Clinical trial NCT04506905
Conditions: Schizophrenia
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-08-28; Completion date: 2022-03-22
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, 2-part clinical study of the safety, tolerability and pharmacokinetics of alternate MK-8189 titration regimens. Part 1 assessed multiple dose once-daily titration regimens of MK-8189 in young adult participants with schizophrenia. Part 2 assessed multiple once-daily doses of MK-8189 in elderly participants with schizophrenia and healthy elderly participants.

Detailed description:

Arms: arm 1: Young adult participants with schizophrenia receive MK-8189 titrated from 16 mg to 24 mg once daily (QD), orally, over a course of 7-day treatment. arm 2: Young adult participants with schizophrenia receive MK-8189 titrated up to 24 mg QD, orally, over a course of 7-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panel. arm 3: Young adult participants with schizophrenia receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over a course of 7-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. arm 4: Elderly adult participants with schizophrenia receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over the course of a 13-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. arm 5: Elderly adult participants with schizophrenia receive MK-8189 titrated from 16 mg to 24 mg QD, orally, over the course of 10-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. arm 6: Healthy elderly adult participants receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over the course of a 13-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. arm 7: Healthy elderly adult participants receive MK-8189 titrated from 16 mg to 24 mg QD, orally, over the course of 10-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. arm 8: Oral tablets of dose-matched placebo to total daily dose of MK-8189. arm 9: Oral tablets of dose-matched placebo to total daily dose of MK-8189.
Interventions: intervention 1: MK-8189 intervention 2: Placebo
Intervention descriptions: intervention 1: MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization intervention 2: Oral tablets of dose-matched placebo to MK-8189 according to randomization

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04506905 
Document Date: 
20-May-2021
A 2-Part Randomized Clinical Study to Evaluate the Safety, 
Tolerability and Pharmacokinetics of Alternate MK-8189 Titration 
Regimens in Young Adult Participants With Schizophrenia and to 
Evaluate the Safety, Tolerability and Pharmacokinetics of MK-
8189 in Elderly Participants With Schizophrenia and Healthy Elderly


PRODUCT: MK-8189  
1
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
This protocol amendment is applicable only to United States.
Protocol Title: A 2-Part Randomized Clinical Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Alternate MK-8189 Titration Regimens in Young Adult Participants 
With Schizophrenia and to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-
8189 in Elderly Participants With Schizophrenia and Healthy Elderly
Protocol Number: 011-05
Compound Number: MK-8189
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
118,986
Approval Date: 20 May 2021
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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
Protocol Amendment 05
20-MAY-2021
Inclusion of healthy elderly participants in additional panels (Panel F and Panel 
G) to support future development of MK-8189.
Protocol Amendment 04
08-MAR-2021
The rationale for the Amendment is to add flexibility to dose a smaller cohort 
(n=8) of participants in Panel D to assess initial tolerability in elderly 
participants and inform titration regimen in Panel E.
Protocol Amendment 03
10-FEB-2021
The rationale for the Amendment is to modify contraceptive language to align 
with an FDA request.
Protocol Amendment 02
21-JAN-2021
The rationale for the Amendment is to modify maximum blood volume 
collected per participant to account for potential additional volume needed to be 
drawn and discarded prior to collection of sample when a catheter is used.
Protocol Amendment 01
09-SEP-2020
The rationale for the Amendment is to address health authority feedback to 
modify screening QTc interval criteria such that only participants with a QTc 
interval of ≤450 msec be included in the current protocol.
Original Protocol
05-MAY-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Addition of healthy elderly panels (Panel F and Panel G) to support future development of MK-8189.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
3 Hypotheses, Objectives 
and Endpoints
4.1 Overall Design
4.2 Scientific Rationale for 
Study Design
4.3 Justification for Dose
5 Study Population
6.1 Study Intervention 
Administered
6.3.1 Intervention 
Assignment
8.10.2 Treatment Period
Details for the addition of Panel F and 
Panel G in this amendment were added to 
applicable sections of the protocol.
Panel F and G will be conducted in the 
same manner as Panel D and Panel E, 
respectively.
Panel F and Panel G will enroll healthy elderly 
participants to evaluate the safety, tolerability and 
pharmacokinetics of MK-8189 in healthy elderly 
participants.
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Section # and Name
Description of Change 
Brief Rationale 
9.3 Hypotheses/Estimation
9.4 Analysis Endpoints
9.6 Statistical Methods
10.8 Appendix 8: Blood 
Volume Table
2.2.2 Preclinical and Clinical 
Studies
Added final, unblinded data from P007.
PN 007 is complete.
2.2.3 Ongoing Clinical 
Studies
Added preliminary blinded safety data 
from ongoing P011.
Part 1 of PN 011 is clinically complete.
Preliminary blinded safety data from adult patients 
with schizophrenia provides information to support the 
evaluation of titration regimens in elderly participants
4.1 Overall Design
Randomization ratio has been deleted from 
this section.
The randomization ratio has been deleted to minimize 
treatment allocation information provided to trial site.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
1.3.1
Schedule of Activities: Part 1 (Panel A and Panel B or C)..........................19
1.3.2
Schedule of Activities: Part 2 (Panel D/Panel F).........................................23
1.3.3
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 1).................28
1.3.4
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 2).................33
1.3.5
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 3).................38
2
INTRODUCTION..........................................................................................................42
2.1
Study Rationale....................................................................................................42
2.2
Background ..........................................................................................................42
2.2.1
Pharmaceutical and Therapeutic Background .............................................42
2.2.2
Preclinical and Clinical Studies ...................................................................43
2.2.3
Ongoing Clinical Studies.............................................................................46
2.3
Benefit/Risk Assessment......................................................................................48
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................48
4
STUDY DESIGN............................................................................................................50
4.1
Overall Design......................................................................................................50
4.2
Scientific Rationale for Study Design.................................................................54
4.2.1
Rationale for Endpoints ...............................................................................55
4.2.1.1
Safety Endpoints................................................................................55
4.2.1.2
Pharmacokinetic Endpoints ...............................................................55
4.2.1.3
Planned Exploratory Biomarker Research.........................................56
4.2.1.3.1
Planned Genetic Analysis ........................................................56
4.2.1.4
Future Biomedical Research..............................................................56
4.2.2
Rationale for the Use of Comparator/Placebo .............................................56
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................57
4.3
Justification for Dose...........................................................................................57
4.3.1
Starting Dose for This Study........................................................................57
4.3.2
Maximum Dose/Exposure for This Study ...................................................58
4.3.3
Rationale for Dose Interval and Study Design ............................................59
4.4
Beginning and End of Study Definition .............................................................60
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4.4.1
Clinical Criteria for Early Study Termination .............................................60
5
STUDY POPULATION ................................................................................................60
5.1
Inclusion Criteria.................................................................................................60
5.2
Exclusion Criteria................................................................................................63
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 ......................................................................67
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................67
5.3.2.1
Caffeine Restrictions..........................................................................67
5.3.2.2
Alcohol Restrictions...........................................................................68
5.3.2.3
Tobacco Restrictions..........................................................................68
5.3.3
Activity Restrictions ....................................................................................68
5.4
Screen Failures.....................................................................................................68
5.5
Participant Replacement Strategy......................................................................68
6
STUDY INTERVENTION............................................................................................68
6.1
Study Intervention(s) Administered...................................................................69
6.2
Preparation/Handling/Storage/Accountability .................................................71
6.2.1
Dose Preparation..........................................................................................71
6.2.2
Handling, Storage, and Accountability........................................................71
6.3
Measures to Minimize Bias: Randomization and Blinding..............................72
6.3.1
Intervention Assignment..............................................................................72
6.3.2
Stratification.................................................................................................73
6.3.3
Blinding........................................................................................................73
6.4
Study Intervention Compliance..........................................................................73
6.5
Concomitant Therapy..........................................................................................73
6.5.1
Rescue Medications and Supportive Care ...................................................74
6.6
Dose Modification (Escalation/Titration/Other)...............................................74
6.7
Intervention After the End of the Study............................................................75
6.8
Clinical Supplies Disclosure................................................................................75
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................75
7.1
Discontinuation of Study Intervention...............................................................75
7.2
Participant Withdrawal From the Study...........................................................76
7.3
Lost to Follow-up .................................................................................................77
8
STUDY ASSESSMENTS AND PROCEDURES........................................................77
8.1
Administrative and General Procedures ...........................................................78
8.1.1
Informed Consent.........................................................................................78
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8.1.1.1
General Informed Consent.................................................................78
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................78
8.1.2
Inclusion/Exclusion Criteria ........................................................................79
8.1.3
Participant Identification Card.....................................................................79
8.1.4
Medical History ...........................................................................................79
8.1.5
Prior and Concomitant Medications Review...............................................79
8.1.5.1
Prior Medications...............................................................................79
8.1.5.2
Concomitant Medications..................................................................79
8.1.6
Assignment of Screening Number...............................................................80
8.1.7
Assignment of Treatment/Randomization Number.....................................80
8.1.8
Study Intervention Administration ..............................................................80
8.1.8.1
Timing of Dose Administration.........................................................80
8.1.9
Discontinuation and Withdrawal .................................................................80
8.1.9.1
Withdrawal From Future Biomedical Research ................................81
8.1.10
Participant Blinding/Unblinding..................................................................81
8.1.11
Domiciling ...................................................................................................82
8.1.12
Calibration of Equipment.............................................................................82
8.2
Efficacy/Immunogenicity Assessments ..............................................................82
8.3
Safety Assessments...............................................................................................82
8.3.1
Physical Examinations.................................................................................82
8.3.2
Vital Signs....................................................................................................83
8.3.2.1
Resting Vital Signs ............................................................................83
8.3.2.2
Orthostatic Vital Signs.......................................................................83
8.3.3
Electrocardiograms ......................................................................................84
8.3.4
Clinical Safety Laboratory Assessments .....................................................85
8.3.5
Suicidal Ideation and Behavior Monitoring.................................................85
8.3.5.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................85
8.3.6
Monitoring for Extrapyramidal Symptoms..................................................86
8.3.7
Assessment of Neuropsychological Effects.................................................86
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................87
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................87
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......89
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...89
8.4.4
Regulatory Reporting Requirements for SAE .............................................89
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................89
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................90
8.4.7
Events of Clinical Interest............................................................................90
8.5
Treatment of Overdose........................................................................................90
8.6
Pharmacokinetics.................................................................................................91
8.6.1
Blood Collection for Plasma MK-8189 .......................................................91
8.7
Pharmacodynamics..............................................................................................91
8.8
Biomarkers ...........................................................................................................91
8.8.1
Planned Genetic Analysis Sample Collection..............................................91
8.9
Future Biomedical Research Sample Collection...............................................91
8.10
Visit Requirements...............................................................................................92
8.10.1
Screening......................................................................................................92
8.10.2
Treatment Period..........................................................................................92
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........93
8.10.4
Poststudy......................................................................................................93
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......93
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................94
9
STATISTICAL ANALYSIS PLAN .............................................................................95
9.1
Statistical Analysis Plan Summary.....................................................................95
9.2
Responsibility for Analyses.................................................................................96
9.3
Hypotheses/Estimation ........................................................................................96
9.4
Analysis Endpoints...............................................................................................97
9.5
Analysis Populations............................................................................................98
9.6
Statistical Methods...............................................................................................98
9.7
Interim Analyses ..................................................................................................99
9.8
Multiplicity .........................................................................................................100
9.9
Sample Size and Power Calculations ...............................................................100
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................101
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......101
10.1.1
Code of Conduct for Clinical Trials...........................................................101
10.1.2
Financial Disclosure...................................................................................103
10.1.3
Data Protection...........................................................................................103
10.1.3.1
Confidentiality of Data ....................................................................104
10.1.3.2
Confidentiality of Participant Records.............................................104
10.1.3.3
Confidentiality of IRB/IEC Information..........................................104
10.1.4
Publication Policy......................................................................................104
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10.1.5
Compliance with Study Registration and Results Posting Requirements .105
10.1.6
Compliance with Law, Audit, and Debarment ..........................................105
10.1.7
Data Quality Assurance .............................................................................106
10.1.8
Source Documents .....................................................................................107
10.1.9
Study and Site Closure...............................................................................107
10.2
Appendix 2: Clinical Laboratory Tests............................................................108
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................110
10.3.1
Definition of AE ........................................................................................110
10.3.2
Definition of SAE ......................................................................................111
10.3.3
Additional Events Reported.......................................................................112
10.3.4
Recording AE and SAE .............................................................................112
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................116
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................117
10.5
Appendix 5: Contraceptive Guidance..............................................................118
10.5.1
Definitions..................................................................................................118
10.5.2
Contraception Requirements......................................................................119
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................120
10.7
Appendix 7: Country-specific Requirements..................................................125
10.8
Appendix 8: Blood Volume Table ....................................................................126
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria (if criteria 
diverges from inclusion/exclusion criteria, more conservative criteria 
should be used)...................................................................................................128
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...130
10.11 Appendix 11: General (Full) and Targeted Neurological Exam ...................131
10.12 Appendix 12: Abbreviations .............................................................................138
11
REFERENCES.............................................................................................................141
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................70
Table 2
Sample Allocation Schedule............................................................................72
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................88
Table 4
Precision Estimates for AUC0-24hr, Cmax, and C24hr................................100
Table 5
Protocol-required Safety Laboratory Assessments........................................108
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LIST OF FIGURES
Figure 1
Study Schema for Part 1 and Part 2 .................................................................18
Figure 2
Part 2 Panel E/G Alternate Dose Regimens if Starting Regimen is 
Titration Regimen 1 or Titration Regimen 2 ...................................................53
Figure 3
MK-8189 Dose-Enzyme Occupancy ...............................................................58
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A 2-Part Randomized Clinical Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Alternate MK-8189 Titration Regimens in Young Adult Participants 
With Schizophrenia and to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-
8189 in Elderly Participants With Schizophrenia and Healthy Elderly
Short Title: Evaluation of MK-8189 Alternate Titration Regimens and Elderly 
Pharmacokinetic Study
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for this study.
In male or female participants with schizophrenia (young adults and elderly) and healthy
elderly participants:
Primary Objectives
Primary Endpoints
Part 1
- To evaluate the safety and tolerability of 
MK-8189 oral, once-daily titration regimens in 
young adult participants with schizophrenia
Part 2
- To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-8189 in 
elderly participants with schizophrenia and 
healthy elderly participants
Part 1 and Part 2
- Adverse experiences, laboratory safety 
tests, electrocardiograms and vital signs
Secondary Objectives
Secondary Endpoints
Part 1
- To characterize MK-8189 pharmacokinetics 
following different titration regimens in young 
adult participants with schizophrenia
Part 2
- To characterize the pharmacokinetics of MK-
8189 following multiple once-daily oral doses 
in elderly participants with schizophrenia and 
healthy elderly participants
Part 1 and Part 2
- AUC0-24hr, Cmax, C24hr, Tmax, CL, 
Vd and apparent t1/2
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of schizophrenia
Population
Young adult and elderly participants with schizophrenia
and healthy elderly participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 13 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 100 total participants may be allocated/randomized in Part 1 (n=28, actual
sample size as Part 1 is clinically complete) and Part 2 (n ~72). In Part 1, approximately 16 
evaluable participants with schizophrenia will complete a generally well-tolerated dose 
titration.
In Part 2, the intent is to evaluate up to 2 panels of elderly participants with schizophrenia 
(Panel D and Panel E) and up to 2 panels of healthy elderly participants (Panel F and Panel 
G).  
Up to approximately 16 participants may be enrolled in Panel D and up to approximately 24 
participants may be enrolled in Panel E to ensure approximately 16 elderly participants with 
schizophrenia complete a generally well-tolerated dose titration. Up to approximately 12 
participants will be enrolled in Panel F and up to approximately 20 participants will be 
enrolled in Panel G to ensure approximately 12 healthy elderly participants complete a 
generally well-tolerated dose titration as described in Section 9.9.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Panel/ Regimen
Use
Part 1 Activea 
MK-8189
4 mg and 
12 mg
QD
Oral
Panel A
Titration Regimen 1:
12 mg x 1 tablet &
4 mg x 1 tablet 
Days 1-3;
12 mg x 2 tablets 
Days 4-7
AND
Panel B
Titration Regimen 2:
12 mg x 2 tablets
Days 1-7
OR
Panel C
Titration Regimen 3:
4 mg x 2 tablets
Day 1;
12 mg x 1 tablet &
4 mg x 1 tablet
Day 2;
12 mg x 2 tablets
Days 3-7
Experi-
mental
Part 1 Placeboa
Placebo
N/A
QD
Oral
Panel A
Titration Regimen 1:
12 mg x 1 tablet &
4 mg x 1 tablet 
Days 1-3;
12 mg x 2 tablets 
Days 4-7
AND
Panel B
Titration Regimen 2: 
12 mg x 2 tablets 
Days 1-7
OR
Panel C
Titration Regimen 3:
4 mg x 2 tablets
Day 1;
12 mg x 1 tablet & 
4 mg x 1 tablet
Day 2;
12 mg x 2 tablets
Days 3-7
Control
Part 2b Active 
MK-8189
4 mg and 
12 mg
QD
Oral
Panel D and Panel F
4 mg x 2 tablets 
Days 1-3;
12 mg x 1 tablet & 
4 mg x 1 tablet 
Days 4-6;
12 mg x 2 tablets 
Days 7-13 
Experi-
mental
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Panel E and Panel G
Titration Regimen 1:
12 mg x 1 tablet & 
4 mg x 1 tablet
Days 1-3;
12 mg x 2 tablets
Days 4-10
OR
Panel E and Panel G
Titration Regimen 2:
12 mg x 2 tablets 
Days 1-7
OR
Panel E and Panel G
Titration Regimen 3:
4 mg x 2 tablets 
Day 1;
12 mg x 1 tablet & 
4 mg x 1 tablet
Day 2;
12 mg x 2 tablets
Days 3-9
Part 2b Placebo
Placebo
N/A
QD
Oral
Panel D and Panel F
4 mg x 2 tablets
Days 1-3;
12 mg x 1 tablet
& 4 mg x 1 tablet
Days 4-6;
12 mg x 2 tablets 
Days 7-13
Panel E and Panel G
Titration Regimen 1:
12 mg x 1 tablet & 
4 mg x 1 tablet
Days 1-3;
12 mg x 2 tablets
Days 4-10
OR
Panel E and Panel G
Titration Regimen 2: 
12 mg x 2 tablets 
Days 1-7
OR
Panel E and Panel G
Titration Regimen 3:
4 mg x 2 tablets
Day 1;
12 mg x 1 tablet&
4 mg x 1 tablet
Day 2;
12 mg x 2 tablets
Days 3-9
Control
Abbreviations: 
QD = Once a day
a
Following completion and review of safety and tolerability data of Panel A, only Panel B or C will 
be conducted.
b
The titration regimen selected for Panel E and Panel G will be based on safety and tolerability data 
from Part 2 Panel D and Panel F, respectively, as well as Part 1 safety and tolerability data. 
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MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Total 
Number of 
Intervention 
Groups/ 
Arms
2 intervention groups
Duration of 
Participation
Part 1
Each participant in Panel A and Panel B or C will participate in the study for 
approximately 7 weeks from the time the participant signs the Informed 
Consent Form through the final contact. After a screening phase of 
approximately 4 weeks, including a washout period of approximately 1 week, 
each participant will receive assigned intervention for 1 week. After the end 
of treatment, each participant will be followed for 2 weeks.
Part 2
Panel D/Panel F: Each participant will participate in the study for 
approximately 8 weeks from the time the participant signs the Informed 
Consent Form through the final contact. After a screening phase of 
approximately 4 weeks, including a washout period of approximately 1 week, 
each participant will receive assigned intervention for 2 weeks. After the end 
of treatment each participant will be followed for 2 weeks. 
Panel E/Panel G: Each participant will participate in the study for 
approximately 7 weeks (Titration Regimen 2) or 7.5 weeks (Titration
Regimens 1 and 3) from the time the participant signs the Informed Consent 
Form through the final contact. After a screening phase of approximately 4 
weeks, including a washout period of approximately 1 week, each participant 
will receive assigned intervention for 1 week (Titration Regimen 2) or 1.5 
weeks (Titration Regimens 1 and 3). After the end of treatment each 
participant will be followed for 2 weeks. 
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
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PRODUCT: MK-8189  
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MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
A list of abbreviations used in this document can be found in Appendix 12.
1.2
Schema
The study design is depicted in [Figure 1].
Figure 1
Study Schema for Part 1 and Part 2
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PRODUCT: MK-8189  
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20-MAY-2021
1.3
Schedule of Activities
1.3.1
Schedule of Activities: Part 1 (Panel A and Panel B or C)
Part 1 (Panel A and Panel B or C)
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~ 14
Administrative Procedures
Informed Consent
X
Section 8.1.1
Informed Consent for Future 
Biomedical Research
X
Section 8.1.1.2
Inclusion/Exclusion Criteria
X
X
Only specific criteria 
will be reviewed prior to 
randomization. Section 5
Participant Identification 
Card
X
Section 8.1.3
Medical History (includes 
psychiatric history and 
substance usage)
X
Substances: drugs, 
alcohol, and caffeine
Section 8.1.4
Prior/Concomitant 
Medication Review
X------------------------------------------------------------------------------------------------------------X
Section 8.1.5
Washout from 
Antipsychotics
X
X
Discontinue medication 
at least 5 days or at least 
3 half-lives (whichever 
is longer) prior to Day -
1. Section 8.1.5.1
Assignment of Allocation 
Number (Randomization)
X
Section 8.1.7
MK-8189/Placebo 
Administration
X
X
X
X
X
X
X
Sections 6.3.1 and 8.1.8
Standard Mealsa
X
X
X
X
X
X
X
X
X
Section 5.3.1
Domiciling in Clinicb
X-------------------------------------------------------------------------------X
Section 8.1.11
Follow-up Phone Call
X
Safety Procedures
Full physical examination
X
X
X
X
Section 8.3.1
Height
X
Section 8.3.1
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 1 (Panel A and Panel B or C)
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~ 14
Weight
X
X
X
X
Section 8.3.1
Full Neurological Exam
X
X
Section 8.3.7 and 
Appendix 11
Targeted Neurological Exam
X
X
X
X
Section 8.3.7 and 
Appendix 11
Vital Signs (heart rate, blood 
pressure)c
X
X
X
X
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
Orthostatic Vital Signs 
(heart rate, blood pressure)d
X
X
X
X
X
X
X
X
X
Section 8.3.2.2
Vital Signs (respiratory rate, 
body temperature)e
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
12-lead Electrocardiogramf
X
X
X
X
X
Section 8.3.3
Serum β-hCG (WOCBP 
only)
X
Appendix 2
Urine Pregnancy Test 
(WOCBP only)g
X
Section 5.1
Serum FSH (WONCBP 
only)
X
Appendix 2
HIV, Hepatitis B and C 
Screen (per site SOP)
X
Appendix 2
UDS/BDS (per site SOP)h
X
X
Appendix 2
Laboratory Safety Test 
(hematology, chemistry, 
urinalysis)e
X
X
X
X
X
Appendix 2
Columbia Suicide Severity 
Rating Scale (C-SSRS)-
Baseline Version
X
Section 4.2.3
Columbia Suicide Severity 
Rating Scale (C-SSRS)-
Since Last Assessment 
Versione
X
X
X
X
X
Section 4.2.3
Barnes Akathisia Rating 
Scale (BARS)e, i
X
X
X
X
X
Section 4.2.1.1
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 1 (Panel A and Panel B or C)
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~ 14
Abnormal Involuntary 
Movement Scale (AIMS)e, i
X
X
X
X
X
Section 4.2.1.1
Simpson Angus Scale
(SAS)e, i
X
X
X
X
X
Section 4.2.1.1
Bond and Lader Visual 
Analog Scale (VAS)e
X
X
X
X
X
Section 4.2.1.1
Brief Psychiatric Rating 
Scale (BPRS)e
X
X
X
X
X
X
Section 4.2.1.1
AE/SAE review
X------------------------------------------------------------------------------------------------------------X
Section 8.4
Pharmacokinetics
Blood for Plasma MK-8189 
and/or Metabolites Assayj
X
X
X
X
X
X
X
Section 8.6.1
Biomarkers
Blood for Genetic Analysisk
X
Collect predose from 
enrolled participants 
only. Section 8.8
AE=adverse event; BDS=blood draw screen; FSH=follicle stimulating hormone; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine 
drug screen; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a. Meals should be given at approximately the same time every day starting on Day -1 through Day 8. Day -1 will be time-matched to Day 1. Breakfast will be 
given at ~ 1-hour postdose, lunch given at ~ 4-hours postdose, a snack given at ~ 8-hours postdose and dinner at ~ 12-hours postdose. All meals will follow 
the completion of all specified procedures at that timepoint.
b.Participants will be confined minimally from Day -6 until Day 9 procedures are complete. 
c.Single HR and BP measurements will be obtained at all timepoints unless otherwise noted. On the following days, specific timepoints are noted:

