A Multiple Ascending Dose Clinical Study to Evaluate the Safety, Tolerability, PK and the Effect of MK-8189 on QTc in Participants With Schizophrenia
Phase: PHASE1
Conditions: Schizophrenia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Multiple Ascending Dose Clinical Study to 
Evaluate the Safety, Tolerability, PK and the 
Effect of MK-8189 on QTc in Participants with 
Schizophrenia
18-Nov-2022
NCT05406440

PRODUCT: MK-8189  
1
PROTOCOL/AMENDMENT NO.: 014-05
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18-NOV-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD)
Protocol Title: A Multiple Ascending Dose Clinical Study to Evaluate the Safety, 
Tolerability, PK and the Effect of MK-8189 on QTc in Participants with Schizophrenia
Protocol Number: 014-05
Compound Number: MK-8189
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
118,986
Approval Date: 18 November 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 5
18-NOV-2022
Allow conduct of Panel C without review of Panel A-1 PK as it has been determined that 
even if PK is not predicted to achieve 2-fold the high clinical exposure scenario, lower 
exposures may support an integrated (non-clinical and clinical) concentration-QTc 
analysis that may negate the need for a TQT study (ICH E14 & S7B Q&A August 2022).
In addition, as evaluation of an MK-8189 dose lower than 80 mg may also support an 
integrated concentration-QTc assessment, language has been removed indicating no 
further panels would be conducted if Panel A-1 is not well tolerated. To note, in Panel A 
of the current protocol, preliminary blinded data indicate doses up to and including 
MK-8189 60 mg are generally well tolerated.
Amendment 4
21-OCT-2022
Addition of a new panel with an alternate dose regimen and removal of unnecessary 
panels based on PK, safety and tolerability information from Panel A.
Amendment 3 
14-SEP-2022
Updates to address FDA comments and other minor editorial updates
Amendment 2
29-JUN-2022
Updates to Schedule of Activities
Amendment 01
26-MAY-2022
Updates to exclusion criteria and ECG requirements 
Original Protocol
11-MAY-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Conducting Panel C may support an integrated (non-clinical and clinical) concentration-QTc analysis negating the need for a TQT 
study per ICH E14 & S7B Q&A August 2022. It has been determined that even if PK is not predicted to achieve 2-fold the high 
clinical exposure scenario, a concentration-QTc analysis at lower exposures may still negate the need for a TQT study. Additionally, 
since lower doses of MK-8189 may also support an integrated concentration-QTc analysis, language has been removed that did not 
allow for Panel C if the dose regimen administered in Panel A-1 was not tolerated. If the Panel A-1 dose regimen is not tolerated, a 
lower dose in Panel C may be evaluated per Section 8.10.6 (Study Design/Dosing/Procedures Modifications Permitted withing 
Protocol Parameters) of the protocol. To note, in Panel A of the current protocol, preliminary blinded data indicate doses up to and 
including MK-8189 60 mg are generally well tolerated (Section 4.3.1). 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
4.1 Overall Design
Removed language requiring the review of 
PK data from Panel A-1 prior to initiation 
of Panel C.
Updated Figure 2 Study Design -Decision 
Tree to remove Panel A-1 tolerability and 
PK requirement to conduct Panel C.
Confirmation of concentrations achieving 2-fold the 
high clinical exposure scenario are no longer critical 
for conduct of Panel C as lower exposures may be 
sufficient to support a concentration-QTc analysis.
A lower dose may support an integrated concentration 
QTc analysis and  Panel C may be conducted at a 
lower dose per Section 8.10.6 if Panel A-1 dose 
regimen is not tolerated.
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Section # and Name
Description of Change 
Brief Rationale 
4.2 Scientific Rationale for 
Study Design
Added language that a concentration QTc 
analysis at lower exposures may negate 
need for TQT study if supported by non-
clinical data. Added reference to ICH E14
& S7B Q&A regulatory guidance.
Confirmation of exposures 2-fold the high clinical 
exposure scenario in Panel A-1 is not critical to dose 
regimen for Panel C.
4.3.1 Starting Dose for this 
Study
Updated language to say that preliminary 
blinded data from Panel A demonstrated 
good tolerability of MK-8189 48 
mg/placebo administered on Day 1 and 
MK-8189 80 60 mg/placebo administered 
on Day 2, (instead of previous 80 
mg/placebo on Day 2).
Minor edit to update erroneous text.
4.3.2 Maximum 
Dose/Exposure for This 
Study
Removed language requiring the review of 
PK data from Panel A-1 prior to initiation 
of Panel C. Added language that MK-8189 
exposures at 80 mg or lower may be 
sufficient to support an integrated waiver 
assessment. Added reference to ICH 
guideline E14 & S7B Q&A  August 2022.
Confirmation of exposures 2-fold the high clinical 
exposure scenario is no longer critical for conduct of 
Panel C.
4.3.3 Rationale for Dose 
Interval and Study Design
Removed language requiring the review of 
PK data from Panel A or Panel A-1 prior 
to initiation of Panel C.
Confirmation of exposures 2-fold the high clinical 
exposure scenario is no longer critical for conduct of 
Panel C.
Throughout
Minor grammatical and typographical 
errors were corrected.
These changes were non-substantial editorial 
corrections.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................30
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.2
Preclinical and Clinical Studies ...................................................................31
2.2.3
Ongoing Clinical Studies.............................................................................32
2.2.3.1
Protocol 011.......................................................................................32
2.2.3.2
Protocol 012.......................................................................................35
2.2.3.3
Protocol 015.......................................................................................35
2.2.3.4
Protocol 013.......................................................................................36
2.2.3.5
Protocol 016.......................................................................................36
2.2.3.6
Protocol 008.......................................................................................37
2.2.4
Information on Other Study-related Therapy ..............................................38
2.3
Benefit/Risk Assessment......................................................................................38
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................38
4
STUDY DESIGN............................................................................................................39
4.1
Overall Design......................................................................................................39
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Efficacy Endpoints.............................................................................42
4.2.1.2
Safety Endpoints................................................................................42
4.2.1.3
Pharmacokinetic Endpoints ...............................................................43
4.2.1.4
Pharmacodynamic Endpoints.............................................................43
4.2.1.5
Planned Exploratory Biomarker Research.........................................43
4.2.1.5.1
Planned Genetic Analysis ........................................................43
4.2.1.6
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator/Placebo .............................................44
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................44
4.3
Justification for Dose...........................................................................................44
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4.3.1
Starting Dose for This Study........................................................................45
4.3.2
Maximum Dose/Exposure for This Study ...................................................45
4.3.3
Rationale for Dose Interval and Study Design ............................................49
4.4
Beginning and End-of-Study Definition ............................................................49
4.4.1
Clinical Criteria for Early Study Termination .............................................50
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................53
5.3
Lifestyle Considerations......................................................................................56
5.3.1
Meals and Dietary Restrictions....................................................................56
5.3.1.1
Diet Restrictions.................................................................................56
5.3.1.2
Fruit Juice Restrictions ......................................................................57
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................57
5.3.2.1
Caffeine Restrictions..........................................................................57
5.3.2.2
Alcohol Restrictions...........................................................................57
5.3.2.3
Tobacco Restrictions..........................................................................57
5.3.3
Activity Restrictions ....................................................................................57
5.4
Screen Failures.....................................................................................................58
5.5
Participant Replacement Strategy......................................................................58
6
STUDY INTERVENTION............................................................................................58
6.1
Study Intervention(s) Administered...................................................................58
6.2
Preparation/Handling/Storage/Accountability .................................................60
6.2.1
Dose Preparation..........................................................................................60
6.2.2
Handling, Storage, and Accountability........................................................60
6.3
Measures to Minimize Bias: Randomization and Blinding..............................61
6.3.1
Intervention Assignment..............................................................................61
6.3.2
Stratification.................................................................................................62
6.3.3
Blinding........................................................................................................62
6.4
Study Intervention Compliance..........................................................................62
6.5
Concomitant Therapy..........................................................................................62
6.5.1
Rescue Medications and Supportive Care ...................................................63
6.6
Dose Modification (Escalation/Titration/Other)...............................................64
6.7
Intervention After the End of the Study............................................................64
6.8
Clinical Supplies Disclosure................................................................................64
6.9
Standard Policies..................................................................................................65
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................65
7.1
Discontinuation of Study Intervention...............................................................65
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7.2
Participant Withdrawal From the Study...........................................................66
7.3
Lost to Follow-up .................................................................................................66
8
STUDY ASSESSMENTS AND PROCEDURES........................................................66
8.1
Administrative and General Procedures ...........................................................67
8.1.1
Informed Consent.........................................................................................67
8.1.1.1
General Informed Consent.................................................................67
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................68
8.1.2
Inclusion/Exclusion Criteria ........................................................................68
8.1.3
Participant Identification Card.....................................................................68
8.1.4
Medical History ...........................................................................................68
8.1.5
Prior and Concomitant Medications Review...............................................69
8.1.5.1
Prior Medications...............................................................................69
8.1.6
Assignment of Screening Number...............................................................69
8.1.7
Assignment of Treatment/Randomization Number.....................................69
8.1.8
Study Intervention Administration ..............................................................70
8.1.8.1
Timing of Dose Administration.........................................................70
8.1.9
Discontinuation and Withdrawal .................................................................70
8.1.9.1
Withdrawal From Future Biomedical Research ................................70
8.1.10
Participant Blinding/Unblinding..................................................................71
8.1.11
Domiciling ...................................................................................................71
