a tool to 
measure treatment effects and are effective scales to monitor the general well-being of the 
psychiatric patients. The BPRS consists of 18 symptom constructs and takes 20 to 30 minutes 
for the interview and scoring. The rater should enter a number ranging from 1 (not present) to 
7 (extremely severe). Zero is entered if the item is not assessed. Participants who experience 
severe psychosis during the study will be discontinued and referred for additional treatment 
as indicated.
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Rescue medications for the management of EPS side effects and administration of standard 
of care practice (oral antipsychotics) in the event of worsening of psychosis while on 
MK-5720 LAI to control symptoms associated with schizophrenia during washout of 
MK-5720 are detailed in Section 6.5.1.
4.2.1.3
Pharmacokinetic Endpoints
One of the primary objectives of the study is to characterize the PK profile of MK-5720 as 
well as MK-8189 as rising single doses of administration of the IM MK-5720 LAI in Period 
2. In order to characterize the PK profile of MK-5720 and MK-8189, noncompartmental PK 
parameters, AUC0-last (MK-5720 only), AUC0-inf, AUC0-28d (MK-8189 only), Cmax, 
C28d (MK-8189 only), Tmax, apparent t1/2, apparent CL/F, and apparent Vz/F will be 
estimated after single-dose IM administration of the MK-5720 LAI. The dose escalation 
criteria based on PK analysis are listed below in [Table 2]. Additionally, in Period 1 of the 
study, one of the exploratory objectives is to characterize the PK profile of MK-8189 
following multiple oral doses of MK-8189. Therefore, the noncompartmental PK parameters, 
AUC0-24, Cmax, Tmax, terminal t1/2 and C24 will be estimated on day 1 and day 7. Plasma 
samples will be analyzed based on prespecified time point sampling mentioned in Section 
1.3.
Table 2
Dose Escalation Criteria Based on PK Analysis
Dose (Panel)
Dose Escalation Decision Criteria
140 mg (C)
28d postdose PK analysis from the preceding doses from Panels A 
and B
280 mg (D) 
28d postdose PK analysis from the preceding dose in Panels C
≤560 mg (E)
28d postdose PK analysis from the preceding dose in Panel D
≤560 mg (F)
28d postdose PK analysis from the preceding dose in Panel E
28d=28 days; PK=pharmacokinetics
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints will be evaluated in this study.
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 
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tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
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 Comparator/Placebo
Placebo will be used in this study to allow for an appropriate assessment of the safety data of 
oral MK-8189 and MK-5720 LAI and to maintain study blinding to reduce bias.
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
The methods used in calculating doses and estimated exposures are detailed in Section 4.3.1 
and Section 4.3.2. 
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An oral tolerability run-in period with MK-8189 is included before administration of the IM 
MK-5720 injection. Due to the short half-life of oral MK-8189 (8-9 h), steady-state plasma 
exposures are likely to be achieved within the first two days following once daily 
administration of MK-8189. Hence, MK-8189 will be administered once-daily for 7 
consecutive days in the oral-run in period to establish individual tolerability in participants at 
steady state prior to IM administration of MK-5720.
As this is a Phase 1 assessment of MK-5720 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
The starting dose of 35 mg is proposed in conformance with the “Guideline on Strategies to 
Identify and Mitigate Risks for First-in- Human Clinical Trials with Investigational 
Medicinal Products” [European Medicines Agency 2007] as well as the MRSD calculation 
[Food and Drug Administration 2005], the MRSD for the first such instance of drug 
administration in humans is based on NOAEL determined in nonclinical safety studies 
performed in the most sensitive and relevant animal species adjusted with allometric scaling 
factors to calculate the HED.
A 4-week, 3-dose level toxicity study was conducted with MK-5720 in rats at (12, 30, 
510 mg/kg/day) and rhesus (12, 36,140 mg/kg/day) to assess the potential toxicity and 
toxicokinetic profile of MK-5720. No treatment related findings were identified in the GLP 
1-month single dose IM toxicity studies with 3-month recovery period conducted with 
MK-5720 in rats and NHPs. Histological findings at the injection sites in rats and NHPs were 
consistent with those typically observed following administration of a long-acting 
formulation that produces an extended-release depot and the inflammatory response 
associated with MK-5720 histomorphology changes at the injection sites findings were 
resolved after a 3-month recovery period in both species.
The NOAELs for MK-5720 were the highest dose tested, 510 mg/kg in rats and 140 mg/kg in 
rhesus. While the NOAEL was the highest dose studied in both species in the 1-month GLP 
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compliant toxicological study, given the rat provides lower overall exposures for M-5720 and 
lower EMs to the projected efficacious dose of MK-5720, rat is determined to be the most 
sensitive species. Therefore, rat NOAEL Cmax and AUC exposure cap for MK-5720 will be 
used for the purposes of safety multiple calculations that corresponds to 2.05 μM*hr and 
0.0129 μM plasma exposures for AUC0-28d and Cmax respectively. See [Table 3] for PK 
exposures of MK-5720 at NOAEL doses in rats and rhesus.
Table 3
Pharmacokinetic Exposures of MK-5720 at NOAEL Doses
Species
Dose (mg/kg)
Cmax (μM)
AUC0-28d(μM.hr)
Rat
510
0.0129
2.05
Rhesus
140
0.0713
9.27
AUC0-28d= area under the concentration-time curve from 0 to 28 days, Cmax=maximum plasma concentration
The calculated HED corresponding to the rat NOAEL adjusted by using an allometric scaling 
factor is 4957 mg (510 mg/kg x 0.162 [rat to human dose conversion factor] x 60 kg 
[estimated human adult weight]). The MRSD calculated by applying a safety factor of 10, 
yields a starting dose of 495 mg. However, a safety factor of 50 has been applied to account 
for variability in the preclinical to clinical translation of input rate for the LAI.  This results
in a MRSD of 99 mg based on rat NOAEL (1/50*4957=99 mg) and 54 mg based on rhesus 
NOAEL (HED=140 mg/kg x 0.324 [rhesus to human dose conversion factor] x 60 kg=2722
mg; 1/50*2722 =54 mg).
The MK-5720 proposed starting dose of 35 mg provides a ~ 1.5- to 2.8-fold safety margin to 
the MRSD of 54 and 99 mg based on the rhesus and rat NOAEL, respectively. The lowest 
weight permitted in the study is 50 kg; even for a 50-kg participant the starting dose of 35 mg 
offers a 1.2-fold safety factor to the more conservative MRSD of 54 mg based on rhesus 
NOAEL. The 35-mg starting dose is also the lowest possible dose of the LAI that can be 
administered accurately via the IM route based on a 0.1-mL administration volume.
The starting dose of 35 mg is estimated to yield a human MK-5720 AUC0-28d of 
0.09 μM*hr with a MK-5720 Cmax of 0.00019 μM that is approximately 23- and 68-fold 
lower than the rat AUC0-28d and Cmax NOAEL exposure cap and 103- and 375-fold lower 
than the rhesus AUC0-28d and Cmax NOAEL, respectively.
 
For more detailed information regarding results from the rat and rhesus toxicological studies, 
please refer to the IB for MK-5720.