Panel A and Panel B:
o
Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs.
o
Day 1, Day 4 and Day 7: 8, 16 and 24 hours postdose 
o
Day 9: Time-matched to 24-hour postdose vital signs

Panel C
o
Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs.
o
Day 1, Day 2, Day 3 and Day 7: 8, 16 and 24 hours postdose
o
Day 9: Time-matched to 24-hour post dose vital signs
d.Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments. Participants should be standing for approximately 2 minutes prior 
to the orthostatic assessments. Orthostatic HR and BP measurements will be obtained on: 

Panel A and Panel B:
06D209
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PRODUCT: MK-8189  
22
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 1 (Panel A and Panel B or C)
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~ 14
o
Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs.
o
Day 1, Day 4 and Day 7: 8, 16 and 24 hours postdose
o
Day 9: Time-matched to 24-hour post dose orthostatic vital signs

Panel C
o
Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs.
o
Day 1, Day 2, Day 3 and Day 7: 8, 16 and 24 hours postdose 
o
Day 9: Time-matched to 24-hour post dose orthostatic vital signs
e.Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints. On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours prior to dosing

Day 1 and Day 4: 8, 16 and 24 hours post-dose
g.In the event the urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required.
h.Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
i. Additional BARS, AIMS and SAS assessments will be conducted as soon as possible when there are observed or reported complaints of dystonia and/or 
akathisia (See Section 8.3.6).
j. MK-8189 plasma PK sample collection: 

Panel A: 
o
Day 1 and Day 4: predose, 2, 6, 8, 10, 12, 16 and 24 hours postdose 
o
Day 7: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Panel B: 
o
Day1: predose, 2, 6, 8, 10, 12 and 16 hours postdose
o
Day 2 and Day 3: predose, 2, 6 and 8 hours postdose
o
Day 7: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Panel C: 
o
Day 1 and Day 2: predose, 2, 6, 8, 10, 12 and 16 hours postdose
o
Day 3: predose, 2, 6, 8, 10, 12, 16 and 24 hours postdose
o
Day 7: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Optional sample when signs of dystonia and/or akathisia occur.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
k.This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does 
not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, 
data analysis will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical research.
06D209
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PRODUCT: MK-8189  
23
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
1.3.2
Schedule of Activities: Part 2 (Panel D/Panel F)
Part 2 Panel D/Panel F
Screening
Washout
Intervention
Poststudy Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12 13 14
15
~20
Administrative 
Procedures
Informed Consent
X
Section 8.1.1
Informed Consent 
for Future 
Biomedical 
Research
X
Section 8.1.1.2
Inclusion/Exclusi
on Criteria
X
X
Only specific 
criteria will be 
reviewed prior to 
randomization.
Section 5
Participant 
Identification 
Card
X
Section 8.1.3
Medical History
(includes 
psychiatric 
history and 
substance usage)
X
Substances: drugs, 
alcohol and 
caffeine
Section 8.1.4
Prior/
Concomitant 
Medication 
Review
X------------------------------------------------------------------------------------------------------------X
Section 8.1.5
Washout from 
Antipsychotics
(Panel D only)
X
X
Discontinue 
medication at 
least 5 days or at 
least 3 half-lives 
(whichever is 
longer) prior to 
Day -1. 
Section 8.1.5.1
06D209
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PRODUCT: MK-8189  
24
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel D/Panel F
Screening
Washout
Intervention
Poststudy Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12 13 14
15
~20
Assignment of 
Allocation 
Number 
(Randomization)
X
Section 8.1.7
MK-8189/
Placebo
Administration
X
X X
X
X
X
X
X
X
X
X
X
X
Sections 8.1.8 and 
6.3.1
Standard Mealsa
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
Section 5.3.1
Domiciling in 
Clinicb
X------------------------------------------------------------------------------X
Section 8.1.11
Follow-up Phone 
Call
X
Safety Procedures
Full physical 
examination
X
X
X
X
Section 8.3.1
Height
X
Section 8.3.1
Weight
X
X
X
X
Section 8.3.1
Full Neurological 
Exam
X
X
Section 8.3.7 and 
Appendix 11
Targeted 
Neurological 
Exam
X
X
X
X
X
X
Section 8.3.7 and 
Appendix 11
Vital Signs (heart 
rate, blood 
pressure)c
X
X
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
Orthostatic Vital 
Signs (heart rate, 
blood pressure)d
X
X
X
X
X
X
X
Section 8.3.2.2
Vital Signs 
(respiratory rate, 
body 
temperature)e
X
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
12-lead ECGf
X
X
X
X
X
X
X
Section 8.3.3
06D209
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PRODUCT: MK-8189  
25
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel D/Panel F
Screening
Washout
Intervention
Poststudy Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12 13 14
15
~20
Serum β-hCG 
(WOCBP only)
X
Urine Pregnancy 
Test (WOCBP 
only)
X
Serum FSH 
(WONCBP only)
X
Appendix 2
HIV, Hepatitis B 
and C Screen (per 
site SOP)
X
Appendix 2
UDS/BDS (per 
site SOP)g
X
X
Appendix 2
Laboratory Safety 
Test (hematology,
chemistry, 
urinalysis)e
X
X
X
X
X
Appendix 2
Columbia Suicide
Severity Rating 
Scale(C-SSRS)-
Baseline Version
X
Section 4.2.3
Columbia Suicide
Severity Rating 
Scale (C-SSRS)-
Since Last
Assessment 
Versione
X
X
X
X
X
Section 4.2.3
Barnes Akathisia
Rating 
Scale(BARS)e, h
X
X
X
X
X
X
Section 4.2.1.1
Abnormal 
Involuntary
Movement Scale
(AIMS)e, h
X
X
X
X
X
X
Section 4.2.1.1
06D209
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PRODUCT: MK-8189  
26
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel D/Panel F
Screening
Washout
Intervention
Poststudy Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12 13 14
15
~20
Simpson Angus 
Scale (SAS)e, h
X
X
X
X
X
X
Section 4.2.1.1
Bond and Lader 
Visual Analog 
Scale (VAS)e
X
X
X
X
X
X
Section 4.2.1.1
Brief Psychiatric 
Rating Scale
(BPRS) (Panel D 
only)e
X
X
X
X
X
X
X
Section 4.2.1.1
AE/SAE review
X----------------------------------------------------------------------------------------------------------X
Section 8.4
Pharmacokinetics
Blood for Plasma 
MK-8189 and/or 
Metabolites 
Assayi
X
X
X
X
Section 8.6.1
Biomarkers
Blood for Genetic 
Analysisj
X
Collect predose 
from enrolled 
participants only.
Section 8.8
AE=adverse event; BDS=blood draw screen; ECG=electrocardiogram; FSH=follicle stimulating hormone; SAE=serious adverse event; SOP=standard operating 
procedure; UDS=urine drug screen; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a. Meals should be given at approximately the same time every day starting on Day -1 through Day 14. Day -1 will be time-matched to Day 1. Breakfast will be 
given at ~1-hour postdose, lunch given at ~4 hours postdose, a snack given at ~8 hours postdose and dinner at ~12 hours postdose. All meals will follow the 
completion of all specified procedures at that timepoint.
b. Participants will be confined minimally from Day -6 until Day 15 procedures are complete. 
c.Single HR and BP measurements will be obtained at all timepoints unless otherwise specified. On the following days, specific timepoints are noted:

Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs

Day 1, Day 4, Day 7 and Day 13: 8, 16 and 24 hours postdose 

Day 15: Time-matched to 24-hour postdose vital signs.
d.Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments. Participants should be standing for approximately 2 minutes prior 
to the orthostatic assessments. Orthostatic HR and BP measurements will be obtained on:

Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs

Day 1, Day 4, Day 7 and Day 13: 8, 16 and 24 hours postdose
06D209
0834NF


PRODUCT: MK-8189  
27
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel D/Panel F
Screening
Washout
Intervention
Poststudy Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12 13 14
15
~20

Day 15: Time-matched to 24-hour postdose orthostatic vital signs
e.Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints. On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours prior to dosing

Day 1, Day 4, Day 7 and Day 13: 8, 16 and 24 hours post-dose
g.Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
h.Additional BARS, AIMS and SAS assessments will be conducted as soon as possible when there are observed or reported complaints of dystonia and/or 
akathisia (See Section 8.3.6).
i. MK-8189 plasma PK sample collection: 

Day 1, Day 4, and Day 7: predose, 2, 6, 8, 10, 12, 16 and 24 hours postdose.