8.1.12
Calibration of Equipment.............................................................................71
8.2
Efficacy Assessments ...........................................................................................72
8.3
Safety Assessments...............................................................................................72
8.3.1
Physical Examinations.................................................................................72
8.3.2
Vital Signs....................................................................................................72
8.3.2.1
Resting Vital Signs ............................................................................73
8.3.2.2
Orthostatic Vital Signs.......................................................................73
8.3.3
Electrocardiograms ......................................................................................73
8.3.4
Clinical Safety Laboratory Assessments .....................................................75
8.3.5
Pregnancy Testing........................................................................................75
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................76
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................76
8.3.6.2
Monitoring for Extrapyramidal Symptoms........................................76
8.3.7
Assessment of Neuropsychological Effects.................................................76
8.3.8
Photograph of Rash......................................................................................76
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................76
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................77
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......79
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...79
8.4.4
Regulatory Reporting Requirements for SAE .............................................79
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................80
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................80
8.4.7
Events of Clinical Interest............................................................................80
8.4.8
Medical Device and Drug-device Combination Products -
PQCs/Malfunctions......................................................................................81
8.5
Treatment of Overdose........................................................................................81
8.6
Pharmacokinetics.................................................................................................81
8.6.1
Blood Collection for Plasma MK-8189 .......................................................81
8.7
Pharmacodynamics..............................................................................................82
8.8
Biomarkers ...........................................................................................................82
8.8.1
Planned Genetic Analysis Sample Collection..............................................82
8.9
Future Biomedical Research Sample Collection...............................................82
8.10
Visit Requirements...............................................................................................82
8.10.1
Screening......................................................................................................82
8.10.2
Treatment Period..........................................................................................83
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................83
8.10.4
Poststudy......................................................................................................83
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......83
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................85
9
STATISTICAL ANALYSIS PLAN .............................................................................86
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses.................................................................................86
9.3
Hypotheses/Estimation ........................................................................................86
9.4
Analysis Endpoints...............................................................................................87
9.5
Analysis Populations............................................................................................87
9.6
Statistical Methods...............................................................................................88
9.7
Interim Analyses ..................................................................................................89
9.8
Multiplicity ...........................................................................................................89
9.9
Sample Size and Power Calculations .................................................................89
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................90
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10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........90
10.1.1
Code of Conduct for Clinical Trials.............................................................90
10.1.2
Financial Disclosure.....................................................................................92
10.1.3
Data Protection.............................................................................................93
10.1.3.1
Confidentiality of Data ......................................................................93
10.1.3.2
Confidentiality of Participant Records...............................................93
10.1.3.3
Confidentiality of IRB/IEC Information............................................93
10.1.4
Publication Policy........................................................................................94
10.1.5
Compliance with Study Registration and Results Posting Requirements ...94
10.1.6
Compliance with Law, Audit, and Debarment ............................................94
10.1.7
Data Quality Assurance ...............................................................................95
10.1.8
Source Documents .......................................................................................96
10.1.9
Study and Site Closure.................................................................................96
10.2
Appendix 2: Clinical Laboratory Tests..............................................................97
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................99
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................99
10.3.2
Definition of AE ..........................................................................................99
10.3.3
Definition of SAE ......................................................................................100
10.3.4
Additional Events Reported.......................................................................101
10.3.5
Recording AE and SAE .............................................................................102
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................105
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................107
10.5
Appendix 5: Contraceptive Guidance..............................................................108
10.5.1
Definitions..................................................................................................108
10.5.2
Contraception Requirements......................................................................109
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................110
10.7
Appendix 7: Country-specific Requirements..................................................115
10.8
Appendix 8: Blood Volume Table ....................................................................116
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................117
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...119
10.11 Appendix 11: Neurological Exam.....................................................................120
10.11.1
General (Full) Neurological Exam.............................................................120
10.11.2
Targeted Neurological Exam.....................................................................125
10.12 Appendix 12: Abbreviations .............................................................................127
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11
REFERENCES.............................................................................................................132
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LIST OF TABLES
Table 1
Study Interventions....................................................................................59
Table 2
Panel A Schizophrenic Sample Allocation Schedule ................................61
Table 3
Panel A-1 Schizophrenic Sample Allocation Schedule.............................61
Table 4
Panel C Schizophrenic Sample Allocation Schedule.................................61
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................78
Table 6
Pharmacokinetic (Blood) Collection Windows for samples not time-
matched to Holter ECG assessments .........................................................84
Table 7
Protocol-required Safety Laboratory Assessments....................................97
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................17
Figure 2
Study Design – Decision Tree ...................................................................40
Figure 3
MK-8189 Dose-Enzyme Occupancy .........................................................46
Figure 4
Predicted Mean ΔΔQTcF Versus the Observed Geometric Mean Cmax 
for Each Dose Level Along With 90% Confidence Band .........................48
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multiple Ascending Dose Clinical Study to Evaluate the Safety, 
Tolerability, PK and the Effect of MK-8189 on QTc in Participants with Schizophrenia
Short Title: MK-8189 Multiple Ascending Dose Clinical Study in Participants with 
Schizophrenia
Acronym: MAD
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in male and female participants with 
schizophrenia:
Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
multiple ascending doses of MK-8189 in 
participants with schizophrenia
•
Adverse events, discontinuation of 
study intervention due to adverse 
events
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Schizophrenia
Population
participants with schizophrenia or schizoaffective disorder
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
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Blinding Roles
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 9 weeks from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Up to 12 participants with schizophrenia will be allocated/randomized for each of Panels A 
and A-1, such that approximately 8 participants are evaluable and complete the study in each 
of these panels. Up to 30 participants with schizophrenia will be allocated/randomized for 
Panel C such that up to 20 participants are evaluable and complete the study in each of these 
panels as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Active
Panel A
MK-8189
12-mg
QD
Oral
4 tablets Day 1,
5 tablets Day 2
Test 
Product
Active 
Panel A-1
MK-8189
12-mg
QD
Oral
4 tablets Day 1,
6 tablets Day 2
4-mg
QD
Oral
2 tablets Day 2
Active 
Panel C
MK-8189
12-mg
QD
Oral
4 tablets Days 1-2, 
6 tablets Day 3
4-mg
QD
Oral
2 tablets Day 3
Placebo
Panel A, 
A-1, C
Placebo
0 mg
QD
Oral
Panel A
4 tablets Day 1,
5 tablets Day 2
Placebo 
Matched 
to Test 
Product
Placebo
0 mg
QD
Oral
Panel A-1
4 tablets Day 1,
6 tablets Day 2
Placebo
0 mg
QD
Oral
Panel A-1
2 tablets Day 2
Placebo
0-mg
QD
Oral
Panel C
4 tablets Days 1-2,
6 tablets Day 3
Placebo
0-mg
QD
Oral
Panel C
2 tablets Day 3
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Total 
Number of 
Intervention 
Groups/
Arms
2 intervention groups
Duration of 
Participation
Panel A and A-1: Each participant will participate in the study for 
approximately 9 weeks from the time the participant provides documented 
informed consent through the final contact. After a screening, phase of 6
weeks, each participant will receive assigned intervention for 
approximately 2 days. After the end-of-treatment each participant will be 
followed for 2 weeks.
Panel C: Each participant will participate in the study for approximately 9
weeks from the time the participant provides documented informed consent 
through the final contact. After a screening, phase of 6 weeks, each 
participant will receive assigned intervention for approximately 3 days. 
After the end-of-treatment each participant will be followed for 2 weeks.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 2.
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1.2
Schema
The study design is depicted in Figure 1
Figure 1
Study Schema
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1.3
Schedule of Activities
Panel A
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-
Dose
1
2
3
4
5
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
Administrative Procedures
Informed Consent
X
Sec. 8.1.1
Informed Consent for FBR
X
Sec. 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion Criteria
X
X
Sec. 5.1, Sec. 5.2 Specific criteria may be 
reviewed before randomization
Medical History (includes 
psychiatric
history and substance usage)
X
Substances: Drugs, alcohol, tobacco, and 
caffeine
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.5
Assignment of
Screening Number
X
Sec. 8.1.6
Washout from current 
antipsychotic therapy
X
X
If on antipsychotic therapy, discontinue 
medication at least 5 days or at least 3 half-
lives (whichever is longer) prior to Day -1. 