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4.3.2
Maximum Dose Exposure for This Study
The maximum dose planned in this study is supported by the 4-week GLP repeat dose 
toxicity study with MK-5720 and also supported by clinical experience with MK-8189 across 
multiple Phase 1 and Phase 2 studies. As recommended by the EMA “Guideline on 
Strategies to Identify and Mitigate Risks for First in-Human Clinical Trials With 
Investigational Medicinal Products” [European Medicines Agency 2007], the maximum
exposure in humans should be predefined and justified based on all available non clinical and 
clinical data, including PD, PK and findings in toxicity studies and exposures at the 
therapeutic dose range.
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Administration of MK-5720IM injection of 12, 30, or 510 mg/kg and 12, 36 and 140 mg/kg 
of MK-5720 formulated as a LAI was administered as a single dose in rats and monkeys 
respectively, with a 1-month toxicity assessment and a 3-month treatment-free period to 
determine the potential toxicity and TK profile of MK-5720. The high-dose was selected to 
assess systemic toxicity at supratherapeutic exposures while the low and mid-dose were 
selected to assess local tolerability at relevant therapeutic exposures. 
IM injection of MK-5720 LAI was generally well-tolerated at all doses (12, 30 and 
510 mg/kg) in rats in the 1-month GLP toxicological study. There were no test article-related 
unscheduled deaths, and no test article-related changes in food consumption, ophthalmic, 
hematology, coagulation, serum biochemistry, or urinalysis parameters. There were no test 
article-related findings in other tissues of any rats in the 510 mg/kg group, indicating no 
systemic toxicity by the test article.
By the end of the 1-month toxicity assessment period, clinical signs (limited to injection site 
swelling) and body weight changes were generally resolved. Alterations in inflammatory 
biomarkers (A2M and AGP) were resolved and were not considered toxicologically 
meaningful. Chronic inflammation or a less pronounced change of local infiltrates at the 
intramuscular injection site observed at final necropsy (1 month after injection) in animals at 
≥30 mg/kg was an expected finding typically observed with administration of long-acting 
formulations in rodents and had resolved in recovery animals necropsied approximately 
4 months after dosing. The NOAEL was 510 mg/kg as injection sites reactions were not 
considered adverse at all dose levels, were reversible at the dose level examined (30 mg/kg) 
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and were consistent with findings typically observed after administration of long-acting 
injectable formulations to rats.
IM injection was considered to be generally well tolerated at all doses (12, 36 and 
140 mg/kg) in monkeys in the 1-month GLP toxicological study. There were no test article-
related unscheduled deaths, and no test article-related changes in body weight, ECG, 
ophthalmic, hematology, or urinalysis parameters. By the end of the 1-month toxicity 
assessment period at doses ≤140 mg/kg, clinical signs had generally resolved and alterations 
in serum markers of inflammation (fibrinogen and C-reactive protein) were not considered 
toxicologically meaningful. 
Minimal to moderate chronic inflammation at the IM injection site observed at final necropsy 
(1-month after injection) was an expected finding typically observed with administration of 
long-acting formulations in nonhuman primates. At the recovery sacrifice (limited to Cohort 
B animals in the low- and mid-dose groups), no test article-related gross or histomorphologic 
findings were observed at the injection site. No foci of chronic inflammation were observed 
in the quadriceps muscle group. Overall, the injection site reaction in the mid- and low-dose 
groups was considered to be in either a resolution phase or recovered after a 1-month toxicity 
assessment and a 3-month treatment-free period.
Based on the presence of test article-related findings at all dose levels, the NOAEL was 
140 mg/ as injection sites reactions were not considered adverse, were reversible at the dose 
levels examined (12 and 36 mg/kg) and were consistent with findings typically observed 
after administration of long-acting injectable formulations to monkeys.
Since the rat NOAEL provides a ~ 1.4X EM for the AUC0-28d compared to 6.4X EM for the
rhesus relative to the highest planned dose of 560 mg of MK-5720 based on the 1-month 
repeat dose toxicological studies, rat is considered the most sensitive species. Thus, the 
NOAEL for the purposes of establishing maximum allowable exposures is 2.05 μM*hr and 
0.0129 μM for AUC0-28d and Cmax, respectively. The highest planned dose of 560 mg of 
MK-5720
 provides a 4.3-fold safety margin to the rat Cmax NOAEL 
exposure cap. Furthermore, no MK-5720-related effects on QTc or HR were noted in 
anesthetized NHPs up to the highest dose tested
 
 
Maximal MK-5720 LAI single doses of up to 560 mg are proposed in the study to generate
safety margins to the 280-mg dose of MK-572
 
 
Importantly, MK-5720 dose flexibility is built in the study as a contingency in the event
resulting MK-8189 plasma concentrations from MK-5720 LAI are lower than that projected 
due to faster depletion of drug from the LAI or due to differences in LAI input rate observed 
in the clinic compared to that observed preclinically resulting in sub-efficacious MK-8189 
plasma concentrations. MK-5720 LAI doses in the study have been selected in the study to 
result in MK-8189 plasma concentrations that remain within the clinical experience 
generated with the oral MK-8189 program in participants with schizophrenia and supported 
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by having sufficient safety margins at the highest dose proposed based on preclinical safety 
data generated with MK-5720 and MK-8189.
The projected MK-5720 exposures corresponding to the highest planned dose of 560 mg of 
MK-5720 LAI
 provides a 4.3 and 1.4-fold safety 
margin to the rat (more sensitive compared to rhesus) MK-5720 Cmax and AUC NOAEL 
exposure cap [refer to Section 4.3.1.2 of MK-5720 IB]. Furthermore, the projected MK-8189 
Cmax and AUC0-28d corresponding to the 560 mg-dose of MK-5720 LAI 
 
, provides a ~15 and 2.5-fold safety margin to the rat MK-8189 Cmax and 
AUC NOAEL and ~ 9 and 3.3-fold to the rhesus Cmax and NOAEL exposure cap, based on 
the 6 and 9-month repeat dose GLP tox study conducted with oral MK-8189 [refer to Section 
4.3.2 of MK-5720 IB]. The projected MK-8189 Cmax exposures corresponding to the 
560- mg dose of LAI (~ 3 µM) is within the range of the highest MK-8189 mean Cmax 
exposure observed with 80-mg dose of oral MK-8189 on Day 2 of ~ 2.63 µM (95% CI 2.08, 
3.32 µM; preliminary data) that was generally well tolerated in participants with 
schizophrenia (P014).
Because studies in preclinical species are not always predictive of what may occur in 
humans, safety of MK-5720 will be assessed throughout the study by monitoring AEs, 
physical/neurological examinations, VS, ECGs, and laboratory safety tests (chemistry, 
hematology, urinalysis). The timing of the safety endpoints has been planned to ensure 
adequate safety monitoring throughout the treatment period, taking into consideration the 
range of potential t1/2 predictions of MK-5720. Participants will be followed for at least 55 
days to allow for adequate MK-5720 washout (~ 5-half-lives based on an estimated t1/2 of 
10 days for MK-8189 in humans). Safety data from each dosing period will be carefully 
reviewed before escalation to the next higher dose. Key safety data such as VS, 12-lead 
ECGs, lab safety tests and physical/neurological examinations will be reviewed for up to at 
least 14 days postdose (Panel A) and up to 28 days postdose for all other panels prior to dose 
escalation to the next higher dose level. Plasma concentrations of MK-5720 from the 
preceding panels will be determined at the allocated PK breaks to ensure that the NOAEL
AUC exposure limits are not exceeded at the doses in the subsequent panels. Since this is the 
first instance of administration of MK-5720 to humans, the dose levels and interval between 
doses may be adjusted based on safety and/or PK data from the prior periods.