Day 13: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Optional sample when signs of dystonia and/or akathisia occur.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
j. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does 
not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, 
data analysis will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical research.
06D209
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PRODUCT: MK-8189  
28
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
1.3.3
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 1)
Part 2 Panel E/G Titration Regimen 1
MK-8189/matching placebo 16 mg x 3 days and 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
~17
Administrative 
Procedures
Informed Consent
X
Section 8.1.1
Informed Consent for 
Future Biomedical 
Research
X
Section 
8.1.1.2
Inclusion/Exclusion 
Criteria
X
X
Only specific 
criteria will 
be reviewed 
prior to 
random-
ization.
Participant 
Identification Card
X
Section 8.1.3
Medical History
(includes psychiatric 
history and substance 
usage)
X
Substances: 
drugs, 
alcohol, and 
caffeine
Section 8.1.4
Prior/Concomitant 
Medication Review
X------------------------------------------------------------------------------------------------------------X
Section 8.1.5
Washout from 
Antipsychotics (Panel E 
only)
X
X
Discontinue 
medication at 
least 5 days 
or at least 3 
half-lives 
(whichever is 
longer) prior 
to Day -1.
Section 
8.1.5.1
06D209
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PRODUCT: MK-8189  
29
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 1
MK-8189/matching placebo 16 mg x 3 days and 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
~17
Assignment of 
Allocation Number 
(Randomization)
X
Section 8.1.7
MK-8189/Placebo
Administration
X
X
X
X
X
X
X
X
X
X
Sections 8.1.8 
and 6.3.1
Standard Mealsa
X
X
X
X
X
X
X
X
X
X
X
X
Section 5.3.1
Domiciling in Clinicb
X---------------------------------------------------------------------------------X
Section 
8.1.11
Follow-up Phone Call
X
Safety Procedures
Full physical 
examination
X
X
X
X
Section 8.3.1
Height
X
Section 8.3.1
Weight
X
X
X
X
Section 8.3.1
Full Neurological Exam
X
X
Section 8.3.7
and Appendix 
11
Targeted Neurological 
Exam
X
X
X
X
X
Section 8.3.7
and Appendix 
11
Vital Signs (heart rate, 
blood pressure)c
X
X
X
X
X
X
X
Section 8.3.2
and 
Section 
8.3.2.1
Orthostatic Vital Signs
(heart rate, blood 
pressure)d
X
X
X
X
X
X
X
Section 
8.3.2.2
Vital Signs (respiratory 
rate, body temperature)e
X
X
X
X
X
X
Section 8.3.2
and 
Section 
8.3.2.1
12-lead ECGf
X
X
X
X
X
X
Section 8.3.3
06D209
0834NF


PRODUCT: MK-8189  
30
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 1
MK-8189/matching placebo 16 mg x 3 days and 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
~17
Serum β-hCG (WOCBP 
only)
X
Urine Pregnancy Test 
(WOCBP only)
X
Serum FSH (WONCBP 
only)
X
Appendix 2
HIV, Hepatitis B and C 
Screen (per site SOP)
X
Appendix 2
UDS/BDS (per site 
SOP)g
X
X
Appendix 2
Laboratory Safety Test 
(hematology, chemistry, 
urinalysis)e
X
X
X
X
X
X
X
Appendix 2
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Baseline 
Version
X
Section 4.2.3
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Since Last
Assessment Versione
X
X
X
X
X
X
Section 4.2.3
Barnes Akathisia
Rating Scale (BARS)e, h
X
X
X
X
X
X
Section 
4.2.1.1
Abnormal Involuntary
Movement Scale
(AIMS)e, h
X
X
X
X
X
X
Section 
4.2.1.1
Simpson Angus Scale
(SAS)e, h
X
X
X
X
X
X
Section 
4.2.1.1
Bond and Lader Visual
Analog Scale (VAS)e
X
X
X
X
X
X
Section 
4.2.1.1
Brief Psychiatric Rating
Scale (BPRS) (Panel E 
only)e
X
X
X
X
X
X
X
Section 
4.2.1.1
06D209
0834NF


PRODUCT: MK-8189  
31
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 1
MK-8189/matching placebo 16 mg x 3 days and 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
~17
AE/SAE review
X-------------------------------------------------------------------------------------------------------------X
Section 8.4
Pharmacokinetics
Blood for Plasma MK-
8189 and/or 
Metabolites Assayi
X
X
X
X
X
Section 8.6.1
Biomarkers
Blood for Genetic 
Analysisj
X
Collect 
predose from 
enrolled 
participants 
only. Section 
8.8
AE=adverse event; BDS=blood draw screen; FSH=follicle stimulating hormone; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine 
drug screen; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a. Meals should be given at approximately the same time every day starting on Day -1 through Day 11. Day -1 will be time-matched to Day 1. Breakfast will be 
given at ~1-hour postdose, lunch given at ~4 hours postdose, a snack given at ~8 hours postdose and dinner at ~12 hours postdose. All meals will follow the 
completion of all specified procedures at that timepoint.
b.Participants will be confined minimally from Day -6 until Day 12 procedures are complete. 
c.Single HR and BP measurements will be obtained at all timepoints unless otherwise noted. On the following days, specific timepoints are noted:

Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs.

Day 1, Day 4 and Day 10: 8, 16 and 24 hours postdose

Day 12: Time-matched to 24-hour postdose vital signs
d.Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments. Participants should be standing for approximately 2 minutes prior to 
the orthostatic assessments. Orthostatic HR and BP measurements will be obtained on: 

Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs.

Day 1, Day 4 and Day 10: 8, 16 and 24 hours postdose

Day 12: Time-matched to the 24-hour postdose orthostatic vital signs
e.Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints. On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours prior to dosing

Day 1, Day 4 and Day 10: 8, 16 and 24 hours post-dose
g.Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
06D209
0834NF


PRODUCT: MK-8189  
32
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 1
MK-8189/matching placebo 16 mg x 3 days and 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
12
~17
h.Additional BARS, AIMS and SAS assessments will be conducted as soon as possible when there are observed or reported complaints of dystonia and/or 
akathisia (See Section 8.3.6). 
i. MK-8189 plasma PK sample collection: 

Day 1 and Day 4: predose, 2, 6, 8, 10, 12, 16 and 24 hours postdose. 

Day 10: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Optional sample when signs of dystonia and/or akathisia occur.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
j. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does 
not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, 
data analysis will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical research.
06D209
0834NF


PRODUCT: MK-8189  
33
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
1.3.4
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 2)
Part 2 Panel E/G Titration Regimen 2
MK-8189/matching placebo 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~14
Administrative 
Procedures
Informed Consent
X
Section 8.1.1
Informed Consent for 
Future Biomedical 
Research
X
Section 8.1.12
Inclusion/Exclusion 
Criteria
X
X
Only specific 
criteria will be 
reviewed prior 
to 
randomization.
Section 5
Participant 
Identification Card
X
Section 8.1.3
Medical History
(includes psychiatric 
history and substance 
usage)
X
Substances: 
drugs, alcohol, 
and caffeine
Section 8.1.4
Prior/Concomitant 
Medication Review
X------------------------------------------------------------------------------------------------------------X
Section 8.1.5
Washout from 
Antipsychotics (Panel 
E only)
X
X
Discontinue 
medication at 
least 5 days or 
at least 3 half-
lives 
(whichever is 
longer) prior to 
Day- 1. 
Section 8.1.5.1
06D209
0834NF


PRODUCT: MK-8189  
34
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 2
MK-8189/matching placebo 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~14
Assignment of 
Allocation Number 
(Randomization)
X
Section 8.1.7
MK-8189/Placebo
Administration
X
X
X
X
X
X
X
Sections 8.1.8 
and 6.3.1
Standard Mealsa
X
X
X
X
X
X
X
X
X
Section 5.3.1
Domiciling in Clinicb
X-----------------------------------------------------------------------------------------------X
Section 8.1.11
Follow-up Phone Call
X
Safety Procedures
Full physical 
examination
X
X
X
X
Section 8.3.1
Height
X
Section 8.3.1
Weight
X
X
X
X
Section 8.3.1
Full Neurological 
Exam
X
X
Section 8.3.7
and Appendix 
11
Targeted 
Neurological Exam
X
X
X
X
Section 8.3.7
and Appendix 
11
Vital Signs (heart 
rate, blood pressure)c
X
X
X
X
X
X
X
Section 8.3.2
and 
Section 8.3.2.1
Orthostatic Vital 
Signs (heart rate, 
blood pressure)d
X
X
X
X
X
X
X
Section 8.3.2.2
Vital Signs 
(respiratory rate, 
body temperature)e
X
X
X
X
X
Section 8.3.2
and 
Section 8.3.2.1
12-lead ECGf
X
X
X
X
X
Section 8.3.3
Serum β-hCG 
(WOCBP only)
X
Urine Pregnancy Test 
(WOCBP only)
X
06D209
0834NF


PRODUCT: MK-8189  
35
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 2
MK-8189/matching placebo 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~14
Serum FSH 
(WONCBP only)
X
Appendix 2
HIV, Hepatitis B and 
C Screen (per site 
SOP)
X
Appendix 2
UDS/BDS (per site 
SOP)g
X
X
Appendix 2
Laboratory Safety 
Test (hematology,
chemistry, 
urinalysis)e
X
X
X
X
X
X
Appendix 2
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Baseline 
Version
X
Section 4.2.3
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Since Last
Assessment Versione
X
X
X
X
X
Section 4.2.3
Barnes Akathisia
Rating Scale 
(BARS)e, h
X
X
X
X
X
Section 4.2.1.1
Abnormal 
Involuntary
Movement Scale
(AIMS)e, h
X
X
X
X
X
Section 4.2.1.1
Simpson Angus Scale
(SAS)e, h
X
X
X
X
X
Section 4.2.1.1
Bond and Lader 
Visual Analog Scale 
(VAS)e
X
X
X
X
X
Section 4.2.1.1
06D209
0834NF


PRODUCT: MK-8189  
36
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 2
MK-8189/matching placebo 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~14
Brief Psychiatric 
Rating Scale (BPRS) 
(Panel E only)e
X
X
X
X
X
X
Section 4.2.1.1
AE/SAE review
X------------------------------------------------------------------------------------------------------------X
Section 8.4
Pharmacokinetics
Blood for Plasma 
MK-8189 and/or 
Metabolites Assayi
X
X
X
X
X
X
Section 8.6.1
Biomarkers
Blood for Genetic 
Analysisj
X
Collect predose 
from enrolled 
participants 
only.
Section 8.8
AE=adverse event; BDS=blood draw screen; ECG=electrocardiogram; FSH=follicle stimulating hormone; SAE=serious adverse event; SOP=standard 
operating procedure; UDS=urine drug screen; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a. Meals should be given at approximately the same time every day starting on Day -1 through Day 8. Day -1 will be time-matched to Day 1. Breakfast will be 
given at ~1-hour postdose, lunch given at ~4 hours postdose, a snack given at ~8 hours postdose and dinner at ~12 hours postdose. All meals will follow the 
completion of all specified procedures at that timepoint.
b.Participants will be confined minimally from Day -1 until Day 9 procedures are complete. 
c.Single HR and BP measurements will be obtained at all timepoints unless otherwise noted. On the following days, specific timepoints are noted:

Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs.

Day 1, Day 4 and Day 7: 8, 16 and 24 hours postdose 

Day 9: Time-matched to 24-hour postdose vital signs
d.Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments. Participants should be standing for approximately 2 minutes prior 
to the orthostatic assessments. Orthostatic HR and BP measurements will be obtained on: 

Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs.

Day 1, Day 4 and Day 7: 8, 16 and 24 hours postdose 

Day 9: Time-matched to 24-hour postdose orthostatic vital signs
e.Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints. On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours prior to dosing

Day 1 and Day 4: 8, 16 and 24 hours post-dose
06D209
0834NF


PRODUCT: MK-8189  
37
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 2
MK-8189/matching placebo 24 mg x 7 days 
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
~14
g.Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
h.Additional BARS, AIMS and SAS assessments will be conducted as soon as possible when there are observed or reported complaints of dystonia and/or 
akathisia (See Section 8.3.6).
i. MK-8189 plasma PK sample collection: 

Day 1: predose, 2, 6, 8, 10, 12 and 16 hours postdose

Day 2 and Day 3: predose, 2, 6 and 8 hours postdose

Day 7: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Optional sample when signs of dystonia and/or akathisia occur.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
j. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does 
not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, 
data analysis will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical research.
06D209
0834NF


PRODUCT: MK-8189  
38
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
1.3.5
Schedule of Activities: Part 2 (Panel E/G Titration Regimen 3)
Part 2 Panel E/G Titration Regimen 3
MK-8189/matching placebo 8 mg x 1 day, 16 mg x 1 day and 24 mg x 7 days
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~16
Administrative 
Procedures
Informed Consent
X
Section 8.1.1
Informed Consent for 
Future Biomedical 
Research
X
Section 8.1.1.2
Inclusion/Exclusion 
Criteria
X
X
Only specific 
criteria will be 
reviewed prior to 
randomization.
Section 5
Participant 
Identification Card
X
Section 8.1.3
Medical History
(includes psychiatric 
history and substance 
usage)
X
Substances: drugs, 
alcohol, and 
caffeine
Section 8.1.4
Prior/Concomitant 
Medication Review
X-----------------------------------------------------------------------------------------------------------X
Section 8.1.5
Washout from 
Antipsychotics (Panel E 
only)
X
X
Discontinue 
medication at least 
5 days or at least 3 
half-lives 
(whichever is 
longer) prior to 
Day- 1
Section 8.1.5.1
Assignment of 
Allocation Number 
(Randomization)
X
Section 8.1.7
06D209
0834NF