For long half-life drugs washout may begin 
on outpatient basis (Sec. 4.1)
Assignment of Treatment Number
X
Sec. 8.1.7
MK-8189 or Placebo 
Administration
X
X
Day 1 48-mg, Day 2 60-mg
Standard Meals a
X
X
X
X
X
X
Sec. 5.3.1
Domicilingb
X -------------------------------------------X
Safety Procedures
Full physical examination
X
X
X
Sec. 8.3.1
Height
X
Weight
X
X
X
X
BMI to be taken only at Screening
Directed Physical Examination
X
X
Sec. 8.3.1
08D4MT

PRODUCT: MK-8189  
19
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-
Dose
1
2
3
4
5
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
Full Neurological Examination
X
X
X
Day -1: within 24 hours of first dose. Upon 
discharge on Day 5.
Sec. 8.3.7 and Appendix 11
Targeted Neurological Examination
X
X
X
X
X
Day 1-5: up to 3 hours pre-dose or 
equivalent. 
Poststudy visit.
Sec. 8.3.7 and Appendix 11
Vital Signs (HR, BP) c
X
X
X
X
X
X
X
X
Sec. 8.3.2
Vital Signs (respiratory
rate, temperature)
X
X
Xd
Xd
Xd
X
X
X
Anytime during screening, Day -1 and 
poststudy visit. 
Predose on Day 1-2 and at 9 hours postdose 
(or equivalent) on Day 1-4. Upon discharge 
on Day 5.  Sec. 8.3.2.
12-lead ECG e
X
X
X
X
X
X
X
X
Sec. 8.3.3
Serum
(hCG; WOCBP only)
X
X
Urine or Serum Pregnancy Test 
(WOCBP only)
X
Urine test will be collected. Serum test will 
be collected in the event that Urine test is 
positive or cannot be confirmed.
Serum FSH - (WONCBP)
X
HIV, hepatitis B and C screen (per 
site SOP)
X
UDS/BDS (per site SOP)
X
X
Screening UDS/BDS is mandatory, any 
additional UDS/BDS are conducted per site 
SOP. UDS prior to randomization will be 
done on the day of admission.
Laboratory Safety Tests: 
(Hematology, Urinalysis, 
Chemistry)
X
X
X
X
X
Collected at predose (or equivalent) after ~8 
hour fast
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
08D4MT

PRODUCT: MK-8189  
20
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-
Dose
1
2
3
4
5
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
Brief Psychiatric Rating Scale 
(BPRS)
X
X
X
X
up to 3 hours pre-dose or equivalent 
timepoint Sec. 8.3.7  
C-SSRS Baseline 
X
up to 3 hours pre-dose equivalent timepoint 
Sec. 8.3.6.1 
C-SSRS Since Last Assessment 
X
X
X
X
up to 3 hours pre-dose or equivalent Sec. 
8.3.6.1 
Barnes Akathisia Rating
Scale (BARS)f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec. 4.2.1.2
Abnormal Involuntary
Movement Scale (AIMS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec. 4.2.1.2
Simpson Angus Scale
(SAS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec. 4.2.1.2
Pharmacokinetics
Blood for Plasma MK-8189 g
X
X
X
X
X
X
Biomarkers
Blood for Genetic Analysis
X
Collect predose from enrolled participants 
only. See section 8.8.1
08D4MT

PRODUCT: MK-8189  
21
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-
Dose
1
2
3
4
5
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
ADA=antidrug antibody; AE=adverse event; BDS=blood drug screen; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; ID=identification; SAE=serious adverse 
event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential.
a.
Meals should be given at approximately the same time starting on Day -1 (Day -6 if washing off antipsychotic therapy) time-matched to postdose meals, through 24 hours 
post last dose including; breakfast at ~1 hour postdose, lunch at ~4 hours postdose, snack at ~8 hours postdose and dinner at ~12 hours postdose. All subsequent meals will 
be unrestricted in timing. All meals will follow the completion of all specified procedures at that timepoint
b.
Participants will be confined minimally from Day -1 until Day 5 procedures are complete. If participant is washing off antipsychotic therapy domiciling will begin on 
Day -6.
c.
HR and BP, Day -1: Triplicate measurements time-matched to 9 hours post dose equivalent measurements 
• Single HR and BP measurements will be obtained at all postdose timepoints on the following days:
• Days 1-2: at 9 hours post-dose
• Days 3-4: 9 post-dose equivalent
• Days 5: Upon discharge from the clinic
d.
Respiratory rate only
e.
12-lead safety ECG measurements. On the following days, specific timepoints are noted:
• Day -1: Triplicate measurements, Time-matched to 9 hours post dose equivalent measurements
• Day 1-2: at 9 hours post-dose
• Day 3-4: at 9 hours post-dose equivalent
• Days 5: Upon discharge from the clinic
f.
Additional BARS, AIMS and SAS assessments should be conducted if possible when there are observed or reported complaints of dystonia and/or akathisia
g.
MK-8189 plasma PK sample collection:
• Day 1: predose, 2, 6, 8, 10, 12, 14, 16 hours postdose
• Day 2: predose, 2, 6, 8, 10, 12, 14, 16, 24, 48, 72 hours post-dose
• Leftover main study plasma will be stored for future biomedical research
All Panels/Periods
08D4MT

PRODUCT: MK-8189  
22
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A-1
Study Period: Screening
Washout
Intervention
Post-study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-Dose
1
2
3
4
5
Post-study
Screening should occur within 6 
weeks prior to Day 1
Administrative Procedures
Informed Consent
X
Sec. 8.1.1
Informed Consent for FBR
X
Sec. 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion Criteria
X
X
Sec. 5.1, Sec. 5.2 Specific criteria 
may be reviewed before 
randomization
Medical History (includes psychiatric
history and substance usage)
X
Substances: Drugs, alcohol, tobacco, 
and caffeine
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.5
Assignment of
Screening Number
X
Sec. 8.1.6
Washout from current antipsychotic 
therapy
X
X
If on antipsychotic therapy, 
discontinue medication at least 5 
days or at least 3 half-lives 
(whichever is longer) prior to Day -1. 
For long half-life drugs washout may 
begin on outpatient basis (Sec. 4.1)
Assignment of Treatment Number
X
Sec. 8.1.7
MK-8189 or Placebo Administration
X
X
Day 1 48 mg, Day 2 80 mg
Standard Meals a
X
X
X
X
X
X
Sec. 5.3.1
Domicilingb
X -------------------------------------------X
Safety Procedures
Full physical examination
X
X
X
Sec. 8.3.1
Height
X
Weight
X
X
X
X
BMI to be taken only at Screening
Directed Physical Examination
X
X
Sec. 8.3.1
Full Neurological Examination
X
X
X
Day -1: within 24 hours of first dose. 
Upon discharge on Day 5.
Sec. 8.3.7 and Appendix 11
08D4MT

PRODUCT: MK-8189  
23
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A-1
Study Period: Screening
Washout
Intervention
Post-study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-Dose
1
2
3
4
5
Post-study
Screening should occur within 6 
weeks prior to Day 1
Targeted Neurological Examination
X
X
X
X
X
Day 1-5: up to 3 hours pre-dose or 
equivalent. 
Poststudy visit.
Sec. 8.3.7 and Appendix 11
Vital Signs (HR, BP) c
X
X
X
X
X
X
X
X
Sec. 8.3.2
Orthostatic VS (HR, BP) c
X
X
X
X
X
X
X
X
Sec. 8.3.2.2
Vital Signs (respiratory
rate, temperature)
X
X
Xd
Xd
Xd
X
X
X
Anytime during screening, Day -1 
and poststudy visit. 
Predose on Day 1-2 and at 9 hours 
postdose (or equivalent) on Day 1-4. 
Upon discharge on Day 5.  Sec. 
8.3.2.
12-lead ECG e
X
X
X
X
X
X
X
X
Sec. 8.3.3
Serum
(hCG; WOCBP only)
X
X
Urine or Serum Pregnancy Test 
(WOCBP only)
X
Urine test will be collected. Serum 
test will be collected in the event that 
Urine test is positive or cannot be 
confirmed.
Serum FSH - (WONCBP)
X
HIV, hepatitis B and C screen (per site 
SOP)
X
UDS/BDS (per site SOP)
X
X
Screening UDS/BDS is mandatory, 
any additional UDS/BDS are 
conducted per site SOP. UDS prior to 
randomization will be done on the 
day of admission.