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4.3.3
Rationale for Dose Interval and Study Design
MK-5720, prodrug of MK-8189, a PDE10A inhibitor, is not considered a compound that can 
pose a potential safety risk to participants and is not a biological molecule and does not 
exhibit species-specific action and is not directed towards immune system targets. MK-5720 
is approximately 650-fold less potent compared to MK-8189 based on in-vitro binding assay 
(MK-5720 PDE10 IC50 of 18.7 nM vs. 0.029 nM for MK-8189) and furthermore, due to the 
rapid bioconversion of MK-5720 to MK-8189 in vivo, MK-5720 concentrations anticipated 
in the clinic should be well below pharmacologically active concentrations and therefore, the 
main pharmacological activity expected in the clinic is a result of the MK-8189 metabolite.
Furthermore, concentrations of MK-5720 will be monitored in the clinic so as not to exceed 
the NOAEL AUC0-28d and Cmax exposure cap.
The study design consists of 6 sequential panels (Panels A to F) and 3 PK breaks between 
Panels B to C, C to D, and E to F, respectively. In each treatment period for each panel of the 
study, participants will be randomized to receive MK-8189/MK-5720 (n=6 to 9) or placebo 
(n=2 to 3) in a blinded manner. All participants in a given panel shall receive the treatment or 
placebo on the same day in time spaced intervals based on Phase 1 clinical research standards 
for compounds not considered to be of high risk of harm. An oral tolerability run-in period 
with MK-8189 is incorporated in the study to
 
 
A washout period of at least 72 hours is included 
between the MK-8189 oral run-in period (Period 1) and the MK-5720 IM administration 
(Period 2) to fully understand the release kinetics and pharmacokinetics of MK-8189 
following IM injection of MK-5720 in the absence of circulating carry-over MK-8189 from 
the prior oral run-in-period. 
The dosing regimen was determined based on the following: clinical safety experience with 
MK-8189, the presence of preclinical safety margins for both MK-5720 and MK-8189, the 
inclusion of extensive safety monitoring in the clinic, and the fact that MK-5720 is not 
considered a compound with a high potential for risk of harm. There will be frequent, careful 
assessments of AEs throughout the postdose period. This recommendation is in keeping with 
the projected safety profile and the ability of the Phase 1 unit to monitor each participant 
closely. Safety data will be reviewed for at least up to 14 days post dose for dose escalation 
to Panel B and up to 28 days postdose for all subsequent panels before dose escalation 
between panels to allow for review of key safety parameters. The 14-day safety review 
period will allow for peak plasma concentrations of MK-8189 to be achieved from the 
MK-5720 LAI. Participants will be followed for at least 55 days allowing for collection of
~ 5 half-lives of MK-8189 based on estimated half-life of ~ 10 days in humans for MK-8189
from MK-5720 LAI.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
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7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
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
A primary objective of this early Phase 1 study is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve PK, pharmacodynamic, and/or biologic 
targets in humans based on preclinical or early clinical data. Therefore, it is possible that 
study participants may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this study. This would not be defined as early termination of 
the study, but rather an earlier than anticipated achievement of the study objective(s). If a 
finding (eg, PK, pharmacodynamic, efficacy, biologic targets, etc) from another preclinical or 
clinical study using the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study results in the study(ies) or program being stopped for 
nonsafety reasons, this also does not meet the definition of early study termination.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical 
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
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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. Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the 
DSM-5 criteria with the onset of the first episode being no less than 2 years prior to 
screening and monotherapy with antipsychotics for treatment should be indicated.
2. Has a total BPRS score of less than 48 with a BPRS score less than 4 for #10 (hostility) 
and #14 (uncooperativeness) at the Screening Visit.
3. Is in the nonacute phase of their illness and clinically stable for 3 months prior to 
screening as demonstrated by:
a.
no clinically significant change in dose of prescribed antipsychotic medication, or 
clinically significant change in antipsychotics medication to treat symptoms of 
schizophrenia for two months prior to screening. Determination of clinical 
significance of dose change is at the discretion of the investigator.
b. no increase in level of psychiatric care due to worsening of symptoms of 
schizophrenia for three months prior to screening.
Note: Participants that are stable but not currently taking antipsychotic medications 
are eligible.
4. Is in good health based on medical history, physical examination, VS measurements, and 
ECGs performed at the Screening Visit and/or prior to randomization. The assessment 
prior to randomization is based on the mean of triplicate measures. Note: The QTcF-
duration must be less than or equal to 450 msec. Repeat 12-lead safety ECGs may be 
performed in participants whose parameters are, per investigator discretion, minimally 
outside the designated range.
5. Is 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.
6. Has a history of receiving and tolerating antipsychotics medication within the usual dose 
range employed for schizophrenia.
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7. Has a stable living situation in which the participant or contact person can be reached by 
the investigator if there is a need for follow up.
8. Participants with hypothyroidism, diabetes, high blood pressure, chronic respiratory 
conditions or other medical conditions could be considered as a candidate for study 
enrollment if their condition is stable and the prescribed dose and regimen of medication 
is stable for at least 3 months prior to screening and there are no expected changes in co-
medication during the study.
9. Participants is able to discontinue the use of all antipsychotic medication at least 5 days 
or 3 half-lives (which ever in longer) prior to the start of the treatment period and during 
the study.
10. Have a normal resting BP (systolic BP is greater than or equal to 90 mm Hg and less than 
or equal to 140 mmHg; diastolic BP is greater than or equal to 60 mmHg and less than or 
equal to 90 mmHg) and normal resting HR (greater than or equal to 45 bpm and less than 
or equal to 100 bpm) in the supine position at the pre-trial (screening) visit and/or prior to 
randomization. Repeat evaluations may be done if the values for a participant are, per 
investigator discretion, minimally outside the designated range. The assessment prior to 
randomization is based on the mean of the triplicate measures. Participants may be 
included if values are outside the normal range but considered not clinically significant 
per investigator discretion.
11. Has regular bowel movements and, in the opinion of the investigator, no clinically 
significant diarrhea or constipation.
Demographics
12. Is an individual of any sex/gender, from 18 years to 60 years of age inclusive, at the time 
of providing the informed consent.
13. The participant has a BMI greater than or equal to 18 and less than or equal to 40 kg/m2
and total body weight of greater than 50 kg (110 pounds) at the Screening Visit. See 
Section 8.3.1 for criteria on rounding to the nearest whole number. BMI = weight 
(kg)/height (m)2.
Male Participants 
14. If capable of producing sperm, the participant agrees to the following during the 
intervention period and for at least the time needed to eliminate the study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for the study intervention is:
-
MK-5720: at least 55 days
•
Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview) as 
detailed below:
-
Uses a penile/external condom when having penile-vaginal intercourse with a 
nonparticipant of childbearing potential who is not currently pregnant and should also 
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be advised of the benefit for that partner to use an additional method of contraception, 
as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is pregnant or 
breastfeeding must agree to use penile/external condom during each episode of sexual 
activity in which the partner is at risk of drug exposure via ejaculate.
-
Contraceptive use by participants capable of producing sperm should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. If the contraception requirements in the local label for any of the 
study interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
Female Participants 
15. A participant assigned female sex at birth is eligible to participate if:
She is a PONCBP, as defined in Appendix 5.