PRODUCT: MK-8189  
39
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 3
MK-8189/matching placebo 8 mg x 1 day, 16 mg x 1 day and 24 mg x 7 days
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~16
MK-8189/Placebo
Administration
X
X
X
X
X
X
X
X
X
Sections 8.1.8 and 
6.3.1
Standard Mealsa
X
X
X
X
X
X
X
X
X
X
X
Section 5.3.1
Domiciling in Clinicb
X--------------------------------------------------------------------------------X
Section 8.1.11
Follow-up Phone Call
X
Safety Procedures
Full physical 
examination
X
X
X
X
Section 8.3.1
Height
X
Section 8.3.1
Weight
X
X
X
X
Section 8.3.1
Full Neurological Exam
X
X
Section 8.3.7 and 
Appendix 11
Targeted Neurological 
Exam
X
X
X
X
X
Section 8.3.7 and 
Appendix 11
Vital Signs (heart rate, 
blood pressure)c
X
X
X
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
Orthostatic Vital Signs
(heart rate, blood 
pressure)d
X
X
X
X
X
X
X
X
Section 8.3.2.2
Vital Signs (respiratory 
rate, body temperature)e
X
X
X
X
X
X
Section 8.3.2 and 
Section 8.3.2.1
12-lead ECGf
X
X
X
X
X
X
X
Section 8.3.3
Serum β-hCG (WOCBP 
only)
X
Urine Pregnancy Test
X
Serum FSH (WONCBP 
only)
X
Appendix 2
HIV, Hepatitis B and C 
Screen (per site SOP)
X
Appendix 2
UDS/BDS (per site 
SOP)g
X
X
Appendix 2
06D209
0834NF


PRODUCT: MK-8189  
40
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 3
MK-8189/matching placebo 8 mg x 1 day, 16 mg x 1 day and 24 mg x 7 days
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~16
Laboratory Safety Test 
(hematology, chemistry, 
urinalysis)e
X
X
X
X
X
X
Appendix 2
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Baseline 
Version
X
Section 4.2.3
Columbia Suicide
Severity Rating Scale
(C-SSRS)- Since Last
Assessment Versione
X
X
X
X
X
X
Section 4.2.3
Barnes Akathisia Rating 
Scale (BARS)e, h
X
X
X
X
X
X
Section 4.2.1.1
Abnormal Involuntary
Movement Scale
(AIMS)e, h
X
X
X
X
X
X
Section 4.2.1.1
Simpson Angus Scale
(SAS)e, h
X
X
X
X
X
X
Section 4.2.1.1
Bond and Lader Visual
Analog Scale (VAS)e
X
X
X
X
X
X
Section 4.2.1.1
Brief Psychiatric Rating
Scale (BPRS) (Panel E 
only)e
X
X
X
X
X
X
X
Section 8.4
AE/SAE review
X-------------------------------------------------------------------------------------------------------------X
Section 8.6.1
Pharmacokinetics
Blood for Plasma MK-
8189 and/or Metabolites 
Assayi
X
X
X
X
X
X
06D209
0834NF


PRODUCT: MK-8189  
41
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
Part 2 Panel E/G Titration Regimen 3
MK-8189/matching placebo 8 mg x 1 day, 16 mg x 1 day and 24 mg x 7 days
Screening
Washout
Intervention
Poststudy
Notes
Scheduled Day
-6
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~16
Biomarkers
Blood for Genetic 
Analysisj
X
Collect predose 
from enrolled 
participants only.
Section 8.8
AE=adverse event; BDS=blood draw screen; FSH=follicle stimulating hormone; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine drug screen; 
WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
a. Meals should be given at approximately the same time every day starting on Day -1 through Day 10. Day -1 will be time-matched to Day 1. Breakfast will be given at ~1-hour 
postdose, lunch given at ~4 hours postdose, a snack given at ~8 hours postdose and dinner at ~12 hours postdose. All meals will follow the completion of all specified 
procedures at that timepoint.
b. Participants will be confined minimally from Day -6 until Day 11 procedures are complete. 
c. Single HR and BP measurements will be obtained at all timepoints unless otherwise noted. On the following days, specific timepoints are noted: 

Day -1 (triplicate measurements): Time-matched to 8, 16 and 24 hours postdose vital signs.

Day 1, Day 2, Day 3 and Day 9: 8, 16 and 24 hours postdose 

Day 11: Time-matched to 24-hour postdose vital signs
d. Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments. Participants should be standing for approximately 2 minutes prior to the orthostatic 
assessments. Orthostatic HR and BP measurements will be obtained on: 

Day -1: Time-matched to 8, 16 and 24 hours postdose orthostatic vital signs.

Day 1, Day 2, Day 3 and Day 9: 8, 16 and 24 hours postdose 

Day 11: Time-matched to 24-hour postdose orthostatic vital signs
e. Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints. On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours prior to dosing

Day 1, Day 2, Day 3 and Day 9: 8, 16 and 24 hours post-dose 
g. Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
h. Additional BARS, AIMS and SAS assessments will be conducted as soon as possible when there are observed or reported complaints of dystonia and/or akathisia (See Section 
8.3.6).
i. MK-8189 plasma PK sample collection: 

Day 1 and Day 2: predose, 2, 6, 8, 10, 12 and 16 hours postdose

Day 3: predose, 2, 6, 8, 10, 12, 16 and 24 hours postdose

Day 9: predose, 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours postdose

Optional sample when signs of dystonia and/or akathisia occur.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
j. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does not approve of the 
planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited to 
CYP2C9. Leftover extracted DNA will be stored for future biomedical research.
06D209
0834NF