Laboratory Safety Tests: (Hematology, 
Urinalysis, Chemistry)
X
X
X
X
X
Collected at predose (or equivalent) 
after ~8 hour fast
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
Brief Psychiatric Rating Scale (BPRS)
X
X
X
X
up to 3 hours pre-dose or equivalent 
timepoint Sec. 8.3.7  
08D4MT

PRODUCT: MK-8189  
24
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A-1
Study Period: Screening
Washout
Intervention
Post-study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-Dose
1
2
3
4
5
Post-study
Screening should occur within 6 
weeks prior to Day 1
C-SSRS Baseline 
X
up to 3 hours pre-dose equivalent 
timepoint Sec. 8.3.6.1 
C-SSRS Since Last Assessment 
X
X
X
X
up to 3 hours pre-dose or equivalent 
Sec. 8.3.6.1 
Barnes Akathisia Rating
Scale (BARS)f
X
X
X
X
X
Up to 3 hours pre-dose on dosing 
days. Any time on non-dosing days 
Sec.4.2.1.2
Abnormal Involuntary
Movement Scale (AIMS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing 
days. Any time on non-dosing days 
Sec.4.2.1.2
Simpson Angus Scale
(SAS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing 
days. Any time on non-dosing days 
Sec.4.2.1.2
Pharmacokinetics
Blood for Plasma MK-8189 g
X
X
X
X
X
X
Biomarkers
Blood for Genetic Analysis
X
Collect predose from enrolled 
participants only. See section 8.8.1
08D4MT

PRODUCT: MK-8189  
25
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel A-1
Study Period: Screening
Washout
Intervention
Post-study
Notes
Scheduled Day Screening
-6
-2
-1
Pre-Dose
1
2
3
4
5
Post-study
Screening should occur within 6 
weeks prior to Day 1
ADA=antidrug antibody; AE=adverse event; BDS=blood drug screen; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; ID=identification; SAE=serious adverse 
event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential.
a.
Meals should be given at approximately the same time starting on Day -1 (Day -6 if washing off antipsychotic therapy) time-matched to postdose meals, through 24 hours 
post last dose including; breakfast at ~1 hour postdose, lunch at ~4 hours postdose, snack at ~8 hours postdose and dinner at ~12 hours postdose. All subsequent meals will 
be unrestricted in timing. All meals will follow the completion of all specified procedures at that timepoint
b.
Participants will be confined minimally from Day -1 until Day 5 procedures are complete. If participant is washing off antipsychotic therapy domiciling will begin on 
Day -6.
c.
HR and BP, Day -1: Triplicate measurements in the supine position, time-matched to 9 hours post dose equivalent measurements. A single orthostatic assessment will be 
conducted following the last supine vital sign measurement.
• Single supine HR and BP measurements followed by orthostatic HR and BP measurements will be obtained at all postdose timepoints. On the following days, specific 
timepoints are noted
• Days 1-2: at 9 hours post-dose
• Days 3-4: 9 post-dose equivalent
• Days 5: Upon discharge from the clinic
d.
Respiratory rate only
e.
12-lead safety ECG measurements. On the following days, specific timepoints are noted:
• Day -1: Triplicate measurements, Time-matched to 9 hours post dose equivalent measurements
• Day 1-2: at 9 hours post-dose
• Day 3-4: at 9 hours post-dose equivalent
• Days 5: Upon discharge from the clinic
f.
Additional BARS, AIMS and SAS assessments should be conducted if possible when there are observed or reported complaints of dystonia and/or akathisia
g.
MK-8189 plasma PK sample collection:
• Day 1: predose, 2, 6, 8, 10, 12, 14, 16 hours postdose
• Day 2: predose, 2, 6, 8, 10, 12, 14, 16, 24, 48, 72 hours post-dose
• Leftover main study plasma will be stored for future biomedical research
All Panels/Periods
08D4MT

PRODUCT: MK-8189  
26
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel C
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1i
Pre-
Dose
1
2
3
4
5
6
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
Administrative Procedures
Informed Consent
X
Sec. 8.1.1
Informed Consent for FBR
X
Sec. 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion Criteria
X
X
Sec. 5.1, Sec. 5.2 Specific criteria may be 
reviewed before randomization
Medical History (includes 
psychiatric
history and substance usage)
X
Substances: Drugs, alcohol, tobacco, and 
caffeine
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.5
Assignment of
Screening Number
X
Sec. 8.1.6
Washout from current 
antipsychotic therapy
X
X
If on antipsychotic therapy, discontinue 
medication at least 5 days or at least 3 half-
lives (whichever is longer) prior to Day -1. 
For long half-life drugs washout may begin 
on outpatient basis (Sec. 4.1)
Assignment of Treatment Number
X
Sec. 8.1.7
MK-8189 or Placebo 
Administration
X
X
X
Day 1-2 48-mg, Day 3 80-mg
Standard Meals a
X
X
X
X
X
X
X
X
Sec. 5.3.1
Domicilingb
X --------------------------------------------------X
Safety Procedures
Full physical examination
X
X
X
Sec. 8.3.1
Height
X
Weight
X
X
X
X
BMI to be taken only at Screening
Directed Physical Examination
X
X
Sec. 8.3.1
Full Neurological Examination
X
X
X
Day -1: within 24 hours of first dose. Upon 
discharge on Day 6.
Sec. 8.3.7 and Appendix 11
08D4MT

PRODUCT: MK-8189  
27
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel C
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1i
Pre-
Dose
1
2
3
4
5
6
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
Targeted Neurological 
Examination
X
X
X
X
X
X
Day 1-5: up to 3 hours pre-dose or 
equivalent. 
Poststudy visit.
Sec. 8.3.7 and Appendix 11
Vital Signs (HR, BP) c
X
X
X
X
X
X
X
X
X
Sec. 8.3.2
Orthostatic VS (HR, BP) c
X
X
X
X
X
X
X
X
X
Sec. 8.3.2.2
Vital Signs (respiratory
rate, temperature)
X
X
Xh
Xh
Xh
X
X
X
X
Sec. 8.3.2, anytime during screening, Day -1, 
and poststudy visit. 
Predose on Days 1-3, and at 9 hours postdose 
(or equivalent) on Day 1-5. Upon discharge 
on Day 6.
24-hour Holter ECG &
Extraction d
X
X
X
X
X
X
X
X
12-lead ECG e
X
X
X
X
X
X
X
X
X
Sec. 8.3.3
Serum (hCG; WOCBP only)
X
X
Urine or Serum Pregnancy Test 
(WOCBP only)
X
Urine test will be collected. Serum test will 
be collected in the event that Urine test is 
positive or cannot be confirmed.
Serum FSH - (WONCBP)
X
HIV, hepatitis B and C screen (per 
site SOP)
X
UDS/BDS (per site SOP)
X
X
Screening UDS/BDS is mandatory, any 
additional UDS/BDS are conducted per site 
SOP. UDS prior to randomization will be 
done on the day of admission.
Laboratory Safety Tests: 
(Hematology, Urinalysis, 
Chemistry)
X
X
X
X
X
Collected at predose (or equivalent) after ~8 
hour fast
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
Brief Psychiatric Rating Scale 
(BPRS)
X
X
X
X
X
up to 3 hours pre-dose Sec. 8.3.7  
08D4MT

PRODUCT: MK-8189  
28
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel C
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1i
Pre-
Dose
1
2
3
4
5
6
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
C-SSRS Baseline 
X
up to 3 hours pre-dose Sec. 8.3.6.1 
C-SSRS Since Last Assessment 
X
X
X
X
X
up to 3 hours pre-dose or equivalent Sec. 
8.3.6.1 
Barnes Akathisia Rating
Scale (BARS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec.4.2.1.2
Abnormal Involuntary
Movement Scale (AIMS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec.4.2.1.2
Simpson Angus Scale
(SAS) f
X
X
X
X
X
Up to 3 hours pre-dose on dosing days. Any 
time on non-dosing days Sec.4.2.1.2
Pharmacokinetics
Blood for Plasma MK-8189 g
X
X
X
X
X
X
X
Sample to be collected within 10 minutes of 
end of ECG extraction window
Biomarkers
Blood for Genetic Analysis
X
Collect predose from enrolled participants 
only. See section 8.8.1
08D4MT

PRODUCT: MK-8189  
29
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
Panel C
Study Period: Screening Washout
Intervention
Post-
study
Notes
Scheduled Day Screening
-6
-2
-1i
Pre-
Dose
1
2
3
4
5
6
Post-
study
Screening should occur within 6 weeks prior 
to Day 1
ADA=antidrug antibody; AE=adverse event; BDS=blood drug screen; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; ID=identification; SAE=serious adverse 
event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs; 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 -2 (Day -6 if washing off antipsychotic therapy) time-matched to postdose meals, through 
Day 5. 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 -2 until Day 6 procedures are complete. If participant is washing off antipsychotic therapy domiciling will begin on Day -
6.
c.
HR and BP, Day -1: Triplicate measurements in the supine position time-matched to 9 hours post dose equivalent measurements. A single orthostatic assessment will be 
conducted following the last supine vital sign measurement.