Informed Consent
16. The participant (or legally acceptable representative) has provided documented informed
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
17. Is 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. Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, 
respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, 
immunological, or cerebrovascular disease, malignance, allergic disease or other chronic 
and/or degenerative process at screening.
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.
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3. Is at imminent risk of self-harm, based on clinical interview and responses on the           
C-SSRS, 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.
4. Has a tattoo, scar, or other physical finding at the area of the injection site that would 
interfere with the evaluation of local tolerability or integrity of the injection site.
5. Has a history of cancer (malignancy).
Exceptions: (1) Participants with adequately treated nonmelanomatous skin carcinoma or 
carcinoma in situ of the cervix may participate in the study; (2) Participants with other 
malignancies which have been successfully treated greater than or equal to 10 years prior 
to the prestudy (screening) visit where, in the judgment of both the investigator and 
treating physician, appropriate follow-up has revealed no evidence of recurrence from the 
time of treatment through the time of the prestudy (screening) visit (except those cancers 
identified at the beginning of this exclusion criteria); or (3) Participants, who, in the
opinion of the study investigator, are highly unlikely to sustain a recurrence for the 
duration of the study.
6. Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than 
schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria within one 
month of screening.
7. Has evidence or history of mental retardation, borderline personality disorder, or organic 
brain syndrome.
8. Has a history of neuroleptic malignant syndrome or moderate to severe tardive 
dyskinesia.
9. Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse.
10. Has a DSM-5 defined substance use disorder (excluding nicotine and caffeine) within 3 
months of screening.
11. Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures.
12. Has a clinically significant history or presence of sick sinus syndrome, first, second, or 
third degree AV block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, 
prolonged QTc interval, or conduction abnormalities.
13. Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
14. Has a family history of sudden death.
15. Has claustrophobia to a degree that prevents tolerance of MRI scanning procedure.
Note: This is only applicable to panels receiving MRIs.
16. Has a metallic implant of any sort that prevents MRI examination including, but not
limited to, aneurysm clips, metallic foreign body, vascular grafts or cardiac implants,
neural stimulator, metallic contraceptive device, metallic tattoo, body piercing that cannot
be removed, cochlear implant, or any other contraindication to MRI examination.
Note: This is only applicable to panels receiving MRIs.
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17. Has a history of any illness that, in the opinion of the study investigator, might confound 
the results of the study or poses an additional risk to the participant by their participation 
in the study.
18. Has been in incarceration or imprisonment within 3 months prior to screening.
19. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
20. Participant has an estimated CrCl less than or equal to 80 mL/min based on the 
Cockcroft-Gault Equation. 
Cockcroft-Gault Equation:
When creatinine is measured in µmol/L, use this formula:
For females, multiply the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
Participants who have a measured CrCl of up to 10% below 80 mL/min may be enrolled 
in the study at the discretion of the investigator.
21. 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.
22. Positive test(s) for HBsAg, hepatitis C antibodies or HIV. 
23. The participant had a major surgery and/or donated or lost 1 unit of blood (approximately 
500 mL) within 4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
24. Has received or is currently receiving treatment with clozapine for any length of time. 
Has received treatment with monoamine oxidase inhibitors within 3 months of screening 
or cariprazine within 2 months of screening.
25. Is unable to be washed off their parenteral depot antipsychotic medication prior to 
screening or requires a dose of a parenteral depot antipsychotic medication during the 
study.
26. Is unable to refrain from the use of co-medication that is a moderate or strong inhibitor or 
inducer of CYP3A 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 (Section 
6.5).
CrCl =
(140 −age <yr>) (body wt <kg>)
(72) (serum creatinine <µmol/L> × 0.0113)
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27. Has received any nonlive vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any nonlive vaccine through 30 days following study intervention. 
Exception: COVID-19 vaccine may be administered. Study intervention must be given at 
least 72 hours following or at least 48 hours prior to any COVID-19 vaccination. 
Investigational COVID-19 vaccines (ie, those not licensed or approved for Emergency 
Use) are not allowed.
28. Has received any live vaccines within 30 days prior to the first dose of study intervention
or is scheduled to receive any live vaccine through 60 days following study intervention.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Prior/Concurrent Clinical Study Experience
29. Participated in another investigational study within 4 weeks (or 5 half-lives, whichever is 
greater) prior to the prestudy (screening) visit. The window will be derived from the date 
of the last visit in the previous study.
Diagnostic Assessments
Not applicable 
Other Exclusions
30. Under the age of legal consent.
31. Does not agree to follow the smoking restrictions as defined by the CRU.
32. 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.
33. 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.
34. Is a regular user (in the opinion of the investigator and Sponsor) of cannabis, a user of 
any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 
years. Participants must have a negative UDS (with the exception of prescribed 
medications permitted at the discretion of the investigator and Sponsor and/or cannabis) 
prior to randomization. 
35. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions). Presents any concern by the investigator regarding safe 
participation in the study or for any other reason the investigator considers the participant 
inappropriate for participation in the study.
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36. 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.
37. 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
Period 1
Participants will fast from all food and drinks, except water, for at least 8 hours before study 
intervention administration. Approximately 240 mL of water will be provided during study 
drug administration but will be restricted 1 hour prior to and 1 hour after study drug 
administration. Participants will fast from all food and drinks, except water, until 1 hour 
postdose. 
Period 2
During the domiciling period, scheduled meals and snack(s) will be provided by the 
investigator per the site’s standard procedures. 
All Periods
Additionally, all laboratory safety assessments will be performed after an 8 hour fast as 
specified in Appendix 2. 
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention in Period 1, throughout the study and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after study intervention administration. On all other days during the study, consumption of 
fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is 
allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants are advised to refrain from consumption of caffeinated beverages or xanthine-
containing products from 12 hours prior to the Screening Visit. A recheck may be needed if 
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participants did not refrain from consuming caffeinated beverages or xanthine-containing 
products 12 hours prior to the Screening Visit.
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from:

12 hours before and after study intervention administration in each treatment period.

12 hours before poststudy visit.
At all other times, 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 prior to 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.
5.5
Participant Replacement Strategy
If a participant withdraws or discontinues from the study a replacement participant may be 
enrolled if deemed appropriate by the investigator and Sponsor. The replacement participant 
will generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/randomization number.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies, MK-8189, MK-5720, placebo, and diluent, will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in [Table 6].