0834NF


0834NF


PRODUCT:  MK-8189  
44
PROTOCOL/AMENDMENT NO.:  011-05  
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
12- mg/placebo Days 7-9, MK-8189 16- mg/placebo Days 10-12, MK-8189 20- mg/placebo 
Days 13-15 and MK-8189 24- mg/Days 16-18. 
In Panel A (healthy participants), overall, multiple oral doses of MK-8189 4 to 24 mg 
administered in a titration regimen were generally and similarly well tolerated by healthy 
Japanese and non- Japanese participants.  There were no serious adverse events (SAEs), 
events of clinical interest (ECIs) or deaths reported.  Of the 16 participants included in the 
safety analysis, 13 (81.3%) experienced 1 or more AEs during the study; 10 (83.3%) 
participants after MK-8189 and 3 (75%) participants after placebo. All AEs were mild to 
moderate in intensity and resolved by the end of the study.  Nine participants (56.3%) 
reported 1 or more AEs that were determined by the investigator to be study intervention 
related; 7 (58.3%) participants after MK-8189 and 2 (50%) participants after placebo. The 
most commonly reported study intervention-related AEs in 2 or more participants were 
dizziness (n=4 [33.3%] following MK-8189 4 mg, 16 mg and 24 mg), headache (n=3 [25%] 
following MK-8189 12 mg, 16 mg and 24 mg), decreased appetite (n=3 [25%] following 
MK-8189 4 mg and 8 mg, n=1 [25%] following placebo), abdominal discomfort (n=2 
[16.7%] following MK-8189 16 mg and 24 mg) and dry skin (n=1 following each of MK-
8189 8 mg [8.3%] and placebo [25%]).
In Panel B, multiple oral doses of MK-8189 4 to 24 mg administered in a titration regimen 
were generally well tolerated by participants with schizophrenia.  There were no SAEs, ECIs 
or deaths reported.  Of the 16 participants included in the safety analysis, 14 (87.5%) 
experienced 1 or more AEs during the study; 10 (83.3%) participants after MK-8189 and 4 
(100%) participants after placebo.  The majority of AEs were mild to moderate in intensity. 
All AEs resolved by the end of the study. Nine participants (56.3%) reported 1 or more AEs 
that were determined by the investigator to be study intervention related; 8 (66.7%) 
participants after MK-8189 and 1 (25%) participant after placebo. The most commonly 
reported study intervention-related AEs in 2 or more participants were headache (n=5 
[41.7%] following MK-8189 8 mg to 24 mg), constipation (n=4 [33.3%] following MK-8189 
16 mg and 20 mg) and nausea (n=2 [16.7%] following MK-8189 16 mg and 20 mg, n=1 
[25%] following placebo). 
In Panel C, multiple oral doses of MK-8189 4 to 24 mg administered in a titration regimen 
(with permitted concomitant antipsychotic standard of care) were generally well tolerated by 
participants with schizophrenia. Of the 17 participants included in the safety analysis, 14 
(82.4%) experienced 1 or more AEs during the study; 13 (100%) participants after MK-8189 
and 1 (25%) participants after placebo. The majority of AEs were mild to moderate in 
intensity.  All AEs resolved by the end of the study except several mild to moderate AEs 
(insomnia, dry mouth, pruritus, back pain and arthralgia) for 1 participant (received placebo) 
who withdrew consent and for which AE status is unknown; all of these AEs were 
considered not related to intervention by the investigator.  Thirteen participants (76.5%) 
reported 1 or more AEs that the investigator considered study intervention related; 12 
(92.3%) participants after MK-8189 and 1 (25%) participant after placebo. The most 
commonly reported study intervention- related AEs in 2 or more participants were decreased 
appetite (n=5 [38.5%] following MK-8189 4 mg, 8 mg, 12 mg and 20 mg), nausea (n=3 
[23.1%] following MK-8189 8 mg, 12 mg and 20 mg), vomiting (n=3 [23.1%] following 
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MK-8189 8 mg, 12 mg and 20 mg), headache (n=3 [23.1%] following MK-8189 8 mg and 16 
mg), abdominal pain upper (n=2 [15.4%] following MK-8189 4 mg and 24 mg), constipation 
(n=2 [15.4%] following MK-8189 16 mg and 24 mg), dizziness (n=2 [15.4%] following MK-
8189 8 mg and 12 mg, n=1 [25%] following placebo) and anxiety (n=2 [15.4%] following 
MK-8189 4 mg and 12 mg). There were no serious adverse events (SAEs), or deaths 
reported.  One participant experienced a nonserious ECI of severe dystonia following MK-
8189 4 mg (with concurrently administered lurasidone, venlafaxine and quetiapine) which 
resolved within ~4 hours. The investigator considered this ECI not related to intervention as 
it was identified that the participant had a history of lurasidone hypersensitivity not reported 
at screening. The participant was subsequently discontinued from intervention (after 2 doses) 
due to a protocol deviation.
In Panel D, multiple oral doses of MK-8189 8 to 48 mg administered in a titration regimen 
were generally well tolerated by participants with schizophrenia.  Of the 26 participants 
included in the safety analysis, 23 (88.5%) experienced 1 or more AEs during the study; 14 
(82.4%) participants after MK-8189 and 9 (100%) participants after placebo.  The majority 
of AEs were mild to moderate in intensity and resolved except for AEs of pruritus, nausea 
and vomiting (all mild) in 1 participant who withdrew consent due to pregnancy (discussed 
below), AEs of dry mouth, headache and muscle tightness (all mild, each AE in 1 participant 
only) in 3 participants who completed the study, an AE of mild contact dermatitis in 1 
participant who discontinued intervention due to another AE (atrial fibrillation, following 
treatment with placebo), and an AE of moderate psychotic disorder in 1 participant who 
discontinued intervention for same.  Intervention for the participants with AEs of psychotic 
disorder and contact dermatitis was placebo and for the remaining participants was MK-
8189.
Seventeen participants (65.4%) reported 1 or more AEs that the investigator considered study 
intervention related; 12 (70.6%) participants after MK-8189 and 5 (55.6%) participants after 
placebo.  The most commonly reported study intervention related AEs (excluding the SAE 
which is discussed below) in 2 or more participants were nausea (n=4 [23.5%] following 
MK-8189 8 mg, 16 mg and 48 mg, n=1 [11.1%] following placebo), anxiety (n=2 [11.8%] 
following MK-8189 16 mg and 24 mg, n=1 [11.1%] following placebo), headache (n=4 
[23.5%] following MK-8189 8 mg to 36 mg, n=1 [11.1%] following placebo), somnolence 
(n=4 [23.5%] following MK-8189 8 mg, n=1 [11.1%] following placebo), dizziness (n=3 
[17.6%] following MK-8189 48 mg), extrapyramidal disorder (n=1 [5.9%] following MK-
8189 48 mg, n=1 [11.1%] following placebo) and palpitations (n=2 [11.8%] following MK-
8189 36 mg and 48 mg).
One participant experienced 1 SAE of severe psychotic disorder which began one day 
following their last dose of intervention (MK-8189 36 mg), resulting in hospitalization and 
intervention discontinuation. The SAE duration was 6 days and resolved following initiation 
of an antipsychotic and anti-anxiolytic. No other AEs were reported by this participant. The 
investigator considered this SAE related to study intervention. Two participants experienced 
non-serious ECIs. One participant experienced an ECI of moderate dystonia 2 days following 
the final dose of study intervention (placebo) which resolved within 3.5 hours. One 
participant experienced ECIs of mild dystonia and mild dyskinesia 3 days following 
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mg/placebo for 4 days.  Panel B initiated dosing with 24 mg of MK-8189 (no titration) for 7 
days.  Part 1 has completed enrollment and dosing and all data are preliminary and blinded. 
No SAEs or deaths were reported.  In Panel A, all 8 participants enrolled completed 
treatment.  The majority of AEs were mild and no AEs were severe in intensity.  Of the 8 
participants, one participant did not dose escalate to 24 mg due to moderate somnolence 
which lasted for 3 days.  For the duration of the somnolence AE, the participant was also 
receiving hydroxyzine, a sedating antihistamine.  Two participants reported an AE of 
dystonia.  One participant reported mild transient dystonia which began 14 hours after the 
first dose and lasted 2 days.  The dystonia was treated with benztropine until it resolved.  
Another participant  reported mild transient dystonia which began 6.5 hours following the 
first dose and resolved in 22 hours. While experiencing dystonia the participant was treated 
with benztropine.  AEs reported that were considered related to study drug included 
decreased appetite (n=2), dystonia (n=2) somnolence (n=2), nightmare (n=1), worsening 
psychosis (n=1), and insomnia (n=1).  
Panel B completed enrollment and dosing.  Eighteen participants were randomized and 14 
completed treatment per protocol.  Of the 4 participants that discontinued treatment, one 
discontinuation was due to an AE of gastroesophogeal reflux disease that was not considered 
related to treatment.  The majority of AEs were mild.  AEs considered related to treatment 
included hypertonia (n=1), decreased appetite (n=1), somnolence (n=1) and increased ALT 
(n=1).  The participant with the AE of elevated ALT had an elevated screening value of 61 
IU/L (normal range 7-52 IU/L).  The Day -1 predose ALT value was also elevated (98 IU/L) 
and continued to increase on Day 7 (116 IU/L) and Day 9 (133 IU/L).  At the post study the 
ALT was still elevated but below the predose value (71 IU/L).  ALP  (normal range 34-104 
IU/L) followed a similar pattern with elevations at screening (130 IU/L), Day -1 predose 
(136 IU/L), Day 7 (143 IU/L), Day 9 (134 IU/L) and at the post study visit (124 IU/L).  
While AST was within the normal range (13-39 IU/L) at screening (26 IU/L) and Day -1 
predose (37 IU/L), values were elevated above the normal range on Day 7 (44 IU/L) and Day 
9 (51 IU/L). At the post dose visit, AST was within the normal range (26 IU/L).  Bilirubin 
was normal throughout the study.  Preliminary data suggest initiation of MK-8189 at a 16 or 
24 mg dose was generally well tolerated. 
Treatment is ongoing in Part 2.  One participant has been dosed to date with no complaints of 
AEs.  
P012 is a Phase 1 study to evaluate the safety, tolerability and PK in participants with hepatic 
impairment and group mean-matched healthy participants.  The trial has initiated but no 
participants have been dosed. 
Protocol 008 is an ongoing Phase 2B randomized, double-blind, placebo- and active 
controlled trial of the efficacy and safety of MK-8189 in adult participants 18 to 50 years of 
age who are experiencing an acute episode of schizophrenia according to DSM-V™ criteria.
A total of 576 participants from approximately 80 sites across the USA, Europe and Asia will 
be recruited into this trial. Treatment duration will be for a period of 12 weeks and includes a 
6-week acute treatment period followed by a 6-week extension period. Eligible participants 
will be randomized to receive one of five treatment sequences with target doses of MK-8189 
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(8 mg, 16 mg and 24 mg QD), risperidone (6 mg QD), or placebo. Placebo completers at 6 
weeks will be allocated to receive MK-8189 24 mg for the remainder of the trial. This trial is 
being conducted in a hospital/acute care setting followed by an outpatient setting. 
Recruitment was initiated Dec2020.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for this study.
In male or female participants with schizophrenia (young adults and elderly) and healthy 
elderly participants:
Objectives
Endpoints
Primary
Part 1
•
To evaluate the safety and tolerability of 
MK-8189 oral, once-daily titration 
regimens in young adult participants with 
schizophrenia
Part 2
•
To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-
8189 in elderly participants with 
schizophrenia and healthy elderly 
participants
Part 1 and Part 2
•
Adverse experiences, laboratory safety 
tests, electrocardiograms and vital 
signs
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Objectives
Endpoints
Secondary
Part 1
•
To characterize MK-8189 
pharmacokinetics following different 
titration regimens in young adult 
participants with schizophrenia
Part 2
•
To characterize the pharmacokinetics of 
MK-8189 following multiple once-daily 
oral doses in elderly participants with 
schizophrenia and healthy elderly 
participants.
Part 1 and Part 2
•
AUC0-24hr, Cmax, C24hr, Tmax, CL, 
Vd and apparent t1/2
Tertiary/Exploratory
Part 1 and Part 2
•
To investigate the relationship between 
CYP2C9 genetic polymorphs and the PK 
of MK-8189. Genetic variation in 
CYP2C9 may be analyzed for association 
with any laboratory or clinical data 
collected in this study.
•
To explore the relationship between 
genetic variation and response to the 
treatment administered, and mechanisms 
of disease. Variation across the human
genome may be analyzed for association 
with clinical data collected in this study.
Part 2
•
To compare the pharmacokinetics of MK-
8189 in elderly participants with 
schizophrenia to dose-matched young 
adult participants with schizophrenia
•
To compare the pharmacokinetics of MK-
8189 in elderly healthy participants to 
dose-matched healthy young adult 
participants
Part 1 and Part 2
•
Germline genetic variation in CYP2C9
and association to clinical data 
collected in this study
•
Germline genetic variation and 
association to clinical data collected in 
this study.
Part 2
•
AUC0-24hr, Cmax, C24hr, Tmax, CL, 
Vd and apparent t1/2
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4
STUDY DESIGN
4.1
Overall Design
This is a 2-part randomized, placebo-controlled, parallel-group, double-blind study of MK-
8189 in participants with schizophrenia and healthy participants. Part 1 will enroll young 
adult participants with schizophrenia and Part 2 will enroll healthy elderly participants and 
elderly participants with schizophrenia.
Part 1
In all panels, participants will be washed off their current antipsychotic therapy.  The 
washout may start with a down titration of the antipsychotic treatment during the screening 
phase per direction of the investigator.  Participants should not receive antipsychotics for at 
least 5 days or 3 half-lives (whichever is longer) prior to Day -1. For longer half-life 
antipsychotics (e.g. aripiprazole and brexpiprazole), if deemed appropriate by the 
investigator, a participant may stop treatment (i.e. 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.  
Decisions regarding the initiation of an alternate titration regimen will be made jointly 
between the principal investigator(s) and Sponsor and will be based on safety and tolerability 
from ~ 8 subjects as further detailed later in this section.
Panel A will enroll up to 16 participants with schizophrenia disorder who will receive 
Titration Regimen 1. An initial cohort of 8 participants will be randomized to active or 
placebo. Beginning on Day 1, participants randomized to MK-8189 will receive 16 mg (1 x 
12-mg tablet and 1 x 4-mg tablet) of MK-8189 on Days 1 to 3 and 24 mg of MK-8189 (2 x 
12-mg tablets) on Days 4 to 7. Participants randomized to placebo will receive the same 
number of tablets matching the MK-8189 tablet strengths in the active group.
After dosing of the initial cohort of 8 participants completes in Panel A, Panel B or Panel C 
will be enrolled. If safety and tolerability data from Panel A indicate a starting dose of MK-
8189 16 mg is generally well tolerated, Panel B will be enrolled. If a starting dose of MK-
8189 16 mg is not generally well tolerated, Panel C will be enrolled.
Panel B will enroll an initial cohort of 8 participants with schizophrenia disorder who will 
receive Titration Regimen 2. Participants will be randomized to MK-8189 or placebo. On 
Days 1 to 7, participants will receive MK-8189 24 mg (2 x 12-mg tablets) or matched 
placebo.
If tolerability issues are due to elimination of dose titration, it will likely be evident within 
the first few days of dosing MK-8189. Thus, an initial assessment of tolerability will be made 
following 3 days of dosing in approximately 8 participants. If MK-8189 is generally well 
tolerated based on AEs, an additional 8 participants will be enrolled into Panel B receiving 
Titration Regimen 2. If Titration Regimen 2 is not generally well tolerated in Panel B (either 
after assessment of the initial cohort [n=8] or full cohort [n=16]), an additional 8 participants 
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will be enrolled in Panel A such that a total of 16 participants will receive Titration 
Regimen 1.
Panel C will enroll 16 participants with schizophrenia disorder and receive Titration Regimen 
3. Participants will be randomized to active or placebo. Participants randomized to MK-8189 
will receive 8 mg on Day 1 (2 x 4-mg tablets), 16 mg on Day 2 (1 x 12-mg tablet and 1 x 4-
mg tablet) and 24 mg (2 x 12-mg tablets) on Days 3 to 7. Participants randomized to placebo 
will receive the same number of tablets matching the MK-8189 tablet strength in the active 
group.
All participants will be confined to the unit from at least Day -6 until Day 9 assessments are 
complete.
Part 2
The goal of Part 2 is to evaluate MK-8189 safety, tolerability and PK and titration regimens 
in elderly participants with schizophrenia disorder (Panels D and E) and healthy elderly 
participants (Panel F and G). Participants will be randomized to MK-8189 or placebo.
Participants with schizophrenia will be washed off their current antipsychotic therapy. The 
washout may start with a down titration of the antipsychotic treatment during the screening 
phase per direction of the investigator.  Participants should not receive antipsychotics for at 
least 5 days or 3 half-lives (whichever is longer) prior to Day -1.  For longer half-life 
antipsychotics (e.g. aripiprazole and brexpiprazole), if deemed appropriate by the 
investigator, a participant may stop treatment (i.e. cessation of AAP) as an outpatient, but 
should be confined the clinical research unit within a week of stopping treatment and 
minimally beginning on Day -6.   Healthy elderly participants (Panel F and G) will be 
domiciled by Day -1.
Panel D will run concurrently with Part 1. Panel D will enroll up to 16 participants with 
schizophrenia disorder. An initial cohort of 8 participants will be randomized to active or 
placebo.  Beginning on Day 1, participants randomized will begin to receive MK-
8189/placebo QD and will be titrated from 8 mg to 24 mg or placebo over the course of a 13-
day treatment period as follows: 8 mg (2 x 4 mg/placebo tablets) Days 1 to 3, 16 mg (1 x 12
mg/placebo tablet and 1 x 4 mg/placebo tablet) Days 4 to 6, 24 mg (2 x 12 mg/placebo 
tablets) Days 7 to 13. This titration schedule has been shown to be well tolerated in a 
previous trial (P007) in young adults with schizophrenia.
Each dose titration decision for each individual participant will occur after 3 days of dosing 
per dose level. If a participant does not tolerate escalation to the next dose, the participant 
may be titrated down to the previous dose. If appropriate medical care necessitates a down-
dose, the investigator may do so independent of consultation with the Sponsor. If the 
participant tolerates continued dosing following down-titration, the participant may continue 
in the trial at that dose until study completion or may be rechallenged at a higher dose. 
During the titration period, rechallenges are only to occur on a regularly scheduled dose 
titration day, ie, Day 7, and will not extend the participant’s time in the study. Any changes 
to the protocol specified titration schedule (eg, the participant remains at their current dose or 
is down titrated) will be documented in a protocol clarification letter.
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Participants will be confined to the unit from Day -6 until the Day 15 postdose assessments 
are complete.
After dosing of the initial cohort of approximately 8 participants, if the dose regimen is found 
to be generally well tolerated, Panel E will be enrolled.  If additional data are required for 
evaluation, additional participants (up to 8) may be enrolled.  The decision to enroll 
additional participants in Panel D or initiate Panel E will be made jointly between the 
investigator(s) and the Sponsor and documented in a protocol clarification letter.  
Panel E will be initiated after completion of Part 1 and dosing of at least 8 participants in 
Panel D. If dosing in Panel D is generally well tolerated and at least 1 of the titration
regimens evaluated in Part 1 of the current protocol is found to be generally well tolerated, 1
of those 3 regimens will be administered in Panel E. 
Assuming that dosing was generally well tolerated in Panel D, the selection of the titration 
regimen for Panel E will be dependent on the safety and tolerability data observed in Part 1 
and will be made jointly between the investigator(s) and the Sponsor and documented in a 
protocol clarification letter. Note: as shown in the Protocol Summary (Section 1), if Titration
Regimen 1 or 3 is selected for evaluation, dosing at 24 mg will be extended to ensure 
evaluation of this MK-8189 dose for 7 days in the elderly population.
An initial cohort (n=4) will be dosed with the selected titration regimen from Part 1 to
initially assess tolerability in a small number of participants. Tolerability will be assessed 
after the third dose and will determine the dose regimen scheme for the remainder of the 
participants; if well tolerated, the remainder of the cohort will be enrolled in the selected dose 
regimen (n=12). However, if the selected regimen is not well tolerated, an additional cohort 
of 4 participants will be enrolled in an alternate (more conservative) dose regimen as shown 
in [Figure 2]. Depending on the initial dose regimen selected for evaluation, this process may 
be repeated as outlined in [Figure 2] such that up to 3 Titration Regimens may be evaluated
with the objective to have 1 of the titration regimens evaluated in ~ 16 participants. The 
decision to initiate an alternate titration regimen will be documented in a protocol 
clarification letter.
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Figure 2
Part 2 Panel E/G Alternate Dose Regimens if Starting Regimen is Titration 
Regimen 1 or Titration Regimen 2
Participants will be confined to the unit from at least Day -6 until the 48-hour postdose
assessments are complete (Day 12, Day 9 and Day 11 for Titration Regimen 1, Titration 
Regimen 2 and Titration Regimen 3, respectively).
For Part 1 and Part 2, all dose titration decisions (where applicable) will be made jointly by 
the investigator and the Sponsor. However, if appropriate medical care necessitates a down-
titration, the investigator may do so independent of consultation with the Sponsor. Any 
changes to the protocol-specified titration schedule (eg, the participant remains at their 
current dose or is down titrated) will be documented in a protocol clarification letter.
In Part 1 and Part 2 Panel E, the dose titration decisions will occur as follows: For Titration
Regimen 1, each dose titration decision for each individual participant will occur after 
administration of the 16-mg dose on Day 3. For Titration Regimen 3, the titration decision 
for each participant will be made following the 16-mg dose (Day 2). For Titration Regimen 2 
(no titration), the safety will be reviewed following 3 days of dosing to evaluate safety and 
tolerability for continued dosing.
Panel F (healthy elderly) will be conducted in the same manner as Panel D; however, up to 
approximately 12 participants will be enrolled. An initial cohort of 6 participants will be 
randomized to active or placebo. If the dose regimen is found to be generally well tolerated, 
Panel G will be enrolled.  If additional data are required for evaluation, additional 
participants (up to 6) may be enrolled.  The decision to enroll additional participants in Panel 
G or initiate Panel F will be made jointly between the investigator(s) and the Sponsor and 
documented in a protocol clarification letter. 
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Panel G (healthy elderly) will be conducted in the same manner as Panel E following 
completion of at least 6 participants in Panel F. However, up to approximately 12 
participants will be enrolled and evaluated within a dose titration regimen (See Figure 2).
In Part 1 and Part 2, safety and tolerability of MK-8189 will be monitored by clinical 
assessment of AEs, repeated measurements of ECGs and VS, physical and neurological 
examinations, and standard laboratory tests (hematology, chemistry, urinalysis). In addition, 
EPS of dystonia and akathisia will be monitored along with psychological effects using 
rating scales. PK of MK-8189 will also be evaluated in both parts of the study.
Because this is a Phase 1 assessment of MK-8189 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.10.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Part 1
In the current trial, a staged approach will be implemented to evaluate the need for titration.
Alternate dose regimens will be evaluated based on tolerability as described in Section 4.1.
While MK-8189 was generally well tolerated in both healthy participants and participants 
with schizophrenia (P003 and P007), the schizophrenia population was selected for 
evaluation in the current trial as preliminary PK data suggest that MK-8189 exposures may 
be greater in the patient population at doses greater than 12 mg. A matched placebo-control 
will be included to reduce bias with regards to the patient reporting and investigator 
assessment of AEs.
Part 2
As schizophrenia is a life-long disease, it is likely the elderly will be an important segment of 
the MK-8189 treatment population. This study part is being conducted to evaluate the safety, 
tolerability and PK of MK-8189 in the elderly population. For Panel D and Panel F, the dose 
regimen selected has been tolerated in young adult participants with schizophrenia and will 
be the dose regimen in the Phase 2b study. For Panel E and Panel G, the titration regimen 
selected will be based on safety and tolerability results of Part 2, Panel D and Panel F, 
respectively and from Part 1 of the current protocol. In Panel E and Panel G, a small cohort 
will initially be dosed. If there are no tolerability concerns, the remainder of the cohort will 
proceed with dosing on the selected regimen. If there are tolerability concerns, the remainder 
of patients may be dosed with an alternative titration regimen as described in Section 4.1.
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of physical and neurological examinations, 
12-lead ECGs, VS, and laboratory safety tests. 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).
In case moderate EPS symptoms in an individual participant persist, the dose will not be 
further up titrated for this participant. Participants with severe EPS symptoms will be 
discontinued if not attenuated with dose reduction, dose titration and/or medical 
management. 
To monitor the psychological well-being, the VAS will be used in all participants. 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.
The C-SSRS will be administered to monitor mood and suicidal ideation and behavior in all 
trial participants (see Section 4.2.3).
4.2.1.2
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189. Therefore, individual 
plasma concentration and actual sample collection times of MK-8189 will be used to derive 
the PK parameter values AUC0-24hr, Cmax, Tmax, C24hr, CL, Vd and apparent t1/2.
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4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
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 absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, polymorphs of CYP2C9 will 
specifically be investigated for association with the PK and PD of MK-8189 since MK-8189 
is partially metabolized by CYP2C9. Genetic variation in CYP2C9 may be analyzed for 
association with any laboratory or clinical data collected in this study.
4.2.1.4
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research 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 that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
A matched placebo-control will be included to reduce bias with regards to the participant 
reporting and investigator assessment of AEs.
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Figure 3
MK-8189 Dose-Enzyme Occupancy 
4.3.2
Maximum Dose/Exposure for This Study
The current trial will evaluate doses up to and including 24 mg. As described in Section 2.2.2
and 2.2.3, previous and ongoing clinical studies have demonstrated that MK-8189 has been 
generally well tolerated up to and including doses of 24 mg. In addition, currently ongoing 
P007 Panel D is evaluating doses up to 48 mg.
Based on a population PK model, the steady-state Cmax and AUC0-24hr at the 24-mg dose 
is predicted to be 0.975 µM and 19 µM.hr. Based on data from the chronic toxicology 
studies, the exposure multiple at the 24-mg dose for AUC0-24hr would be ~ 7-fold based on 
the 6-month rat study and ~9-fold based on the 9-month monkey study. Brief summaries of 
the chronic toxicology studies supporting dose escalation are provided below:
In the 6-month rat study, doses of 0, 25, 100 and 750 mg/kg/day were evaluated. Two high-
dose (750 mg/kg/day) female rats were found dead (Week 13 and Week 24) with acute 
tubular necrosis (with and without tubular mineralization). Therefore, the 100 mg/kg/day 
dose was considered the no observed adverse effect level (NOAEL) for this study (AUC0-
24hr = 130 μM∙hr), providing an exposure margin of ~ 7-fold over the predicted 
supratherapeutic exposure of 19 μM∙hr at the 24-mg dose.
In the 9-month monkey study, doses of 0, 30/10/3, 150 or 600/300 mg/kg/day of MK-8189 
were administered. Renal tubular degeneration was observed in the high-dose group 
(600/300 mg/kg/day). The NOAEL for target organ toxicity is 150 mg/kg/day
(AUC0-24hr = 170 μM∙hr), providing ~9-fold over the predicted supratherapeutic exposure 
of 19 μM∙hr at the 24-mg dose.
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The effects of MK-8189 on measures of cardiac conduction and repolarization were assessed 
in both in vitro (hERG current [IKr] evaluation) and in vivo (anesthetized guinea pigs and 
conscious telemetered monkey models). MK-8189 inhibited hERG current with an IC50 
value of 44 μM, providing a margin of 1,128-fold to the projected median unbound Cmax in 
humans at 24 mg (0.039 μM). In an anesthetized guinea pig study, MK-8189 had no effects 
on HR and ECG parameters. Average peak plasma concentrations of MK-8189 measured 
during the 20-min infusions of 10, 30 and 60 mg/kg were 56, 150 and 236 μM, respectively. 
Thus, the NOEL/NOAEL in this study was 236 μM, providing an exposure margin of ~ 242-
fold relative to the projected clinical Cmax of 0.975 μM.
In a telemetry study in monkeys, single oral doses of 2, 5, and 20 mg/kg were evaluated and 
test article-related dose-independent increases in HR, blood pressure (BP) and the rate-
corrected QT interval were observed. In a second study at lower oral doses of 0.03, 0.1 and
0.3 mg/kg, there were no test article-related effects. Thus, the no-observed effect level was a 
single-oral dose of 0.3 mg/kg providing exposure margins of <1-fold of the projected clinical 
Cmax. A number of studies were conducted to determine the underlying cause (see MK-8189 
IB for additional details). The general conclusion from these studies was that increases in 
HR, BP and QT interval likely occur due to a stress induced release of epinephrine 
subsequent to PDE10A target engagement in conscious rhesus monkeys and therefore, these 
changes in QT, HR and BP are not relevant to humans.
Therefore, clinical and preclinical data support dose escalation to 24 mg in the current study.
In addition, during the study, safety and tolerability will be carefully assessed including 
scales to assess dystonia. Dose escalation may be stopped based on tolerability.
4.3.3
Rationale for Dose Interval and Study Design
Part 1
To date, across the multiple-dose clinical trials, MK-8189 has been titrated to the highest 
dose; each dose was administered for 3 days prior to escalation and the starting dose has 
ranged from 2 mg to 8 mg. This study will evaluate whether simplified titration schemes or 
no titration are generally well tolerated. This study will initiate with 16 mg QD for 3 days 
prior to dose escalation. If this titration scheme is well tolerated, then the next panel will 
initiate dosing at the highest likely clinical dose of 24 mg. If tolerability is not considered 
acceptable, then the next panel will follow a more conservative dose escalation scheme and 
initiate dosing at 8 mg, as described in Section 4.1.
Part 2
Panel D and Panel F: The regimen has been shown to be generally well tolerated in young 
adults with schizophrenia and the tolerability profile of titration regimens up to 24 mg has 
been similar in healthy participants and participants with schizophrenia.  These data support 
evaluation in the elderly population with and without schizophrenia.
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Panel E and Panel G: The dosing scheme will be based on the regimen in Panel D and Panel 
F, respectively, being generally well tolerated as well as the safety and tolerability profile 
observed in Part 1. If the dosing scheme selected is not well tolerated it will also be adjusted 
as described in Section 4.1.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female participants with schizophrenia (Parts 1 and 2) and healthy elderly participants
(Part 2 only) between the ages of 18 and 60 years (Part 1) and 61 and 80 years (Part 2) will 
be enrolled in this study. However, in Part 2, only approximately 25% of participants 
between the ages of 61 and 64 years may be enrolled in each panel.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is 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.
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2. Has a BMI ≤40 kg/m2 (participants with schizophrenia) or ≤32 kg/m2 (healthy 
participants), inclusive. See Section 8.3.1 for criteria on rounding to the nearest whole 
number. BMI = weight (kg)/height (m)2.
3. Has no clinically significant abnormality on 12-lead safety ECG performed at the 
prestudy (screening) visit and/or prior to randomization. The Day 1 predose assessment 
(prior to randomization) is based on the mean of the triplicate measures. Note: The QTcF 
duration must be ≤450 msec and the PR interval <230 msec. Repeat 12-lead safety ECGs 
may be performed in participants whose parameters are, per investigator discretion, 
minimally outside the designated range. Appendix 9 provides a table of the 12-Lead 
Electrocardiogram Abnormality Criteria.
4. Has a normal resting BP (systolic BP is ≥90 mmHg and ≤140 mmHg; diastolic BP is ≥60 
mmHg and ≤90 mmHg) and normal resting heart rate (≥45 beats per minute [bpm] and 
≤100 bpm) in the semirecumbent position at the prestudy (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 for the Day -1 8 hour time-
matched assessment. Participants may be included if values are outside the normal range 
but considered not clinically significant per investigator discretion.
5. Participants with hypothyroidism, diabetes, high BP, chronic respiratory conditions or 
other mild forms of these medical conditions could be considered as candidates 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 
comedication during the study.
6. Has regular bowel movements and, in the opinion of the investigator, no clinically 
significant diarrhea or constipation.
7. 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 (applies 
to participants with schizophrenia only).
8. Has a total BPRS score of <48 with a BPRS score <4 for #10 (hostility) and #14 
(uncooperativeness) at the screening visit (applies to participants with schizophrenia 
only).
9. Is in the nonacute phase of their illness and clinically stable for 3 months prior to 
screening as demonstrated by (applies to participants with schizophrenia only):
a.
no clinically significant change in dose of prescribed antipsychotic medication, or 
clinically significant change in antipsychotic medication to treat symptoms of 
schizophrenia for 2 months prior to screening;
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b. no increase in level of psychiatric care due to worsening of symptoms of 
schizophrenia for 3 months prior to screening.
10. Has a history of receiving and tolerating antipsychotic medication within the usual dose 
range employed for schizophrenia (applies to participants with schizophrenia only).
11. Has a stable living situation in which the patient or a contact person can be reached by 
the investigator if there is a need for follow up (applies to participants with schizophrenia 
only).
12. Is able to discontinue the use of all antipsychotic medication at least 5 days prior to the 
start of the treatment period and during the study period (applies to participants with 
schizophrenia only).
Demographics
13. Is male or female, from 18 (Part 1) or 61 (Part 2) years to 60 (Part 1) or 80 (Part 2) years
of age inclusive, at the time of signing the informed consent.
Female Participants
14. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 14 days after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention. Note: 
participants intending to rely on abstinence as a birth control method should agree to 
use double-barrier control methods if they engage in intercourse.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 48 hours before the first dose of study 
intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
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•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
15. The participant (or legally acceptable representative if applicable) has provided written 
documented informed consent/assent for the study. The participant may also provide 
consent/assent for future biomedical research. However, the participant may participate in 
the main study without participating in future biomedical research.
Additional Categories
16. Is willing to comply with the study restrictions (see Section 5.3 for a complete summary 
of study restrictions).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Is a WOCBP who has a positive urine pregnancy test within 48 hours before the first dose 
of study intervention (see Appendix 5). If the urine test cannot be confirmed as negative, 
a serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
2. Has evidence or history of mental retardation, borderline personality disorder, anxiety 
disorder, or organic brain syndrome.
3. Has a history of neuroleptic malignant syndrome or moderate to severe tardive 
dyskinesia.
4. Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse. 
5. Has a DSM-5 defined substance use disorder (excluding nicotine and caffeine) within 3
months of screening.
6. Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures. 
7. Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, 
respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, 
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immunological or cerebrovascular disease, malignance, allergic disease or other chronic 
and/or degenerative process at screening.
8. 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.
9. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
10. 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.
11. Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
12. Has a family history of sudden death.
13. 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.
14. For Part 2 participants only: Participant has an estimated eGFR <60 mL/min/1.73 m2
based on the MDRD.