• Single supine HR and BP measurements followed by orthostatic HR and BP measurements will be obtained at all postdose timepoints. On the following days, specific 
timepoints are noted;
• Days 1-3: at 9 hours post-dose
• Days 4-5: 9 post-dose equivalent
• Days 6: Upon discharge from the clinic
d.
(24-hour) Holter ECG measurements will be performed from approximately 30 minutes prior to dose administration and until 24 hours post-dose.
ECG data will be extracted on:
• Day -1 (baseline measurement): time matched to dosing days at the following timepoints: 0.5hr, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16 
• Day 1: predose, 0.5hr, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16 hours postdose
• Day 2: predose, 1, 2, 6, 8, 10, 12, 14, 16 postdose
• Day 3: pre-dose, 1, 2, 6, 8, 10, 12, 14, 16, 24, 36 hours post-dose. In addition, Holter ECGs will be obtained 48 (Day 5) and 72 hours (Day 6) following the Day 3 dose.
e.
12-lead safety ECG measurements. On the following days, specific timepoints are noted:
• Day -1: Triplicate measurements, Time-matched to 9 hours post dose equivalent measurements
• Day 1-3: at 9 hours post-dose
• Day 4-5: at 9 hours post-dose equivalent
• Days 6: Upon discharge from the clinic
f.
Additional BARS, AIMS and SAS assessments should be conducted if possible when there are observed or reported complaints of dystonia and/or akathisia
g.
MK-8189 plasma PK sample collection:
• Day 1: predose, 0.5hr, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16 hours postdose
• Day 2: predose, 1, 2, 6, 8, 10, 12, 14, 16 hours postdose 
• Day 3: predose, 1, 2, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 hours post-dose
• Leftover main study plasma will be stored for future biomedical research
h.
Respiratory rate only
i.       Participants should be encouraged to have periods of ambulation, outside of the rest periods required prior to and during Holter extraction
All Panels/Periods
08D4MT

PRODUCT: MK-8189  
30
PROTOCOL/AMENDMENT NO.: 014-05
MK-8189-014-05 FINAL PROTOCOL
18-NOV-2022
2
INTRODUCTION
2.1
Study Rationale
This study is being conducted to support efforts to de-risk the potential for MK-8189 to 
prolong QT as required by ICH E14.  Thus, this study will be conducted to 1) evaluate a 
supratherapeutic dose regimen in participants with schizophrenia to support, if required, a 
TQT in participants with schizophrenia and 2) perform a concentration-QTc analysis in 
participants with schizophrenia receiving supratherapeutic doses such that the need for a 
TQT study may be negated.
To appropriately interrogate the potential for a drug to prolong QT, a TQT study requires the 
administration of a supratherapeutic dose that is expected to cover the high clinical exposure 
scenario; this reflects the exposure of the drug when affected by the intrinsic or extrinsic 
factor that causes the greatest increase in plasma concentrations.  Thus, this study will 
evaluate safety, tolerability, and PK of multiple oral doses of MK-8189 at doses that will 
result in concentrations that are greater to those expected when MK-8189 is co-administered 
with a strong CYP3A inhibitor (1.27-fold increase in Cmax), the factor which is expected to 
cause the greatest increase in MK-8189 concentrations. Doses up to 80 mg of MK-8189 will 
be evaluated to provide a clinical margin of 2-fold to the predicted steady-state Cmax 
following administration of MK-8189 24 mg, the highest clinical dose evaluated in Phase 2B.  
Conducting TQT studies in participants with schizophrenia is challenging; this patient 
population is expected to have several co-morbidities and concomitant therapy which could 
confound a QTc assessment. Thus, to avoid confounding the QTc assessment, patients would 
be required to wash off their stable regimen of antipsychotic therapy for several weeks as 
well as other treatments that may affect heart rate and therefore QTc evaluation.  To ensure 
appropriate power and account for discontinuations, it is anticipated that approximately 100 
participants with schizophrenia would need to be enrolled. Therefore this study will also 
evaluate whether a concentration-QTc analysis could be conducted in a smaller number of 
participants (n=30) in a study of shorter duration than a TQT study would require. Thus one 
panel of participants will be escalated over 3 days to 80 mg of MK-8189 which may provide 
exposures approximately 2-fold peak concentrations following MK-8189 coadministration 
with strong CYP3A inhibitor at steady-state (high clinical exposure scenario).  Achieving 
these exposures and assessing ECG parameter values, would support a concentration-QTc 
assessment and de-risk the potential for MK-8189 to induce QT prolongation, even in the 
absence of a positive control, which is required in a TQT study.  
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-8189.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8189 is a potent and selective inhibitor of PDE10A that is being developed as a novel
therapeutic for the treatment of schizophrenia.
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The PDE10A enzyme metabolically inactivates the ubiquitous second messengers, cAMP 
and cGMP [Bender, A. T. and Beavo, J. A. 2006] and is highly expressed in the target
nucleus of the corticostriatal pathway, the striatum [Seeger, T. F., et al 2003].
Preclinical pharmacology studies demonstrate that PDE10A inhibition increases
cAMP/cGMP signaling in pathways that have been associated with underlying pathology
(glutamate) as well as clinically validated therapeutics (dopamine D2 receptor antagonists)for 
schizophrenia. Enhanced signaling in these pathways is hypothesized to restore behavioral 
inhibition that is impaired in schizophrenia [Grauer, S. M., et al 2009] [Schmidt, C. J., et al 
2008]. PDE10A inhibitors may potentially be an alternative treatment as monotherapy and/or 
adjunct treatment in schizophrenia patients who have inadequate response to first line AAP
treatment.
2.2.2
Preclinical and Clinical Studies
Preclinical and clinical study information can be found in the MK-8189 IB.
Completed Phase 1 Clinical Studies:
As part of the Phase 1 program, three single-dose clinical studies, one DDI study, and two 
multiple- dose clinical studies have been completed with MK-8189. Overall, 146 participants 
have received at least one dose of MK-8189; 71 healthy participants and 75 participants with 
schizophrenia. Single doses of MK-8189 up to 6 mg have been given to 48 healthy men; 22 
with an IR formulation and 26 with a CR formulation. Ten healthy male and female 
participants received multiple doses titrated up to 12 mg over 14 days (P003 Part 3) and 12 
healthy male and female participants received doses titrated up to 24 mg over 18 days (P007 
Panel A). Thirty-three male and female participants with schizophrenia were titrated up to 
doses of 16 mg over 14 days (P003), 25 participants with schizophrenia were titrated up to 24 
mg over 18 days (P007 Panel B and C) and 17 participants with schizophrenia were titrated 
up to 48 mg over 15 days (P007 Panel D). All multiple-dose studies were conducted with a 
CR formulation.
Overview of Pharmacokinetics:
Following multiple doses of the controlled release formulation, MK-8189 exposure increased 
approximately proportionally with dose over the range of doses tested (2 to 48 mg) in all 
populations. Median Tmax of MK-8189 as monotherapy ranged from 10 to 24 hours with a 
t1/2 of approximately 10.9 hours. Based on completed studies, data suggest that the 
exposures at steady state for a given dose are generally comparable between healthy 
participants and participants with schizophrenia administered MK-8189 as monotherapy.
MK-8189 is a CYP3A substrate and in a DDI study (P006) the coadministration of extended 
release 240-mg diltiazem, a moderate CYP3A inhibitor, increased MK-8189 AUC and Cmax 
by approximately 2-fold and 1.3-fold, respectively. Preliminary data from an ongoing DDI 
study (P015, described in 2.2.3) demonstrated that coadministration of itraconazole, a strong 
CYP3A inhibitor, increased MK-8189 AUC and Cmax by approximately 1.2-fold and 1.14-
fold, respectively, and were generally consistent with the results observed in the diltiazem 
study.  Collectively, these results confirm that MK-8189 is a CYP3A substrate. Preliminary 
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data from an ongoing hepatic impairment study (P012) demonstrated that MK-8189 AUC 
and Cmax were approximately 1.18-fold and 1.22-fold higher in participants with moderate 
hepatic impairment compared to healthy matched controls, respectively.  Preliminary results 
from an ongoing study in adult and elderly (P011) suggest that PK exposures in elderly 
participants with and without schizophrenia are generally similar to one another and similar 
to those observed in adult participants < 60 years of age with schizophrenia. 
Overview of Safety:
MK-8189 was generally well tolerated across the Phase 1 studies. The most common 
treatment-related adverse events [AEs] (≥5%) following treatment of MK-8189 (n=146) 
across the completed 6 Phase 1 studies in healthy participants and participants with 
schizophrenia were headache (16.4%) somnolence (12.3%), decreased appetite (10.3%), 
nausea (9.6%), fatigue (8.9%), dizziness (8.9%), vomiting (6.2%) diarrhea (6.2%), akathisia 
(6.2%), and anxiety (6.2%). Most AEs were mild to moderate in severity. There were no 
deaths and two SAEs. One participant experienced an SAE of gastroenteritis in P003 which
was not considered treatment related. The other SAE of psychosis occurred in a participant 
with schizophrenia in P007. Both SAEs are detailed in the IB. 