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Table 6
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
Panel 
A
Experimental
MK-8189
Drug
Tablet
4 mg
4 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
A
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Period 1
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
A
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL 35 mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
A
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg
IM
Period 2 
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
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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
Panel 
B 
Experimental
MK-8189
Drug
Tablet
4 mg
8 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
B
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg 
0 mg
Oral
Period 1
Placebo
IMP
Provided 
Centrally 
by the 
Sponsor
Panel 
B
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL 70 mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
B
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg
IM
Period 2
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
C
Experimental
MK-8189
Drug
Tablet
4 mg 
12 mg
16 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
C
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Period 1
Placebo
IMP
Provided 
centrally 
by the 
Sponsosr
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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
Panel 
C
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL 140 mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
C
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg
IM
Period 2
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
D
Experimental
MK-8189
Drug
Tablet
12 mg
24 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsosr
Panel 
D
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Period 1
Placebo
IMP
Provided 
centrally 
by the 
Sponsosr
Panel 
D
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL 280 mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
sponsor
Panel 
D
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg
IM
Period 2
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
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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
Panel 
E
Experimental
MK-8189
Drug
Tablet
12 mg
48 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
E
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Period 1
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
E
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL ≤560 
mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
E
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg 
IM
Period 2
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
F
Experimental
MK-8189
Drug
Tablet
12 mg
48 mg
Oral
Period 1
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Panel 
F
Placebo 
Comparator
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Period 1
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
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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
Panel 
F
Experimental
MK-5720
Drug
Injection, 
Powder, For 
Suspension
350 mg/mL ≤560 
mg
IM
Period 2
Test 
Product
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
Panel 
F
Placebo 
Comparator
Placebo
Drug
Injection, 
Powder, For 
Suspension
0 mg
0 mg
IM
Period 2
Placebo
IMP
API and 
excipients 
provided 
centrally 
by the 
Sponsor
API=active pharmaceutical ingredient; EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; N/A= not applicable; 
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.
In this protocol, placebo for MK-5720 is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
Those who receive placebo in Period 1 will receive placebo in Period 2. Those receiving MK-8189 in Period 1 will receive MK-5720 in Period 2. 
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All supplies indicated in [Table 6] will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
MK-8189
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant.
MK-5720
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is in Section 4.3.
MK-5720 and placebo dosage form will be prepared and dosed per the instructions outlined 
in the Method of Preparation Document and Study Operations Manual. 
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.
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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.
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 7].
Table 7
Allocation of Participants to Treatment
Panel
N
MK-8189 Treatment Period 1
MK-5720 Treatment Period 2
Panel A
6
4 mg
35 mg
2
Placebo
Placebo
Panel B
6
8 mg
70 mg
2
Placebo
Placebo
Panel C
9
Less than or equal to 16 mg
Less than or equal to 140 mg
3
Placebo
Placebo
Panel D
9
Less than or equal to 24 mg
Less than or equal to 280 mg
3
Placebo
Placebo
Panel E
9
Less than or equal to 48 mg
Less than or equal to 560 mg 
3
Placebo
Placebo
Panel F
9
Less than or equal to 48 mg
Less than or equal to 560 mg 
3
Placebo
Placebo
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, MK-5720 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.
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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 participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention. 
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 60 days after the last dose of study 
intervention.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-incompetent 
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
Nonlive vaccines may only be administered in consultation with the Sponsor prior to or 
following the receipt of study intervention according to the time frames specified in 
Exclusion Criteria (Section 5.2).
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) 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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Paracetamol/acetaminophen (up to 4 g per day), ibuprofen (up to 1.2 g per day) and antacids 
(eg, magnesium hydroxide) may be used for minor ailments without prior consultation with 
the Sponsor.
Medications to treat mild chronic conditions such as hypothyroidism, diabetes, high blood 
pressure, chronic respiratory conditions or other mild medical conditions are allowed during 
the study if the prescribed dose and regimen of medication are stable for at least 3 months 
prior to screening and there are no expected changes in co-medication during the study. 
Inclusion of participants being administered concomitant medications that have not been 
stable for 3 months must be discussed with the Sponsor. Moderate to strong inhibitors or 
inducers of CYP3A are not allowed as MK-8189 is being metabolized by these CYP 
enzymes and co-administration of inhibitors or inducers may potentially alter the metabolism 
and PK of MK-8189.The Sponsor Clinical Director should be contacted if there are any 
questions regarding concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
For the treatment of EPS, such as acute dystonia, all participants may be treated with an 
anticholinergic. If the symptoms are unresponsive to anticholinergic treatment, a 
benzodiazepine can be used. CRUs will be staffed with medically trained personnel with 
appropriate access to full service acute-care hospitals to facilitate rapid institution of medical 
intervention.
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 resolve 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.
Anticholinergics benzodiazepines and β-adrenergic blockers are often used in the treatment 
of EPS and are considered standard practice. Oral anticholinergic treatment is also used as 
concomitant medication to prevent EPS symptom with antipsychotic medication.
Participants will be washed off from their antipsychotic treatment (Section 8.1.5.1). The 
duration of washout period should be at least 5 days or cover at least 3 half-lives of the drug 
(whichever is longer) prior to Day -1 assessments in Period 1. During the washout and 
treatment period, a benzodiazepine and zolpidem may be used to treat withdrawal symptoms. 
The drugs indicated above should not be inhibitors or inducers of CYP3A and CYP2C9 (see 
Section 6.5 for further details), thus no effect on the PK of MK-8189 would be expected 
during coadministration.
In the event that the patient must be discontinued due to worsening of psychosis while on 
MK-5720, standard of care practice should be initiated, utilizing the lowest dose of an oral 
antipsychotic required to control symptoms during washout of MK-5720. Approved oral 
antipsychotic medications for this study are outlined in [Table 8] based on prior clinical 
experience with addition of oral MK-8189 to the antipsychotic medications at the dose range 
mentioned below and that were generally well tolerated in 2 clinical studies conducted with 
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oral MK-8189 (P003 and P007). The medications listed below or use of any other standard of 
care oral antipsychotic medications may be used following prior consultation of the PI with 
the Sponsor. 
Table 8
Approved Oral Antipsychotic Medications 
Medication 
Name
Total Daily Dose Range 
Coadministered with MK-8189
Target Daily Dose Range for 
Schizophrenia in Adults 
Quetiapine
50 to 600 mg
50 to 750 mga
Aripiprazole
7.5 to 30 mg
10 to 15 mgb
Risperidone
0.5 to 8 mg
2 to 8 mgc
Olanzapine
10 to 40 mg
5 to 20 mgd
Ziprasidone 
60 to 80 mg
40 to 200 mge
Lurasidone
60 to 80 mg
40 to 160 mgf
a
[U.S. Prescribing Information 2020]
b
[U.S. Prescribing Information 2017]
c
[U.S. Prescribing Information 1993]
d
[U.S. Prescribing Information 2011]
e
[U.S. Prescribing Information 2010]
f
[U.S. Prescribing Information 2013]
For patients who may experience anxiety during an MRI scan and require prophylaxis, the 
investigator may use a short to intermediate duration benzodiazepine, such as lorazepam, if 
deemed necessary and after prior consultation with the Sponsor.
6.6
Dose Modification (Escalation)
All dose-escalation decisions will be made jointly by the investigator and the Sponsor. 
Members of the Sponsor safety review team will include: the trial clinical director, trial 
clinical scientist, senior level clinical director and trial biostatistician. Additional Sponsor 
attendees may include a clinical research associate and a pharmacologist. The Sponsor safety 
review team will obtain input from the investigator regarding his/her evaluation of safety and 
tolerability from the previous dosing period and his/her recommendation to dose escalate in 
the next panel.
Each dose-escalation decision will occur after at least 8 (Panels A and B) and 12 (Panels C 
through F) evaluable participants have completed the previous dose level (participants will be 
randomized to receive MK-5720 or placebo in a 3:1 ratio, respectively).
Dose-escalation decisions will be based on blinded key safety variables, with summary 
statistics as needed. Safety variables will include, vital signs, 12-lead ECG, laboratory safety 
tests, AE, and neurological assessments from the previous dose levels up to at least 14 days
postdose. PK data may be included in the dose-escalation decisions (Section 2.1 and 
Section 2.2).