Participants who have an eGFR or measured creatinine clearance of up to10% below 
of either 60 mL/min (for creatinine clearance) or 60 mL/min/1.73m2 (for eGFR) may 
be enrolled in the study at the discretion of the investigator.
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creat)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if African American])
At the discretion of the investigator a measured creatinine clearance, as determined by a 
24-hour urine collection, may be used in place of, or in conjunction with, the estimate of 
the eGFR.
15. Has a 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 non-prescription drugs or food.
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16. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
17. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
18. 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 1 month 
of screening (applies to participants with schizophrenia only).
19. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator 
(applies to healthy participants only).
20. 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 (applies to participants with 
schizophrenia only).
21. 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 CSSRS) in the 
past 5 years or suicidal behavior in their lifetime (applies to healthy participants only).
Prior/Concomitant Therapy
22. Has received treatment with clozapine for schizophrenia or treatment with monoamine 
oxidase inhibitors within 3 months of screening or cariprazine within 2 months of 
screening.
23. Has received a parenteral depot antipsychotic medication within 3 months of screening.
24. Is unable to refrain from the use of co-medication with a moderate or strong inhibiting or 
inducing effect on CYP3A and/or CYP2C9 beginning approximately 2 weeks or 
5 half-lives, whichever is longer, prior to administration of the initial dose of trial drug 
and throughout the trial or is unable to refrain from the use of sensitive substrates of 
CYP2B6. (see Section 6.5).
Prior/Concurrent Clinical Study Experience
25. Has 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.
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Diagnostic Assessments
Not Applicable.
Other Exclusions
26. Is under the age of legal consent.
27. Has been in incarceration or imprisonment within three months prior to screening.
28. Is a current smoker (applies to healthy participants only) or is a smoker (applies to 
participants with schizophrenia only) that does not agree to follow the smoking 
restrictions as defined by the CRU.
29. Consumes greater than 3 glasses of alcoholic beverages (1 glass 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 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
30. 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.
31. Is a regular user of cannabis, 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 cannabis and/or prescribed concomitant medications permitted at the 
discretion of the PI and Sponsor) prior to randomization.
32. 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.
33. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2.
On full PK sampling days, participants will fast from all food and drinks, except water, for 
at least 8 hours prior to study drug administration until 1-hour postdose. Participants will fast 
from all food and drinks except water between study drug administration and the first 
scheduled meal. Meals and snack(s) will be provided by the investigator at time points 
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indicated in the Schedule of Activities. Participants will fast from all food and drinks except 
water between meals and snacks. The caloric content and composition of meals will be the 
same on each full PK sampling day in each panel (for this study the meal content should be 
consistent within a given clinical site). After the 24-hour postdose procedures have been 
completed, subsequent meals and snacks will be unrestricted in caloric content, composition 
and timing.
Water will be provided during study drug administration. Water will be restricted 1 hour 
prior to and 1 hour after study drug administration.
On all other days, participants will fast from all food and drinks, except water, for at least 
8 hours prior to study drug administration. Participants will remain fasted until 1-hour
postdose. Meals and snacks will be unrestricted in caloric content, composition and timing.
Standard meals on Day -1 will be time-matched to Day 1.
Each study drug administration will need to be taken with water. Water will be restricted 
1 hour prior to and 1 hour after study drug administration.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study and until the poststudy visit.
On full PK sampling days, participants will refrain from the consumption of all fruit juices 
24 hours prior to study drug administration.
On all other days during the study, the consumption of all fruits and fruit juices (except for 
grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits. 
On full PK sampling days, participants will be permitted to consume approximately 2 units 
of caffeinated beverages or xanthine-containing products only between 1 hour and 2 hours 
postdose. Otherwise, participants will refrain from consumption of such products 8 hours 
prior to study drug administration until the last PK assessment is complete.
On all other days, caffeinated beverages or xanthine-containing products will be limited to 
no more than 6 units per day (1 unit = 120 mg of caffeine).
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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 (1 glass 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, weight lifting, running, 
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study drug, throughout the study 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 discontinues from study intervention or withdraws from the study, a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies, study intervention(s) provided by the Sponsor, will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in [Table 1].
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen
Use
IMP/
NIMP
Sourcing
Active
Experi-
mental
MK-8189
Drug
Tablet
4 mg
12 mg
All dose 
levels
Oral
Titration 
Regimens 1, 2, 
3 and Panel 
D/F dose 
regimen
Experi-
mental
IMP
Provided 
Centrally
Placebo
Placebo 
Comparator
MK-8189
Drug
Tablet
0 mg
All dose 
levels
Oral
Titration 
Regimens 1, 2, 
3 and Panel 
D/F dose 
regimen
Placebo
IMP
Provided 
Centrally
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in [Table 1] will be provided per the "Sourcing" column depending 
upon local country operational requirements. If local sourcing, every attempt should be made 
to source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation schedule for Parts 1 and 2 is provided in [Table 2].
Table 2
Sample Allocation Schedule
Part 1
Panel
Patients
(n)
Day 1
Day 2
Day 3
Days 4-7
A
12
16 mg QD
24 mg QD
4
PBO
PBO
B
12
24 mg
4
PBO
C
12
8 mg QD
16 mg QD
24 mg QD
4
PBO
PBO
PBO
Part 2
Panel
Patients (n)
Days 1-3
Days 4-6
Days 7-13
D/F
12 (Panel D);
10 (Panel F)
8 mg QD
16 mg QD
24 mg QD
4 (Panel D);
2 (Panel F)
PBO
PBO
PBO
Part 2
Panel
Patients (n)
Days 1-3
Days 4-10
E/G
TR1
12 (Panel E);
10 (Panel G)
16 mg QD
24 mg QD
4 (Panel E);
2 (Panel G)
PBO
PBO
Part 2
Panel
Patients (n)
Days 1-7
E/G
TR 2
12 (Panel E);
10 (Panel G)
24 mg QD
4 (Panel E);
2 (Panel G)
PBO
Part 2
Panel
Patients (n)
Day 1
Day 2
Days 3-9
E/G
TR 3
12 (Panel E); 10 
(Panel G)
8 mg QD
16 mg QD
24 mg QD
4 (Panel E)
2 (Panel G)
PBO
PBO
PBO
TR = Titration Regimen; n=number; PBO=placebo; QD=once daily
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6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. MK-8189 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.5
Concomitant Therapy
Concurrent use of any prescription or nonprescription medication, during the ongoing study 
(ie, after randomization or intervention allocation) must first be discussed between the 
investigator and Sponsor prior to administration, unless appropriate medical care necessitates 
that therapy or vaccination should begin before the investigator and Sponsor can consult. The 
participant will be allowed to continue in the study if both the Sponsor and the investigator 
agree.
Acetaminophen 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 is stable for at least three months 
prior to screening and there are no expected changes in co-medication during the study. 
Moderate to strong inhibitors or inducers of CYP3A and/or CYP2C9 are not allowed as 
MK-8189 is being metabolized by these CYP enzymes and co-administration of inhibitors or 
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inducers may potentially alter the metabolism and PK of MK-8189. In addition, MK-8189 is 
a mild inducer of CYP2B6 in human hepatocytes at drug concentrations of ≥10 μM and 
therefore co-medication with substrates for CYP2B6 should be avoided (ie, efavirenz and 
bupropion). See also Section 6.5.1 on rescue medication.
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.
In case the participant presents with signs of akathisia without signs of dystonia, the 
participant can be treated with a β-adrenergic blocker. If symptoms do not disappear with the 
β-adrenergic blocker, treatment with an anticholinergic may be used. An anticholinergic may 
be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred 
treatment based on a participant’s medical history and/or concomitant medication.
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 symptoms with antipsychotic medication.
Patients will be washed off from their antipsychotic treatment (Section 8.1.5.1). 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.
6.6
Dose Modification (Escalation/Titration/Other)
In Part 1, Panel A (Titration Regimen 1), Panel C (Titration Regimen 3), and if applicable for 
Part 2 (ie, a treatment with a titration scheme is selected), dose titration decisions will be 
made jointly by the investigator and the Sponsor. However, if a participant needs to be 
discontinued or have a dose reduction based on safety/tolerability, the principal investigator 
may do so independent of consultation with the Sponsor.
For Titration Regimen 1 and the dose regimen given in Panel D and Panel F, each dose 
titration decision for each individual participant will occur after 3 days of dosing per dose 
level. For Titration Regimen 3, the titration decision for each individual will be made 
following the 16 mg Dose (Day 2). 
For Titration Regimen 2 (no titration), safety and tolerability data will be reviewed following 
3 Days of dosing to determine if dosing for an individual participant should continue at that 
dose level.
Dose titration decisions for each participant will be based on available (as per the SoA) 
safety variables: VS, 12-lead safety ECG, laboratory safety tests, AEs, C-SSRS, BPRS, and 
EPS evaluations from the previous dose levels.
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If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose titration, the dose will not be increased as planned. Instead, participants may:
•
Skip a single dose and dosing may continue at the same dose level or adjusted 
downwards 
•
Receive the same dose level to further explore safety and tolerability at that level
•
Receive a lower dose of the study intervention
•
Stop dosing 
If appropriate medical care necessitates dosing to be stopped or a lower dose given, the 
investigator may do so without consultation with the Sponsor.
Participant discontinuation criteria are outlined in Section 7.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity . The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, a protocol clarification letter.
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, or through 
the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 8.1.9, or if available, a protocol clarification 
letter.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed 278 mL (Appendix 8).
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written 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 dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The 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 future biomedical research 
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 future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written 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. This will also 
include any psychiatric history of the participant.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 3 months before starting the study. Use of any prescription or nonprescription 
medication during the washout period should first be discussed between the investigator and 
Sponsor, unless appropriate medical care necessitates that therapy or vaccination should 
begin before the investigator and Sponsor can consult. Note: medications permitted under 
Section 6.5 of the protocol do not need to be discussed prior to use.
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. The washout may start with a down 
titration of the antipsychotic treatment during the screening phase per direction of the 
investigator.  For longer half-life antipsychotics (e.g. aripiprazole and brexpiprazole), if 
deemed appropriate by the investigator, a participant may stop treatment (i.e. 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. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention(s) will be monitored by the investigator and/or study 
staff.
8.1.8.1
Timing of Dose Administration
MK-8189/placebo dosing will occur once daily in the morning following an 8-hour fast. 
Participants will receive each oral dose of MK-8189/placebo with ~ 240 mL water.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.10.4. to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period ( Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
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8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to 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 drug, the reason thereof, etc., in the medical chart. 
If it is not possible to record this assessment in the chart prior to the unblinding, the 
unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
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.
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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
Healthy elderly participants will be domiciled by Day -1. Participants with schizophrenia will 
report to the CRU at least 6 days prior to treatment with MK-8189 on Day 1 and all 
participants will remain in the unit until the 48-hours postdose procedures are complete. At 
the discretion of the investigator, participants may be requested to remain in the CRU longer. 
Participants may be permitted to leave the unit, for emergency situations only, during the 
domiciling period at the discretion of the investigator after discussion with the Sponsor. The 
decision how to monitor the participant will be at the discretion of the investigator after 
discussion with the Sponsor.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn/collected by visit 
and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as 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.
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BMI
Body Mass Index equals a person’s weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed at 
prespecified timepoints noted in the SoA (Section 1.3).
•
Blood pressure and heart rate measurements (to be taken before blood collection for 
laboratory tests) will be assessed in a semirecumbent position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
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 semirecumbent 
position for at least 10 minutes prior to having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, respiratory rate and body temperature at 
timepoints indicated in the SoA. The correct size of the BP cuff and the correct positioning 
on the participants’ 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 on Day -1 as indicated in the SoA. The mean of Day -1 time-matched 
triplicate measurements will be used as the baseline to calculate change from baseline for 
postdose safety evaluations (and for rechecks, if needed). Screening and postdose VS 
measurements will be single measurements.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained. Participants should 
be semirecumbent for at least 10 minutes and then stand upright for 2 minutes prior to 
measurement of orthostatic VS.
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8.3.3
Electrocardiograms
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to 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 semirecumbent for at least 10 minutes prior to each ECG 
measurement.
At baseline, when triplicate ECG are required, 3 individual ECG tracings should be obtained 
as close as possible in succession, but no more than 2 minutes apart. The full set of triplicates
should be completed in less than 5 minutes. The mean of these measurements will be used as 
the baseline measurement to calculate change from baseline for safety evaluations (and for 
rechecks, if needed).
Single 12-lead ECGs will be obtained postdose and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA (see Section 
1.3) using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Appendix 9 for evaluation and withdrawal criteria and 
additional QTc readings that may be necessary.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
During each treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with mean predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the mean QTc interval increase from baseline for any postdose 
time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
If the QTc interval is ≥500 msec on any postdose ECG, the Sponsor should be notified, and 
the ECGs should be reviewed by a cardiologist. The participant should be telemetry-
monitored (until the QTc is <500 msec) or should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a cardiac or intensive care unit) 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.
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If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
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 operations manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
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, prior to 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 
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assessor should also inquire and document if this is also present at the time of the screening 
visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. 
Participants who report suicidal ideation with intent, with or without a plan or method (ie, a 
positive response to items 4 or 5 in the assessment of suicidal ideation on the C-SSRS) or 
suicidal behavior must be evaluated that day by a psychiatrist or other trained mental health 
professional who is a licensed psychologist, social worker, or mental health nurse practitioner 
(or comparable professional qualification in countries outside the United States). Subsequent 
to that evaluation, only those participants whose suicidal ideation is considered by the 
evaluator to be passive, and who expressly deny any intent to act, and who, after evaluation, 
are not judged to be at serious risk for self-harm during the course of the study may continue 
in the study; other participants must be discontinued from study participation and receive 
appropriate clinical follow-up care to ensure their safety. 
In addition, all AEs of suicidal ideation or behavior must be recorded as an ECI (See 
Section 8.4.7). Sites are to designate which health care professionals are to be responsible for 
acute care on-site and to specify referral center(s) to be used for further evaluation.
8.3.6
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. The operations manual contains sample 
forms of the BARS, AIMS and SAS.
8.3.7
Assessment of Neuropsychological Effects
For the assessment of psychological effects, the VAS will be completed at times specified in 
the SoA. Prior to the initial administration of the VAS, participants will be trained by study 
staff and will practice the assessment.
In addition, the BPRS will also be completed at times specified in the SoA.
A general (full) Neurological Exam will be performed at the Screening visit and Baseline 
(Day -1). A targeted Neurological Exam will be administered at times specified in the SoA.
The operations manual contains sample forms of the VAS, BPRS and Appendix 11 contains 
the general and targeted Neurological Exams.
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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 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 consent form is signed but 
before intervention allocation/randomization, must be reported by the investigator for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo, or a 
procedure.
From the time of intervention allocation/randomization through 14 days following 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 of the time 
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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in [Table 3].
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting 
Time Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 24 hours of 
learning of event
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)
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI 
(do not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
Overdose
Report if:
- receiving placebo run-in 
or other run-in medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3. Dystonia
4. New or worsening tardive dyskinesia
5. QTcF interval of ≥500 msec (the average of 3 QTcFs will be used)
6. Suicidal ideation, suicidal behavior
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.
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8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of PK/PD
will be collaboratively determined by the Sponsor (eg, samples at lower doses may not be 
assayed if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional PD markers.
8.6.1
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and 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 will be drawn for CYP2C9 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical 
research if the participant signs the future biomedical research consent.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research
•
Leftover main study plasma from MK-8189 and/or metabolites assay stored for future 
research.
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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 4 weeks prior to 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 
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
Part 1
Participants who meet selection criteria for enrollment will participate in Panel A, Panel B or 
Panel C after washing off their current atypical antipsychotic medication. Approximately 32 
participants may be enrolled in Part 1.
On treatment days between Day 1 and Day 7, participants will be dosed once daily with 
MK-8189 or matching placebo and have procedures completed per the SoA. Participants will 
remain in the unit until Day 9 procedures are complete.
Part 2
Participants with Schizophrenia: Participants who meet selection criteria for enrollment will 
participate in Part 2 after washing off their current atypical antipsychotic medication. Up to 
approximately 16 participants will be enrolled in Panel D. In Panel E, 24 participants may be 
enrolled if more than 1 titration regimen is evaluated as described in Section 4.1. The intent 
is to have ~16 participants complete one titration regimen in Panel E.
Healthy elderly participants: Up to approximately 12 participants will be enrolled in Panel F. 
In Panel G, up to 20 participants may be enrolled if more than 1 titration regimen is evaluated 
as described in Section 4.1. The intent is to have ~12 participants complete one titration 
regimen in Panel G.
Panel D/F Dose Regimen: On treatment days between Day 1 and Day 13, participants will be 
dosed once daily with MK-8189 or matching placebo and have procedures completed per the 
SoA. Participants will remain in the unit until Day 15 procedures are complete.
Panel E/G Titration Regimen 1: On treatment days between Day 1 and Day 10, participants 
will be dosed once daily with MK-8189 or matching placebo and have procedures completed 
per the SoA. Participants will remain in the unit until Day 12 procedures are complete.
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Panel E/G Titration Regimen 2: On treatment days between Day 1 and Day 7, participants 
will be dosed once daily with MK-8189 or matching placebo and have procedures completed 
per the SoA. Participants will remain in the unit until Day 9 procedures are complete.
Panel E/G Titration Regimen 3: On treatment days between Day 1 and Day 9, participants 
will be dosed once daily with MK-8189 or matching placebo and have procedures completed 
per the SoA. Participants will remain in the unit until Day 11 procedures are complete.
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.10.4
Poststudy
After completion of treatment, participants will resume the use of their own antipsychotic 
medication after the 48-hour postdose procedures are complete per the SoA and be 
discharged at the discretion of the investigator. A phone call should occur ~ 5 days after 
discharge from the unit to check for any side effects and medication compliance.
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for MK-8189 is the critical procedure.
At any postdose time point, the blood sample for MK-8189 needs to be collected as close to 
the exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed prior or after the 
prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director. Blood samples should be taken after vital sign and ECG 
assessments or there should be a 10-minute window between a blood draw and the start of a 
vital sign or ECG assessment.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
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The following variance in procedure collection times will be permitted.
•
PK collections may be obtained:
•
Predose within 1 hour prior to dosing
•
within +/- 20 minutes of all postdose theoretical timepoints.
•
Predose standard safety evaluations:
•
Vital signs within 15 minutes from the theoretical timepoint
•
ECG within 2 hours prior to first dose
•