In a Phase 2 POC trial (P005), MK-8189 was generally well tolerated by the 90 participants 
who received at least one dose of the once daily MK-8189 (titrated every 3 days from 4 mg 
to 8 mg and 12 mg, as tolerated). Participants were dosed after they were able to taper off 
psychotropic medications. Adverse Events that occurred in ≥5% of participants in the
MK-8189 intervention group and had greater incidence than placebo were diarrhea, nausea, 
vomiting, decreased appetite, akathisia, dystonia, headache, sedation, somnolence, anxiety, 
and insomnia. No deaths were reported in the P005 study. No SAEs were reported for 
participants on MK-8189. Eight participants [8.9%]) had an AE of dystonia and 2 
participants (2.2%) had an AE of oromandibular dystonia. 
Detailed PK and safety information from individual completed studies are summarized in the 
IB.
2.2.3
Ongoing Clinical Studies
As of 14-February-2022, three Phase 1 trials and one Phase 2 trial are ongoing. All data 
presented are preliminary. 
2.2.3.1
Protocol 011
P011 is a Phase 1 multiple-dose, randomized, double-blind, placebo-controlled, multicenter, 
2-part study. Part 1 (Panel A/B/C) evaluated the safety and tolerability of different titration 
regimens (including without titration) in participants ≤60 years of age with schizophrenia. 
Part 1 is clinically complete and all data are preliminary and blinded. Panel C was not 
conducted per protocol since the regimens in Panel A and B were generally well tolerated. 
Part 2 is evaluating the safety, tolerability, and PK of MK-8189 in elderly participants with 
schizophrenia and healthy elderly participants between 61 and 80 years of age (inclusive). 
All data presented are blinded.
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In Part 1, Panel A, participants with schizophrenia initiated dosing with 16 mg of 
MK-8189/placebo for 3 days, then escalated to 24 mg/placebo for 4 days. In Panel A, all 8 
participants enrolled completed treatment. Most AEs were mild, and no SAEs or deaths were 
reported. All AEs resolved. Of the 8 participants, one participant did not dose escalate to 24 
mg/placebo due to moderate somnolence which lasted for 3 days. The participant was also 
receiving hydroxyzine, a sedating antihistamine. 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. The participant continued dosing with 
MK-8189/placebo without recurrence of dystonia. Another participant reported mild transient 
dystonia which began 6.5 hours following the first dose, was treated with benztropine and 
resolved in 22 hours. The participant continued in the study and escalated to 24 mg/placebo 
without a recurrence of dystonia. AEs reported (including those already discussed) 
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).
In Panel B, participants with schizophrenia were dosed with 24 mg of MK-8189/placebo (no 
titration) for 7 days. In Panel B, enrollment and dosing are complete. Eighteen participants 
were randomized and 14 completed treatment per protocol. Of the 4 participants that 
discontinued treatment, 3 withdrew consent and 1 participant discontinued due to AEs of 
nausea and vomiting that were not considered related to treatment. No AEs were considered 
severe and the majority of AEs were mild. Except for an unrelated AE of ligament sprain, all 
AEs resolved. AEs considered related to treatment included somnolence (n=2), hypertonia 
(n=1), decreased appetite (n=1), musculoskeletal stiffness (n=1) and increased ALT (n=1). 
No AEs of akathisia or dystonia were reported.
Treatment is ongoing in Part 2. Panel D is currently enrolling elderly participants with 
schizophrenia. Participants will receive MK-8189 8 mg/placebo Days 1-3, MK-8189 16 
mg/placebo Days 4-6 and MK-8189 24 mg/placebo Days 7-13. Fifteen participants have 
been dosed and 10 completed the study. No deaths or SAEs have been reported. Most AEs 
were mild or moderate; 1 AE was severe (described below). All AEs reported to date have 
resolved except an AE of a small forehead bump considered not treatment related. Five 
participants have discontinued the trial: Two participants withdrew consent. One participant 
reported an AE of severe somnolence which began following the 8 mg/placebo dose and 
resolved on Day 3. On Day 3 following treatment with 8 mg/placebo, the same participant 
had an AE of moderate dystonia which resolved in 2 days with a single dose of 
cyclobenzaprine. This participant also reported moderate akathisia following treatment with 
8 mg/placebo which continued for 3 weeks. This participant had drug interrupted and 
subsequently discontinued following the second 16 mg/placebo dose due to moderate 
treatment-related AEs of rash and conjunctivitis. 
One participant experienced dystonia of the throat after the Day 3 16 mg/placebo dose which 
was treated with benztropine. Tightness of the throat muscles which the investigator 
considered to be mild dystonia persisted for 2 weeks. The participant discontinued treatment 
prior to the Day 4 dose. The participant had also reported hypoesthesia, dizziness, dysgeusia 
and ear discomfort which were considered treatment-related.
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Another participant discontinued due to an AE of internal restlessness in the predawn hours 
of Day 7. This participant also reported involuntary movement of lower extremities the 
evening prior. These AEs led the participant to withdrawal from the study and the participant 
discontinued dosing prior to the first dose of 24 mg/placebo. 
As of the cut-off date, this panel was actively dosing and the following treatment related AEs 
have been reported to date (includes AEs which have been reported above); dystonia (n=2), 
internal restlessness (n=2), somnolence (n=1), akathisia (n=1), conjunctivitis (n=1), rash 
(n=1), dizziness (n=1), dysgeusia (n=1), ear discomfort (n=1), oral hypoesthesia (n=1) and 
involuntary movement of lower extremities (n=1).
Panel F is clinically complete and enrolled 6 healthy elderly participants with the same 
treatment regimen as Panel D. Five participants completed the trial and one participant 
discontinued due to an AE. Most AEs were mild in intensity and no deaths or SAEs have 
been reported. Except for hyponatremia (discussed below), all other reported AEs resolved. 
One subject discontinued the trial due to treatment related AEs of nausea, vomiting, 
dyspepsia, and hyponatremia. This participant also reported diarrhea prior to the onset of 
nausea and vomiting. The hyponatremia was ongoing at the time of participant discharge. 
One participant was down-titrated from 24 mg/placebo to 16 mg/placebo following the onset 
of moderate EPS. The EPS had a duration of approximately 2 weeks and was managed 
intermittently with benztropine. This participant completed treatment and the study. The 
treatment-related AEs reported (including those discussed above) were decreased appetite 
(n=1), dizziness (n=1), nausea (n=1), vomiting (n=1), dyspepsia (n=1), hyponatremia (n=1), 
somnolence (n=1), involuntary muscle contractions (n=1), tremor (n=1), extrapyramidal 
disorder (n=1) and salivary hypersecretion (n=1).
Panel G completed dosing in healthy elderly participants. Participants received MK-8189 16 
mg/placebo Days 1-3, MK-8189 24 mg/placebo Days 4-10. Fifteen participants were 
enrolled. Most AEs were mild. Three AEs were severe (2 participants with severe 
somnolence and 1 participant with severe hypnagogic hallucination) and are described 
below; no deaths or SAEs were reported. All AEs resolved. Three participants discontinued 
due to treatment related AEs. Beginning on the evening of Day 7, following 2 days of dosing 
with MK-8189 24 mg/placebo, one participant reported mild akathisia (~20 hour), moderate 
tactile hallucinations (15 min), mild palpitations (2 min) and bilateral hand hyperhidrosis 
(5 hour) and severe hypnagogic hallucinations (5 min). The participant reported these AEs on 
the morning of Day 8, the dose was held, the participant received treatment with benztropine 
and all AEs resolved. Later in the afternoon of Day 8, the participant had a recurrence of 
akathisia, bilateral hand hyperhidrosis, tactile hallucinations and reported sinus tachycardia, 
all which resolved with benztropine. The participant discontinued treatment due to these 
AEs. This participant also had a brief episode (~30 min) of mild oral mandibular dystonia on 
Day 1 (16 mg/placebo) that resolved spontaneously.
Another subject discontinued due to an AE of mild akathisia (~24 hour) following a 16 
mg/placebo dose on Day 3 which resolved with benztropine. 
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One subject discontinued after 2 days of dosing at the 24 mg/placebo dose (Day 5) due to 
moderate oromandibular dystonia (~6 hours) and moderate anxiety (<24 hours duration); 
both AEs responded to treatment. 