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If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose escalation, the dose will not be increased as planned. Instead, participants may:
•
receive the same dose level to further explore safety and tolerability at that level,
•
receive a lower dose of the study intervention (with or without food),
•
receive the same or lower dose as a divided dose, or
•
dosing may be stopped.
Participant discontinuation criteria are outlined in Section 7.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
If any of the below stopping rules are met, the study will be paused, and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. To continue the study 
(on joint agreement with the Sponsor and investigator), a substantial amendment will be 
submitted for approval.
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator.
2. Two (2) or more participants within a Panel (at the same dose level) report Severe 
Nonserious AEs considered related to the study intervention by the investigator.
If any of the above stopping rules are met, subsequent higher doses will be lowered based on 
joint agreement of the Sponsor and investigator in order for the study to continue.
3. Should the emerging PK (mean) data indicate that the maximum clinical exposure (Cmax
or AUC), as defined in Section 4.3 will be exceeded, subsequent higher doses will be 
adjusted based on joint agreement of the Sponsor and investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10).
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See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
Procedures conducted as part of a site generic screening (with an ERC/IRB approved site 
generic screening consent) on potential participants (eg, blood count, vital signs, ECG, 
etc) and obtained before signing of study ICF may be used for screening or baseline 
purposes provided the procedures met the protocol specified criteria and were performed 
within the screening window defined in this protocol.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed the volume mentioned in the Study Operations manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
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acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
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 his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her 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.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 3 months before starting the study. 
Washout From Antipsychotics:
All participants will be washed out from their antipsychotic medication at least 5 days or at 
least 3 half-lives (whichever is longer) prior to Day -1 in Period 1. The washout may start 
with a down titration of the antipsychotic treatment during the screening period per direction 
of the investigator. For longer half-life antipsychotics (eg, aripiprazole and brexpiprazole), if 
deemed appropriate by the investigator, a participant may stop treatment (ie, cessation of 
AAP) as an outpatient, but should be confined to the clinical research unit within a week of 
stopping treatment and minimally beginning on Day -6.
Participants may restart their antipsychotics therapy following completion of the last study 
procedures on Day 55 in Period 2.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
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will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Period 1
Study intervention(s) will be administered by the investigator and/or study staff. Participants 
will fast from all food and drinks, except water, for at least 8 hours prior to study drug 
administration each day. Approximately 240 mL of water will be provided during study drug 
administration but will be restricted 1 hour prior to and 1 hour after study drug 
administration. Details on water and dietary restrictions are outlined in Section 5.3.1. Site 
staff will ensure that participants have swallowed study treatment.
Period 2
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee according to the specifications within the pharmacy manual.
In Panels A to C, participants will receive an IM injection in the deltoid. For Panels D to F, 
participants will receive an IM injection in the deltoid or in their gluteal muscle as directed 
by the Sponsor.
Study intervention and placebo will be provided to the study staff will require reconstitution 
by site staff according to the directions in the Method of Preparation. Study intervention(s) 
will be provided to the study staff in prefilled syringes from the pharmacy. Syringes will be 
covered with a blinding label. However, there is a significant visual difference between the 
active and placebo formulations, the unit staff who are involved in study drug administration 
cannot be involved in other areas of study conduct to maintain blinding. Site staff should use 
the appropriate needle length and gauge for administering study intervention based on the 
BMI of the participants. 
8.1.8.1
Timing of Dose Administration
Period 1
All doses of the study medication will be given in the morning at approximately the same 
time each day and will occur after an 8-hour overnight fast, as described in the SoA.
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Period 2
Study drug administration will occur according to the SoA and Method of Preparation 
document. Once the study intervention(s) are filled into syringes, it may be stored at ambient 
conditions as directed in the Method of Preparation document.
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. If a participant discontinues for any reason at any 
time during the course of the study, 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 1.3 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 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
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and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the intensity
of the AEs observed, the relation to study intervention, the reason thereof, etc, in the medical 
record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
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 medication will be domiciled in the CRU 
from up to Day -6 prior to dose administration (to start the washout period of current 
antipsychotic medication) in Period 1 and will remain in the CRU until all 28 days postdose
procedures have been completed in Period 2. Participants not currently being treated with 
antipsychotic medication may be domiciled minimally starting on Day -2 in Period 1. At the 
discretion of the investigator, participants may be requested to remain in the CRU longer.
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 to be drawn over the course of the study (from prestudy 
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to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in the Study Operations Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted according to the SoA by an investigator 
or medically qualified designee (consistent with local requirements) per institutional 
standard. Height and weight will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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 (Section1.3).
•
Blood pressure and heart rate measurements will be assessed in a supine position as well 
as orthostatic positions with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
•
VS measurements should be taken before blood collection for laboratory tests.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
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.
The predose (baseline) HR and BP will be triplicate measurements, obtained at least 1 to 2 
minutes apart within 3 hours of dosing MK-8189/placebo in Period 1 (Day 1 only) 
MK-5720/placebo in Period 2. The mean of these measurements will be used as the baseline 
to calculate change from baseline for safety evaluations (and for rechecks, if needed). 
Postdose VS measurements will be single measurements in both Periods.
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Body Temperature
Body temperature will be measured via the oral route. The same method must be used for all 
measurements for each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained at timepoints 
indicated in the SoA. 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, and QTc 
intervals. Refer to Appendix 9 for evaluation and potentially significant findings.
•
At each time point when triplicate ECG are required, 3 individual ECG tracings should 
be obtained at least 1 minute apart. The full set of triplicates should be completed in no 
more than 6 minutes.
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. Female participants may need to remove interfering garments.
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.
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 on telemetry, 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.
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A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
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 laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Suicidal Ideation and Behavior Monitoring
8.3.5.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior at screening, the 
assessor should also inquire and document if this is also present at the time of the Screening 
Visit.
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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.
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.
8.3.6
Monitoring for Extrapyramidal Symptoms 
The investigator or qualified designee will complete the BARS, AIMS and SAS at times 
specified in the SoA. Additional assessments at unscheduled times outside of the SoA will be 
conducted by study staff, as soon as reasonably possible, if it is observed or a participant 
reports complaints of dystonia and/or akathisia.
8.3.7
Assessment of Neuropsychological Effects
A general (full) Neurological Exam will be performed at the Screening visit, predose in 
Period 1 and 2, prior to discharge in Period 2, and at the Day 56 outpatient visit. A targeted 
Neurological Exam will be administered at times specified in the SoA. 
A BPRS evaluation will be performed at Screening, Baseline in Period 1 and will also be 
completed at times specified in the SoA.
The General and Targeted Neurological Exams are contained in Appendix 11.
8.3.8
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 drug relationship.
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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/randomization, must be reported by 
the investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention randomization through 14 days after cessation of intervention, 
all AEs, SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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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 9].
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 9
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
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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
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.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities 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.
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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.
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. 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 
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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 discontinuation
4. Treatment-emergent adverse event of new or worsening tardive dyskinesia
5. Suicidal ideation, suicidal behavior
6. Moderate or severe depression
7. Moderate or severe mood swings
8. Dystonia
9. Akathisia
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in
consultation with the Sponsor.
Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma collected will be measured for evaluation of PK will be 
collaboratively determined by the Sponsor (eg, samples at lower doses may not be measured 
if samples at higher doses reveal undetectable drug concentrations). If indicated, these 
samples may also be measured and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers. Blood samples collected may be 
stored and further analysis may be performed, if required.
8.6.1
Blood Collection for Plasma MK-5720 and MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.
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8.7
Pharmacodynamics
Not applicable
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 drawn 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 future 
biomedical research is approved, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1, but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the 
Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of 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
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.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
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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 SoA (Section 1.3) and Administrative and General Procedures (Section 8).
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, all study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. The subset of study procedures completed will be 
communicated in a PCL.
8.10.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last study 
procedure for the poststudy visit in Period 2. If the poststudy visit occurs less than 14 days 
after the last study procedure, a subsequent follow-up telephone call should be made at 
14 days post the last study procedure to determine if any AEs have occurred since the 
poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for MK-5720 is the critical procedure.
At any postdose time point, the blood sample for MK-5720 must be collected as close to the 
exact time point as possible. All other procedures should be completed as close to the 
scheduled time as possible. Study procedures can be performed before or after the scheduled 
time.
1. 12-Lead Safety ECG
2. Vital signs
a.
Resting BP and HR
b. Orthostatic BP and HR
3. Laboratory safety tests
4. Neurological exams: C-CSSRS, BPRS, BARS, AIM, SAS
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
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•
PK Collection as outlined in [Table 10].
Table 10
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
Predose
- 3 hours
0 to <12 h
5 min
12 to <24 h
15 min
24 to <48 h
30 min
48 to <672 h
2 h
>672 h
48 h
•
Predose standard safety evaluations: VS and ECG at 3 hours; laboratory safety tests and 
physical examination at 24 hours
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
examination
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time
-
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
-
From 48-hours to 168-hours postdose may be obtained within 2 hours of the 
theoretical sampling time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-5720 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 or decrease in the dose of the study intervention administered in any given 
panel
•
Interchange of doses between panels
•
Entire panel(s) may be omitted
•
Remove a planned PK pause if agreed by Sponsor and investigator if no further increases 
in total daily dose
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•
Addition of PK pause
•
Modification of the PK sample processing and shipping details based on newly available 
data
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK data (eg, to obtain data closer to the time of peak plasma 
concentrations). If indicated, these collected samples may also be assayed in an exploratory 
manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, 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
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in the SAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Department of the Sponsor.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.3
Analysis Endpoints
9.3.1
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse events and discontinuation 
of study intervention due to adverse event(s), in addition to laboratory safety tests, ECGs, 
and vital signs. Baseline is defined as measurements obtained pre-dose Day 1.  These
endpoints will be calculated for both periods (oral run-in doses of MK-8189 and IM single-
ascending doses of MK-5720). 
Pharmacokinetics: The pharmacokinetic variables of plasma MK-5720 AUC0-last, AUC0-
inf, Cmax, Tmax, CL/F, Vz/F and apparent terminal t1/2 will be evaluated along with the 
plasma MK-8189 AUC0-28d, AUC0-inf, Cmax, Tmax, C28d, CL/F, Vz/F and apparent 
terminal t1/2. These PK endpoints apply to Period 2 (IM single-ascending doses of MK-
5720).
9.3.2
Secondary Endpoints
Pharmacokinetics: The following PK endpoints apply to Period 2 (IM single-ascending doses 
of MK-5720).
For each site of administration, the pharmacokinetic variables of plasma MK-5720 AUC0-
last, AUC0-inf, Cmax, Tmax, CL/F, Vz/F and apparent terminal t1/2 will be evaluated along 
CCI
CCI
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with the plasma MK-8189 AUC0-28d, AUC0-inf, Cmax, Tmax, C28d, CL/F, Vz/F and 
apparent terminal t1/2. 
9.3.3
Exploratory Endpoints
Pharmacokinetic: Following oral run-in doses of MK-8189 (Period 1), the pharmacokinetic 
variables of plasma MK-8189 AUC0-24, Cmax, Tmax, C24 and apparent terminal t1/2 will 
be evaluated.
Following IM single-ascending doses of MK-5720 (Period 2), the depot volume and surface 
area calculated via intensity threshold-based segmentation of the MRI images will be 
evaluated to better understand any differences in pharmacokinetics between patients.
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
Safety Analyses will be conducted in the APaT population, which consists of all 
randomized/allocated participants who received at least one dose of study intervention. 
Participants will be included in the treatment group corresponding to the study intervention 
they actually received for the analysis of safety data using the APaT population. This will be 
the treatment group to which they are randomized except for participants who take incorrect 
study intervention for the entire treatment period; such participants will be included in the 
treatment group corresponding to the study intervention actually received.
Analyses of laboratory test results, vital signs, and ECG measurements will include only 
participants with at least one measurement obtained after at least one dose of study 
intervention. If the analysis will assess change from baseline, a baseline measurement is also 
required.
9.4.2
Per-Protocol (PP) Population
The population includes the subset of participants who comply with the protocol sufficiently 
to ensure that generated data will be likely to exhibit the effects of treatment, according to the 
underlying scientific model. Compliance covers such considerations as exposure to 
treatment, availability of measurements and absence of important protocol deviations. 
Important protocol deviations will be identified to the extent possible prior to unblinding by 
individuals responsible for data collection/compliance, and its analysis and interpretation. 
Any participants or data values excluded from analysis will be identified, along with their 
reason for exclusion, in the CSR. At the end of the study, all participants who are compliant 
with the study procedure as aforementioned and have available data from at least one 
treatment will be included in the primary analysis dataset. This population will be used for
the PK analyses.
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9.5
Statistical Methods
9.5.1
Statistical Methods for Safety Analyses
Safety will be summarized separately for the oral run-in doses of MK-8189 [Period 1] and 
IM single-ascending doses of MK-5720 [Period 2].  The following will be done for both 
periods.  
Incidence of AEs will be descriptively summarized. Summary statistics and plots will be 
generated for raw laboratory safety tests, ECGs, and VS as well as for change from baseline, 
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). 
Summary statistics and plots will be generated for BARS, AIMS, SAS, and BPRS, as well as 
for change from baseline. Responses to the C-SSRS will be listed.
9.5.2
Statistical Methods for Pharmacokinetic Analyses
The following analyses are for Period 1 of the protocol (oral run-in doses of MK-8189). 
Individual values will be listed for each PK parameter, 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 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 
is the observed variance on the natural log-scale).
The following analyses are for Period 2 of the protocol (IM single-ascending doses of MK-
5720).
Model-based PK summary
Separately for each PK parameter, individual values of plasma MK-5720 (AUC0-last, AUC-
inf, and Cmax) and plasma MK-8189 (AUC0-28d, AUC0-inf, Cmax, and C28d), after 
administration of a single dose of MK-5720 from Panels A through F will be natural log-
transformed and evaluated with a linear effects model containing a fixed effect for treatment. 
Kenward and Roger's method will be used to calculate the denominator degrees of freedom 
for the fixed effects. Ninety-five percent CIs for the least squares means for each treatment 
will be constructed on the natural log scale and will reference a t-distribution. Exponentiating 
the least-squares means and lower and upper limits of these CIs will yield estimates for the 
population GMs and CIs about the GMs on the original scale. A sample code is as follows:
proc mixed data=adpp;
class treatment;
model lnpk=treatment/ddfm=kr;
lsmeans treatment/alpha=0.05 cl;
run;
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PK Comparison of Deltoid vs Gluteal Muscle
A comparison between Deltoid and Gluteal Muscle will be evaluated using the above linear 
model at a common dose level for plasma MK-5720 and plasma MK-8189.  If appropriate, 
dose normalization prior to construct of comparison and subsequent calculation of the 
geometric mean ratios and corresponding 90% confidence interval will be implemented. 