Laboratory safety tests and physical exam within 48 hours prior to first dose
•
Postdose standard safety evaluations: 
•
Vital signs and ECG within 20 minutes from the theoretical timepoint
•
Laboratory safety tests within 90 minutes prior to the theoretical timepoint
•
Study intervention administration may be given within 30 minutes from the theoretical 
timepoint.
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8189 in humans, and the PK, PD, 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
•
Repeat of a Panel at the same dose regimen or more conservative dose regimen.
•
Entire panels may be omitted
•
Adjustment of the dosing interval (eg, divided doses [BID to QD, QD to BID, TID, or 
vice versa])
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•
Addition of PK pause
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK sample processing and shipping details based on newly available 
data
•
A single dose may be skipped, and dosing may continue at the same dose level or 
adjusted downward.
The PK/PD sampling scheme currently outlined in the protocol may be modified during the 
study based on newly available PK or PD 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 PD 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 employ 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.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (Section 9.2).
Safety: Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead 
ECGs, and/or 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). For vital signs, time-matched Day -1 readings will 
be used as baseline.  For all other endpoints, baseline is defined as average of predose Day 1 
or Day -1 readings.
For all panels, summary statistics and plots will be generated for BARS, AIMS and SAS, 
VAS, and BPRS as well as for change from baseline. Responses to the C-SSRS will be listed.
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Pharmacokinetics: 
Separately for each part and each PK parameter, individual values of AUC0-24hr, Cmax, and 
C24hr at each dose level will be natural log-transformed and evaluated with a linear mixed 
effects model containing a fixed effect for dose and a random effect for subject. For each PK 
parameter, GM and corresponding ninety-five percent Cis for each dose will be provided.
The comparison of elderly participants with schizophrenia to young adults with 
schizophrenia will be made using data from Part 2 and Part 1, and historical data from P007 
(Panel B and D). Separately for each PK parameter individual values of AUC0-24hr, Cmax, 
and C24hr at each dose level (16 mg and 24 mg at steady state) will be natural log-
transformed and evaluated with a linear mixed effects model containing fixed effects for 
dose, population (elderly, adult), and population by dose interaction and a random effect for 
subject. For each population, GMs and corresponding 95% CIs for each dose will be
provided.  Similarly, the comparison of healthy elderly participants (Panels F and G) to 
healthy young adults (Panel A in P007) will be made using the above described model.
9.2
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
Pharmacology Department of the Sponsor. If, after the study has begun, changes are made to
the statistical analysis plan stated below, then these deviations to the plan will be listed, along 
with an explanation as to why they occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Objectives
Primary
Part 1
•
To evaluate the safety and tolerability of MK-8189 oral, once-daily titration regimens in 
young adult participants with schizophrenia
Part 2
To evaluate the safety and tolerability of multiple once-daily oral doses of MK-8189 in 
elderly participants with schizophrenia and healthy elderly participants.
Secondary
Part 1
•
To characterize MK-8189 pharmacokinetics following different titration regimens in 
young adult participants with schizophrenia
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Part 2
•
To characterize the pharmacokinetics of MK-8189 following multiple once-daily oral 
doses in elderly participants with schizophrenia and in healthy participants.
Exploratory
Part 1 and Part 2
•
To investigate the relationship between CYP2C9 genetic polymorphs and the PK and PD
of MK-8189. Genetic variation in CYP2C9 may be analyzed for association with any 
laboratory or clinical data collected in this study.
•
To explore the relationship between genetic variation and response to the treatment 
administered, and mechanisms of disease. Variation across the human genome may be 
analyzed for association with clinical data collected in this study.
Part 2
•
To compare the pharmacokinetics of MK-8189 in elderly participants with schizophrenia 
to dose-matchedyoung adult participants with schizophrenia
To compare the pharmacokinetics of MK-8189 in elderly healthy participants to dose-
matched healthy young adult participants.
9.4
Analysis Endpoints
Safety: Primary safety endpoints will include all types of adverse experiences, in addition to 
laboratory safety tests, 12-lead ECGs, and VS. For vital signs, time-matched Day -1 readings 
will be used as baseline.  For all other endpoints, baseline is defined as the predose Day 1 or 
Day -1 readings, as appropriate.
For all panels, summary statistics will be generated for BARS, AIMS, SAS, VAS, and BPRS 
as well as for change from baseline. The difference from baseline will be computed on the 
original scale (raw change from baseline). Responses to the C-SSRS will be listed. The C-
SSRS will be used to systematically and prospectively ascertain and document the 
occurrence of suicidal events (ie, ideation and behavior). Responses on the C-SSRS are 
classified according to 11 prespecified categories as described in the operations manual. The 
most severe treatment-emergent ideation and behavior event reported at a visit will be used 
for analysis and reporting. An event is considered treatment-emergent during the assessment 
phase if it newly emerged or is more severe compared to recent history (ie, protocol-defined 
recent history prior to entering the trial as stated in the Inclusion/Exclusion criteria for 
suicidal ideation/behavior, up to and including the randomization visit).
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Secondary Endpoints
Pharmacokinetics: MK-8189 PK variables (AUC0-24hr, Cmax, C24hr, Tmax, CL, Vd and
t1/2) are of secondary interest in adult and elderly participants with schizophrenia and 
healthy participants
Exploratory Endpoints
Comparison of young adults versus elderly: MK-8189 PK variables MK-8189 (AUC0-24hr, 
Cmax, C24hr, Tmax, CL, Vd, and apparent t1/2).
9.5
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. 
All Participants as Treated (ApasT): The All Participants as Treated Population consists of 
all participants who received at least one dose of treatment. This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will 
be likely to exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
measurements and absence of important protocol deviations. Important protocol deviations 
will be identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation. Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR. 
At the end of the study, all participants who are compliant with the study procedure as 
aforementioned and have available data from at least one treatment (dose level) will be 
included in the Per-Protocol dataset. This population will be used for the PK analysis.
9.6
Statistical Methods
Safety 
Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead ECGs, 
and/or 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). For vital signs, time-matched Day -1 readings will be used as 
baseline.  For all other endpoints, baseline is defined as the predose Day 1 or Day -1 
readings, as appropriate.
For both parts, summary statistics and plots will be generated for BARS, AIMS, SAS, VAS, 
and BPRS as well as for change from baseline. Responses to the C-SSRS will be listed.
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Pharmacokinetics
Separately for each part and each PK parameter, individual values of AUC0-24hr, Cmax, and 
C24hr at each dose level will be natural log-transformed and evaluated with a linear mixed 
effects model containing a fixed effect for dose and a random effect for subject. For each PK 
parameter, GM and corresponding 95% CI for each dose will be provided.
Comparison of Elderly Participants and Young Adults
The comparison of elderly participants with schizophrenia to young adults with 
schizophrenia will be made using data from Part 2 (Panels D and E) and Part 1, and historical 
data from P007 (Panels B and D). Separately for each PK parameter, individual values of 
AUC0-24hr, Cmax, and C24hr at each dose level (16 mg and 24 mg at steady state) will be 
natural log-transformed and evaluated with a linear mixed effects model containing fixed
effects for dose, population (elderly, adult), and population by dose interaction and a random 
effect for subject. Kenward and Roger’s method will be used to calculate the denominator 
degrees of freedom for the fixed effects. For each population, 95% CIs for the least squares 
means for each dose will be constructed on the natural log scale. 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. Individual PK values, GMs and 95% CIs
will be shown graphically by population. A two-sided 90% CIs for the true differences in 
mean for log-transformed AUC0-24r, Cmax, and C24hr (elderly – adults) will also be 
computed from the model. These CIs will be exponentiated to obtain the 90% CIs for the 
AUC0-24hr, Cmax, and C24hr true geometric mean ratios (elderly/adults). Additionally, a 
plot of GMR with corresponding 90% CI will also be provided.
Similarly, the comparison of healthy elderly participants (Panels F and G) to healthy young 
adults (Panel A in P007) will be made using the above described model.
The exploratory objective pertaining to the assessment of relationship between CYP2C9 
genetic polymorphs and the laboratory, and PK of MK-8189, and the relationship between 
genetic variation and response to the treatment may be addressed in a separate report.
Descriptive Statistics 
For each Part and panel, individual values will be listed for each PK parameter AUC0-24hr, 
Cmax, C24hr, Tmax, CL, Vd, and t1/2 by dose (and day where applicable), 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 CV (calculated as 
100 x standard deviation/arithmetic mean), median, minimum, maximum, GM, and 
geometric percent CV (calculated as 100 x sqrt(exp(s2) – 1), where s2 is the observed 
variance on the natural log-scale).
9.7
Interim Analyses
No interim analyses are planned
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9.8
Multiplicity
No multiplicity adjustments are needed, as there are no hypotheses.
9.9
Sample Size and Power Calculations
Since there are no hypotheses, no power calculations are provided.
Comparison of Elderly vs Young Adults (Exploratory): The between-subject standard 
deviation estimates for healthy and participants with schizophrenia used in the calculations 
below were obtained from 24 mg dose in MK-8189 PN007 Panel A and Panel B, 
respectively. At each of the comparable doses, the precision of the estimates of GMR 
obtained from the study can be assessed by calculating the half-width of the 90% CIs for the 
GMRs (elderly/adults) expected for the given sample size and assumed between-subject 
standard deviation. [Table 4] below shows the half-width of the 90% CI for the true GMR for 
PK parameters, AUC0-24hr, Cmax, and C24hr.
Table 4
Precision Estimates for AUC0-24hr, Cmax, and C24hr
PK 
Parameter
Observed 
(Log) Between-
Subject SD
N 
(Log) Half-
Width of 90% 
CI
Observed 
GMR 
(elderly/adults)
90% CI Based on 
Observed GMR
elderly with schizophrenia vs adults with schizophrenia
AUC0-24hr
0.38
12 elderly 
12 adults
0.266
1.00
(0.77, 1.31)
Cmax
0.37
12 elderly 
12 adults
0.259
1.00
(0.77, 1.30)
C24hr
0.48
12 elderly 
12 adults
0.336
1.00
(0.71, 1.40)
healthy elderly vs healthy adults 
AUC0-24hr
0.60
10 elderly 
12 adults
0.443
1.00
(0.64, 1.56)
Cmax
0.48
10 elderly 
12 adults
0.354
1.00
(0.70, 1.43)
C24hr
1.11
10 elderly 
12 adults
0.822
1.00
(0.44, 2.27)
AUC=area under the time-concentration curve from 0 to 24 hours; C24hr=concentration at 24 hours; CI=confidence 
interval: Cmax=maximum concentration; GMR=geometric mean ration; N=number; PK = pharmacokinetic, SD = 
standard deviation , 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, 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 
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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.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in [Table 5] will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
Table 5
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
Blood Urea Nitrogen 
(BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate or 
CO2
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(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)
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Laboratory 
Assessments
Parameters
Other 
Screening Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
Urine alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines); If the clinical site’s drug 
evaluation routinely detect additional agents, the relevance of positive findings for 
exclusion will be discussed with the Sponsor.
•
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
•
Serology (HIV antibody, hepatitis B surface antigen [HbsAg], and hepatitis C virus 
antibody)
NOTES:
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
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female 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, Mullerian 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 female
-
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 women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c Male condoms must be used in addition to hormonal contraception.
d If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation. 
e IUS is a progestin releasing IUD.
f
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but 
not highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male and female condom should not be used together (due to risk of failure with friction).
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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 Research
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 Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or 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.
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 Research
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 are 
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 which 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.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing 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 Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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 Specimens
Future biomedical research specimens will be stored in the biorepository for potential
analysis for up to 20 years from the end of the main 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 utilized 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 
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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 Security
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 Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
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 Research
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@merck.com.
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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
Part 1: All Panels 
Pre-study
(Screening)
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests including 
Serum β-hCG (WOCBP only) or 
Serum FSH (WONCBP only)
1
3
1
5
12.5
62.5
HIV/Hepatitis Screen 
(per site SOP)
1
1
8.5
8.5
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-8189 and/or 
metabolites assay 
(Panel A)
26
26
4.0
104.0
Blood for MK-8189 and/or 
metabolites assay 
(Panel B)
25
25
4.0
100.0
Blood for MK-8189 and/or 
metabolites assay
(Panel C)
34
34
4.0
136.0
Blood for IV catheter flush 
(Panel A) a
33
2.0
66.0
Blood for IV catheter flush 
(Panel B) a
32
2.0
64.0
Total Blood Volume per Participant for Panel Ab
249.5 mL
Total Blood Volume per Participant for Panel Bb
243.5 mL
Total Blood Volume per Participant for Panel Cb
215.5 mL
a
If IV catheter use is necessary to support blood collection, additional blood (up to 2 mL per collection) may be 
collected and discarded prior to drawing the sample.
b
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. 
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Part 2: All Panels
Pre-study
(Screening)
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests including 
Serum FSH (Panel D/F)
1
3
1
5
12.5
62.5
Laboratory Safety Tests including 
Serum FSH (Panel E/G Titration 
Regimen 1)
1
5
1
7
12.5
87.5
Laboratory Safety Tests including 
Serum FSH 
(Panel E/G Titration Regimens 2 
& 3)
1
4
1
6
12.5
75.0
HIV/Hepatitis Screen 
(per site SOP)
1
1
8.5
8.5
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-8189 and/or 
metabolites assay
(Panel D/F and Panel E/G
Titration Regimen 3)
34
34
4.0
136.0
Blood for MK-8189 and/or 
metabolites assay 
(Panel E/G Titration Regimen 1)
26
26
4.0
104.0
Blood for MK-8189 and/or 
metabolites assay
(Panel E/G Titration Regimen 2)
25
25
4.0
100.0
Blood for IV catheter flush 
(Panel D/F) a
41
2.0
82.0
Blood for IV catheter flush 
(Panel E/G Titration Regimen 1) a
35
2.0
70.0
Blood for IV catheter flush 
(Panel E/G Titration Regimen 2) a
33
2.0
66.0
Blood for IV catheter flush 
(Panel E/G Titration Regimen 3) a
42
2.0
84.0
Total Blood Volume per Panel D/F Participantb
297.5 mL
Total Blood Volume per Panel E/G Titration Regimen 1 Participantb
278.5 mL
Total Blood Volume per Panel E/G Titration Regimen 2 Participantb
258.0 mL
Total Blood Volume per Panel E/G Titration Regimen 3 Participantb
312.0 mL
a
If IV catheter use is necessary to support blood collection, additional blood (up to 2 mL per collection) may be 
collected and discarded prior to drawing the sample..
b
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria (if criteria 
diverges from inclusion/exclusion criteria, more conservative criteria should be 
used)
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant Post
Randomization Findings 
(clarification on action to take)
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 Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; or 
PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB (ICRBBB) 
(QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant Post
Randomization Findings 
(clarification on action to take)
Other Intra-Ventricular 
Conduction Delay
QRS ≥130 ms
QRS ≥130 ms + Increase of ≥10 ms
QTc (B or F)
Male
QTc ≥470 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
Female
QTc ≥480 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
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 Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes (In 2 
or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
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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 of 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:
1. The participant may be excluded from the study;
2. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
3. The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
4. 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 (Full) and Targeted Neurological Exam
The General (Full) and Targeted Neurological Examination will be performed at the time 
points specified in the Schedule of Activities (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 his or her medical judgment.
The General (Full) Neurological Examination
The General (Full) Neurological Examination includes all of the modules listed below and is
intended to be a general screening examination.
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 volunteer’s use of language throughout the interview.
C. Orientation (time, place, person)
D. Attention/Concentration
Ask the subject to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite months 
backwards or spell a 5 unique letter word (e.g. “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 one 
error. 
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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)
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
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test e.g. by rubbing fingers 
on each side of subject’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
MODULE 3 - MOTOR SYSTEM
A. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows and at the knees (bilaterally). 
3. There is a small, continuous resistance to passive movement.
4. Observe for involuntary movements (e.g., 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
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B. Muscle Strength
1. Ask the subject to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
2. Test proximal limb strength by having the volunteer 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
3. Test distal limb strength by having the volunteer conduct dorsiflexion and plantar 
flexion of the volunteer’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally, and compare one side to the other.
Score: left and right
Grade: 5/5: normal; 
4/5: movement against resistance impaired; 
3/5: movement against gravity but not against resistance; 
2/5: visible movement but not against gravity; 
1/5: visible contraction; 
0/5: no visible activity
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C. Pronator Drift
1. Ask the volunteer to hold both arms straight forward with, palms up and eyes closed for 
~10-15 seconds as tolerated; watch for how well the arm position is maintained.
2. Instruct the volunteer to keep both arms still while you tap them briskly downward. The 
volunteer 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
MODULE 4 - REFLEXES
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at Investigator's discretion (e.g. 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
MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer 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 subject will be asked to 
strike his 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 MN weakness.)
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B. Point-to-Point Movements
1. Ask the volunteer 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 subject 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 volunteer to stand with both feet together and eyes closed for 20 to 
30 seconds without support.
2. Be prepared to catch the volunteer if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the volunteer 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
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
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.
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F. Stereognosis:  (identify common objects placed in hand, e.g., coin, key).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
Targeted Neurological Exam
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
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)
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
MODULE 3 - MOTOR SYSTEM
B. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows (may also move wrists simultaneously) and at 
the knees (bilaterally). When testing the upper limbs, do this again while the subject 
makes large repetitive movements with the opposite arm (e.g. patting the palm of the 
hand on the knee).
3. There is a small, continuous resistance to passive movement.
Score: left and right
Grade: NORMAL, IMPAIRED, or DECREASED and describe abnormality
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MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer 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 subject will be asked to 
strike his 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 MN weakness.)
D. Gait
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally.
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
AAP
atypical anti-psychotics
AE
adverse event 
AIMS
abnormal involuntary movement scale
ALT
alanine aminotransferase
APasT
All participants as treated
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC0-24hr
area under the concentration-time curve from 0 to 24 hours
AV
atrioventricular
BARS
Barnes Akathisia Rating Scale
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BPRS
Brief Psychiatric Rating Scale
BUN
Blood Urea Nitrogen
C24hr
concentration at 24 hours
cAMP
cyclic adenosine monophosphate
CGI-S
Clinical Global Impression – severity scale
cGMP
cyclic guanosine monophosphate
CI
confidence interval
CL
clearance
Cmax
maximum concentration
CNS
central nervous system 
CR
controlled release
CRF
case report form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
CYP2B6
Cytochrome P450 2B6
CYP2C9
Cytochrome P450 2C9
CYP3A
cytochrome P4503A
DDI
drug-drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EO
enzyme occupancy
EPS
extrapyramidal symptoms
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GCV
geometric coefficient of variation
GI
gastrointestinal
GM
geometric mean
GMR
eometric mean ratio
hERG
human ether-á-go-go-related gene
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
investigational new drug 
IR
immediate release
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhoea method
LS
least squares means
MDRD
modification of diet in renal disease
NCS
not clinically significant
NDA
new drug application 
NIMP
Non-Investigational Medicinal Product
NOAEL
no observed adverse effect level 
NOEL
no observed effect level
PANSS
Positive and Negative Syndrome Scale
PBO/pbo
placebo
PCL
protocol clarification letter
PD
pharmacodynamic
PDE10A
phosphodiesterase 10A
PK
pharmacokinetic
PP
Per-protocol
POC
proof of concept
PRO
patient-reported outcome
QD
once a day
RBC
Red blood count
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SAS
Simpson Angus Scale
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SoA
schedule of activities
SOP
Standard operating procedure
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TID
three times a day
Tmax
time of maximum concentration
UDS
urine drug screen
VAS
Bond and Lader Visual Analog Scale
Vd
volume of distribution
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
06D209
0834NF