Two participants were reported to have severe somnolence. In both participants the 
somnolence began within 2 hours of their first dose of study intervention (16 mg/placebo) 
and resolved in ≤ 10 hours. All treatment- related AEs reported (including those discussed 
above) were somnolence (n=4), akathisia (n=3), oromandibular dystonia (n=2), myalgia 
(n=2), tremor (n=2), headache (n=2), involuntary muscle contractions (n=2), tactile 
hallucination (n=1), palpitations (n=1), bilateral hand hyperhidrosis (n=1), hypnagogic 
hallucination (n=1), sinus tachycardia (n=1), restlessness (n=1), dyspepsia (n=1), vomiting 
(n=1), paresthesia (n=1), insomnia (n=1), apathy (n=1) dysphonia (n=1), salivary 
hypersecretion (n=1), anxiety (n=1), bilateral hands rapid alternating movements (n=1) and 
smell sensitivity (n=1).
2.2.3.2
Protocol 012
P012 is an open-label single-dose Phase 1 study to evaluate the safety, tolerability, and PK in 
participants with hepatic impairment and matched healthy participants. As of the cut-off date, 
7 participants with moderate hepatic impairment have received a single 4 mg dose of 
MK-8189. No SAEs or deaths have been reported. The following treatment related AEs 
(duration) have been reported by 4 participants: One participant had mild AEs of a hot flush 
(40 min), vomiting (1 episode) and leg cramps (10 min). One participant had a mild AE of 
dizziness (<1 day). One participant had mild AEs of headache (<1 day), anxiety (30 min) and 
affect lability (30 min).
2.2.3.3
Protocol 015
P015 is a DDI trial to evaluate the effect of multiple-doses of itraconazole, a strong CYP3A 
inhibitor, on the single-dose PK of MK-8189. In Period 1, 14 participants received a single 
dose of 4 mg of MK-8189. In Period 2, participants received a loading dose of itraconazole 
of 200 mg BID on Day 1 and received 200 mg QD on Days 2 to 8. On Day 4, participants 
were coadministered 4 mg of MK-8189 with itraconazole. P015 was clinically complete as of 
the cut-off date.  No deaths or SAEs have been reported. Of the 14 participants, 7 have 
reported at least one AE considered related to MK-8189 and/or itraconazole (duration). One 
participant discontinued due to AE of mild rash (2 days) to itraconazole. In Period 1 on Day 
1, one participant reported mild AEs of somnolence (1 day) and dizziness (8.5 hours) 
considered related to MK-8189. In Period 2 on Day 4, this same participant reported mild 
restlessness (20 hours) and an ECI of dystonia (12 hours) of moderate severity considered 
related to MK-8189 and itraconazole. The dystonia resolved without treatment. Following a 
blood draw, two other AEs, mild pre-syncopal event (5 min) and mild faint sensation (12 
min), were also reported by this participant but neither were considered related to study 
intervention. One other participant reported an AE of mild dystonia (~ 2 days) which began 
in Period 2 on Day 5. The dystonia resolved without treatment and was considered related to 
MK-8189 and itraconazole. One participant had mild AEs of somnolence (2 days) and 
diarrhea (9 days). The somnolence began in Period 1 on Day 1 and was considered related to 
MK-8189, and the diarrhea began in Period 2 prior to co-dosing of MK-8189 and was 
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considered related to itraconazole. Three other participants reported mild diarrhea (5 hours, 3 
days and 6 days) which began in Period 2 prior to MK 8189 administration.
2.2.3.4
Protocol 013
P013 (non-IND study) is a multiple ascending dose, randomized, double-blind, placebo-
controlled (3:1) parallel-group study being conducted in China to evaluate the safety, 
tolerability, and PK of MK-8189 titrated from 8 mg to 24 mg in healthy Chinese participants 
(n=16). P013 was clinically complete as of the cut-off date. All data presented are blinded.
There were no SAEs or deaths reported. One participant discontinued due to an AE of 
moderate delusion with a duration of 15.5 hours following their first dose of MK-8189 8 
mg/placebo. This participant also had the following AEs (duration): mild somnolence on 2 
occasions (6 hours and 18.5 hours), moderate depressed mood (3 days), mild dystonia (7.5 
hours), and mild insomnia on two occasions (7.5 hours and 4 days).
One participant reported an AE of suicidal ideation without intent which lasted for 5 seconds 
following their second dose of 24 mg/placebo: It was reported that after a dream the 
participant had mood swings and was crying. The concept of transient suicide appeared. He 
was observed during the clinical course. The subject did not receive treatment for the event. 
The participants mood AE resolved in 20 minutes. On Study Day 12, the participant received 
their last dose of 24 mg of MK-8189/ placebo per protocol. The investigator considered 
suicidal ideation (mild) to be related to study intervention. This subject also reported AEs 
(duration) of mild headache (3 hours), mild somnolence (18.5 hours), mild cognitive disorder 
(16 hours), mild anxiety (14 hours), mild tremor (12 hours) following the first dose of 8 
mg/placebo, mild ventricular tachycardia (1.3 weeks) with ventricular rate ranging from 62 to 
78 bpm (Screening ventricular rate was 75 bpm), mild increased total bilirubin (also elevated 
at Screening) with direct bilirubin within the normal range (3 weeks) following their second 
12 mg/placebo dose, mild unrelated pharyngeal swelling (9 hours) following their second 16 
mg/placebo dose, mild insomnia (5 days) two days following their last 24 mg/placebo dose, 
mild hyperphosphatemia (1.7 weeks), mild hypercalcemia (also elevated at Screening) (1.7 
weeks) three days following their last 24 mg MK-8189/placebo dose.
The most frequently reported treatment related AEs (N ≥2) were somnolence (N=12), 
insomnia (N=10), decreased appetite (N=5), dystonia (N=5), nausea (N=5), akathisia (N=3), 
anxiety (N=3), tremor (N=3), blood bilirubin increased (N=2), delusion (N=2), headache 
(N=2), hyperhidrosis (N=2) and vomiting (N=2). The majority of AEs reported were mild 
and no AEs were severe. The AEs of akathisia, dystonia, delusions, and most AEs of anxiety 
and somnolence resolved within a few hours. Most of these AEs resolved spontaneously and 
only one AE of dystonia, anxiety and akathisia were treated. One participant had moderate 
depressed mood beginning with the 8 mg/placebo dose which resolved within 3 days with 
continued dosing. Other mood AEs resolved within hours with continued dosing. 
2.2.3.5
Protocol 016
P016 is a randomized, double-blind, placebo-controlled parallel-group, multiple ascending 
dose study conducted in Belgium to evaluate the safety, tolerability, and PK of MK-8189 
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titrated from 8 mg to 72 mg in 25 healthy participants. Participants were administered the 
following dose regimen; 8 mg/placebo Day 1, 16 mg/placebo Day 2, 24 mg/placebo Day 3, 
48 mg/placebo Day 4 and Day 5, 72 mg Day 6. Data are preliminary and blinded. No SAEs 
or deaths occurred.  
During dosing of the first 12 participants, 4 out of 12 did not dose escalate to the highest dose 
of 72 mg due to tolerability issues. Per protocol, if 4 participants randomized to MK-8189
did not dose escalate the stopping rules were met and the trial would be terminated. Though 
the trial remained blinded, conservatively it was decided to stop the trial and therefore no 
further participants were dosed. Two participants did not dose escalate from 48 mg/placebo 
to 72 mg/placebo and discontinued treatment due to mild and moderate adverse events of 
vomiting following their second dose of 48 mg. One of these participants also discontinued 
treatment due to moderate anxiety (9 hours) following their second dose of 48 mg/placebo. A 
third participant was down-titrated following their first dose of 48 mg to 24 mg due to 
moderate somnolence; the somnolence resolved prior to the 24 mg dose administration. A 
fourth participant discontinued treatment following their 24 mg/placebo dose due to severe
akathisia (duration 22.5 hours) and moderate affect lability which began after the 16 
mg/placebo dose (4 days). After the 72 mg dose, one participant reported mild dystonia on 
one occasion lasting 17 minutes. One other participant reported a mild AE of oral dyskinesia 
following the 16 mg dose which lasted for 3 hours. Another participant reported intermittent 
mild akathisia after administration of the 72mg dose. The majority of AEs were mild and 
only one severe AE (akathisia described above) was reported. AEs reported by more than one 
participant regardless of causality were as follows: nausea (n=7), decreased appetite (n=6), 
headache (n=5), nightmare (n=4), insomnia (n=4), restlessness (n=3), leukocyturia (n=3), 
dizziness (n=2), hematuria (n=2), palpitations (n=2), diarrhea (n=3), dyspepsia (n=2), 
eructation (n=2), pyuria (n=2), systolic blood pressure increased (n=2), muscle spasms (n=2), 
myalgia (n=2), akathisia (n=2), somnolence (n=2), vomiting (n=2) and affect lability (n=2).
With the exception of a poststudy unrelated AE of leukocyturia in one participant, all other 
AEs resolved. Administration of MK-8189/placebo up to 24 mg was generally well tolerated.
The aggressive titration regimen above 24 mg was not generally well tolerated in healthy 
participants.