Descriptive Statistics
Individual values will be listed for each PK parameter by treatment (for MK-5720 and MK-
8189), 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 x standard 
deviation/arithmetic mean), median, minimum, maximum, geometric mean, and geometric 
percent CV (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the 
natural log-scale).
QTc Analysis
QTc will be evaluated through development of a model describing the relationship between 
QTc change from baseline and MK-5720 plasma concentrations and the relationship between 
QTc change from baseline and MK-8189 plasma concentrations. Details of the 
concentration-QTc analysis will be specified in a separate modeling analysis plan (MAP). 
This MAP will be completed prior to unblinding and database lock. The planned analysis 
will be aligned with the Scientific White Paper on Concentration-QTc modeling - A Review 
[Garnett, C., et al 2017]. Results of this analysis will be reported separately from the CSR.
Counts will be provided by dose and time point for QTc values falling in the following 
ranges: ≤450, >450, >480 and >500 msec. Counts will also be provided by dose and time 
point for QTc change from baseline values falling in the following ranges: <30, ≥30 and ≥60 
msec. Means and 90% confidence intervals for QTc and QTc change from baseline will be 
provided for each dose.
CCI
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Exploratory Analysis
The depot volume and surface area from the MRI images will be summarized using 
descriptive statistics including mean, standard deviation, median, minimum, and maximum, 
by deltoid muscle and gluteal muscle.
9.6
Interim Analyses
During the in-life portion of the trial, descriptive summary level results (PK, biomarkers, 
and/or safety (labs, VS, ECGs)) will be prepared as needed to support decision-making 
meetings such as dose escalation meetings. The aggregate summaries will be presented in an 
unblinded manner. No individual participant level results will be provided. There are no 
planned interim analyses to test any formal hypotheses.
9.7
Multiplicity
The hypothesis related to target PK will be addressed using posterior probabilities, therefore, 
there is no need for a multiplicity adjustment.
9.8
Sample Size and Power Calculations
The following power applies to Period 2 of the protocol (IM single-ascending doses of MK-
5720).
CCI
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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 
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includes proactive identification of critical to quality factors utilizing a risk-
based approach. Plans are then developed to assess and mitigate risks to those
factors as appropriate during the trial. All trial protocols are and will be assessed 
for the need and capability to enroll underrepresented groups. Participants must 
meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment,
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to 
the trial protocol, and in signing the protocol, agree to support these ethical and 
scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
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.
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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.
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.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
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.
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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 11] will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.3 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 11
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
(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)
Other Screening 
Tests

FSH (as needed in PONCBP only)

Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) or specify 
other tests if applicable
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; PONCBP=person of nonchildbearing potential;
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; ULN=upper limit of normal; WBC=white blood cell
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.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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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.
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.
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•
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).
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.
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•
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.)
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.
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•
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.
•
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).
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-
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 Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
Nonparticipant of Childbearing Potential
A nonparticipant assigned female sex at birth is considered fertile and capable of becoming 
pregnant following menarche until becoming postmenopausal unless permanently sterile (see 
below):
Nonparticipants assigned female sex at birth who are in the following categories are not 
capable of becoming pregnant and, therefore, not considered of CBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Hysterectomy
-
Bilateral salpingectomy
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-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Müllerian agenesis, androgen insensitivity).
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
10.5.2
Contraceptive Requirements
Not applicable 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2
Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Blood Volume Table
Please refer to the Study Operations Manual for Blood Volume Table.
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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
None
None
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 ≥200 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 ≥120 ms
QRS ≥130 ms + Increase of ≥10 ms
QTc ( 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;; 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 a repeat 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:
a.
The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter the study.
b.
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
A2M
alpha-2-macroglobulin
AAP
atypical antipsychotics
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AGP
alpha-1-acid glycoprotein
AIMS
abnormal involuntary movement scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
API
active pharmaceutical ingredient 
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-28d
area under the concentration-time curve from 0 to 28 days
AUC0-inf
area under the concentration-time curve from 0 to infinity
AUC0-last
area under the concentration-time curve from 0 to last measurable 
concentration
AV
atrioventricular
BARS
Barnes Akathisia Rating Scale
BDS
blood drug screen
BLA
biologics license application
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BPRS
Brief Psychiatric Rating Scale
C28d
concentration at Day 28
cAMP
cyclic adenosine monophosphate
CCU
cardiac care unit
cGMP
cyclic guanosine monophosphate
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Abbreviation
Expanded Term
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system
CL
clearance
CL/F
apparent clearance
COVID-19
coronavirus disease of 2019
CR
controlled-release
CRF
case report form
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
trough concentration
CV
coefficient of variation
CYP
cytochrome p450
CYP2C9
cytochrome p450 2c9
CYP3A
cytochrome p4503a
DDI
drug-drug interaction
DFC
dry fill capsule
DILI
drug-induced liver injury
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
eDMC
external data monitoring committee 
eGFR
estimated glomerular filtration rate
EM
exposure multiple
EMA
European Medicines Agency
EO
enzyme occupancy
EPS
extrapyramidal symptoms
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Abbreviation
Expanded Term
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
full analysis set
FIH
first in human
FSH
follicle-stimulating hormone
GCP
good clinical practice
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GLP
good laboratory practice
GM
geometric mean
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HED
human equivalent dose 
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
ID
identification
IEC
Independent Ethics Committee
IM
intramuscular 
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IR
immediate release
IRB
Institutional Review Board
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Abbreviation
Expanded Term
IV
intravenous
IWG
International Working Group
LAI
long acting injectable 
LLN
lower limit of normal
MAD
maximum administered dose
MDRD
modification of diet in renal disease
MRI
magnetic resonance imaging
mRNA
messenger RNA
MRSD
maximum recommended starting dose
NCS
not clinically significant
NDA
New Drug Application
NHP
nonhuman primate
NOAEL
no observed adverse effect level
NR
normal range
OTC
over the counter
P
protocol (number)
PANSS
Positive and Negative Syndrome Scale 
PCL
protocol clarification letter
PCP
primary care physician
PDE
phosphodiesterase 
PDE10A
phosphodiesterase 10A
PET
positron emission tomography
PK
pharmacokinetic
po
orally
POC
proof of concept
PONCBP
person of nonchildbearing potential 
PP
per-protocol
PQC
product quality complaint
PR
pulse rate
QD
once daily
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Abbreviation
Expanded Term
QM
once monthly 
QP2
Department of Quantitative Pharmacology and Pharmacometrics
QTc
QT corrected using Fridericia’s formula
RNA
ribonucleic acid
RR
respiratory rate
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Simpson Angus Scale
SD
standard deviation
SGA
second generation antipsychotic
SIM
site imaging manual
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOP
standard operating procedures
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TK
toxicokinetics
Tmax
time to maximum plasma concentration
t1/2
half life
UDS
urine drug screen
ULN
upper limit of normal
Vd
volume of distribution
Vz/F
apparent volume of distribution
VS
vital signs
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11
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[05MLJP]
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