PRODUCT: MK-8189  
141
PROTOCOL/AMENDMENT NO.: 011-05 
MK-8189-011-05 FINAL PROTOCOL
20-MAY-2021
11
REFERENCES
[Bender, A. T. and 
Beavo, J. A. 2006]
Bender AT, Beavo JA. Cyclic nucleotide 
phosphodiesterases: molecular regulation to 
clinical use. Pharmacol Rev 2006;58:488-520.
[03RW09]
[Grauer, S. M., et al 
2009]
Grauer SM, Pulito VL, Navarra RL, Kelly MP, 
Kelley C, Graf R, et al. Phosphodiesterase 10A 
inhibitor activity in preclinical models of the 
positive, cognitive, and negative symptoms of 
schizophrenia. J Pharmacol Exp Ther 
2009;331(2):574-90.
[03RW0C]
[Schmidt, C. J., et al 
2008]
Schmidt CJ, Chapin DS, Cianfrogna J, Corman 
ML, Hajos M, Harms JF, et al. Preclinical 
characterization of selective phosphodiesterase 
10A inhibitors: a new therapeutic approach to 
the treatment of schizophrenia. J Pharmacol Exp 
Ther 2008;325(2):681-90.
[03RW0F]
[Seeger, T. F., et al 
2003]
Seeger TF, Bartlett B, Coskran TM, Culp JS, 
James LC, Krull DL, et al. 
Immunohistochemical localization of PDE10A 
in the rat brain. Brain Res 2003;985:113-26.
[03RW0G]
06D209
0834NF