2.2.3.6
Protocol 008
P008 is an ongoing Phase 2B randomized, double-blind, placebo- and active controlled trial 
of the efficacy and safety of MK-8189 in adult participants 18 to 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. Recruitment was initiated in December 2020. Treatment duration 
will be for a period of 12 weeks and includes a 6-week acute treatment period followed by a 
6-week extension period. Eligible participants will be randomized to receive one of five 
treatment sequences with target doses of MK-8189 (8 mg, 16 mg, and 24 mg QD), 
risperidone (6 mg QD), or placebo. Placebo completers at 6 weeks will be allocated to 
receive MK-8189 24 mg for the remainder of the trial. This trial is being conducted in a 
hospital/acute care setting followed by an outpatient setting.
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2.2.4
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine. 
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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in male and female participants with 
schizophrenia:
Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
multiple ascending doses of MK-8189 in 
participants with schizophrenia
•
Adverse events, discontinuation of 
study intervention due to adverse 
events
Secondary
•
Not applicable
•
Not applicable
Tertiary/Exploratory
•
To estimate the pharmacokinetics of MK-
8189 following multiple ascending doses 
of MK-8189 in participants with 
schizophrenia
•
AUC0-24, Cmax, C24, AUC0-inf,
Tmax, CL/F, Vz/F and apparent t1/2
•
To evaluate the effect of MK-8189 
concentrations on QTc interval and ECG 
parameters in participants with 
schizophrenia
•
QTc, PR and RR intervals, heart rate, 
QRS duration, T wave morphology, 
presence of U waves and outlier 
assessment
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Objectives
Endpoints
•
To investigate the relationship between 
the genetic polymorphisms of CYP2C9 
and the pharmacokinetics of MK-8189. 
Variation in CYP2C9 alleles may be 
analyzed for association with any 
laboratory or clinical data collected in this 
study.
•
Germline genetic variation in CYP2C9 
and association to clinical data 
collected in this study
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind, multiple-
panel study of MK-8189 in participants with schizophrenia.
Panels A and A-1 will enroll up to 12 participants each with schizophrenia (9 on active and 
3 on placebo). Participants will be randomized to receive orally administered rising-doses of 
MK-8189 or placebo. For Panel A, participants will receive MK-8189 48 mg/placebo Day 1, 
MK-8189 60 mg/placebo Day 2. For Panel A-1, participants will receive MK-8189 
48 mg/placebo Day 1, MK-8189 80 mg/placebo Day 2.
Panel C will initiate if the dose regimen in Panel A and Panel A-1 are found to be generally 
well tolerated. Panel C will enroll up to 30 participants with schizophrenia (18 on active and 
12 on placebo). Participants will be randomized to receive orally administered rising-doses of 
MK-8189 or placebo; MK-8189 48 mg/placebo Days 1-2, MK-8189 80 mg/placebo Day 3.
Following completion of dosing in each Panel A and Panel A-1, the decision on which dose 
regimen to evaluate next per Figure 2 will be made jointly by the investigator and sponsor 
following a review of the adverse event data. The dose regimen selected will be documented 
in a Protocol Clarification Letter.
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Figure 2
Study Design – Decision Tree
If applicable, participants will be washed off their current antipsychotic therapy.  The 
washout may start with a down titration of the antipsychotic treatment during the screening 
phase per direction of the investigator.  Participants should not receive antipsychotics for at 
least 5 days or 3 half-lives (whichever is longer) prior to Day -1.  For longer half-life 
antipsychotics (eg, aripiprazole and brexpiprazole), if deemed appropriate by the 
investigator, a participant may stop treatment (ie,cessation of atypical antipsychotic therapy) 
as an outpatient, but should be confined to the clinical research unit within a week of 
stopping treatment and minimally beginning on Day -6.  If participants are not currently 
receiving antipsychotic therapy, they will be domiciled beginning on Day -1 through 72 
hours post dose in Panels A and A-1, on Day -2 through 72 hours post dose in Panel C.  All 
participants in Panel C will have 24-hour Holter recordings on Day -1, which will be 
considered baseline, as specified in the SoA. In addition, Holter monitoring recordings and 
blood sampling for PK will be conducted on days and timepoints specified in the SoA up to 
72 hours following the last dose administration. Blood sampling for PK will be within 10 
minutes of the end of the ECG extraction period. Participants in Panel C should be 
encouraged to have periods of ambulation, outside of the rest periods required prior to and 
during Holter extraction, to procure wide ranges of heart rates on Day -1 to support the 
concentration-QTc analysis.
Following 72- hour assessments, antipsychotic standard of care may be restarted. At the 
investigator’s discretion, the participant may be domiciled for a longer duration if up titration 
is observation is required.
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Titration will occur per the investigator’s medical discretion based on the tolerability of 
MK-8189 within an individual participant. Anytime during the dose escalation, if the 
investigator deems it necessary, dose escalation within an individual may be paused 
temporarily for the duration of any tolerability issues involved and resumed immediately at 
the next dose level. Any changes to the dose regimen will not prolong an individual’s 
participation in the trial and therefore it is acknowledged that failure to adhere to the 
protocol-defined titration regimen may result in some participants not reaching the escalation 
targets. Regardless of the state of the dose escalation of each participant it is important to 
keep participants in the study as the data collected at all doses could still be valuable for the 
purposes of defining a clinical tolerability margin. In Panel C, the 24-Holter extraction and 
PK sampling will not be repeated within an individual at the same dose level. Any changes to 
the protocol specified treatment regimen will be documented in a Protocol Clarification 
Letter.  
Because this is a Phase 1 assessment of MK-8189 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The adaptive nature of this study design allows for the exploration of the safety and
tolerability of multiple ascending dose regimens to support both a TQT study (Panels A, A-1) 
and concentration-QT analysis (Panel C). This study will allow for the selection of the 
optimal dose-regimen for a TQT study.  To support a TQT study, the dose evaluated should 
achieve peak concentrations that are approximately 2-fold the steady-state Cmax following 
administration of the highest clinical dose of MK-8189.  Titration within an individual per 
protocol will be based on the tolerability profile (AE data) and will be at the discretion of the 
investigator. Prior to this amendment, Panel A was completed. Eleven participants were 
enrolled and all completed treatment per protocol and the dose regimen was found to be well 
tolerated. Preliminary PK analysis from this panel showed exposures were not sufficient to 
support a TQT study; mean peak concentrations approximated only 1.7-fold the predicted 
steady-state Cmax following administration of 24 mg vs the required 2-fold multiple. As 
such, this amendment is including Panel A-1 to evaluate the safety, tolerability, and PK of 
MK-8189 48 mg administered on Day 1 and 80 mg administered on Day 2.
In order for concentration-QT analysis (Panel C) to negate the need for a TQT study, key 
elements must be included in the study design including 1) administration of a dose that 
provides concentrations that are at least 2-fold those observed at the highest clinical dose 
when administered under conditions where exposures are expected to maximally increase.  In 
the case to MK-8189, this scenario would be co-administration of MK-8189 with a CYP3A 
inhibitor, which results in a 27% increase in peak concentrations. 2) a sufficient sample size 
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(evaluable data from 12 active and 8 placebo) and 3) robust ECG assessments time-matched 
to PK assessments.  In addition, if an exposure of 2-fold the high clinical exposure scenario 
cannot be achieved, a lower exposure multiple may be acceptable if non-clinical data also 
support the lack of a QT effect at sufficient margins to the clinical dose (ICH E14 and S7B 
Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential-Questions and Answer-Guidance for the Industry August 2022 (Final)) [European 
Medicines Agency 2022]. Thus, in Panel C, this study will collect Holter recordings for 24-
hour periods at multiple dose levels, with additional recordings at 48 and 72 h following the 
last dose to assess the ECG parameter intervals across a wide range of concentrations. 
Replicate ECGs and central core lab assessments are incorporated in the design to assess 
ECG intervals with reduced variability. The PK assessments on the same days/timepoints 
will facilitate further exploration of temporal and concentration dependance on ECG 
parameters.
As all participants are domiciled throughout the trial, there is adequate monitoring for any 
safety concerns and participants will be continued to be domiciled for 72 hours following the 
last dose of study intervention. Thus, the sponsor feels the evaluation of a dose regimen to 
support a TQT study or concentration-QT analysis can be evaluated safely.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Not Applicable
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of neurological exams, physical exams, ECGs, 
VS, and laboratory safety tests. The C-SSRS will be administered to monitor mood and 
suicidal ideation and behavior in all trial participants (see Section 4.2.). 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.
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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.
4.2.1.3
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189. Therefore, individual 
plasma concentration and actual sample collection times of MK-8189 will be used to derive 
the PK parameter values AUC0-24, Cmax, Tmax, C24, CL/F, Vz/F, and apparent t1/2.
4.2.1.4
Pharmacodynamic Endpoints
An exploratory objective of this trial is to evaluate effects of a supra-therapeutic dose of MK-
8189 on QTc interval in participants with schizophrenia. The potential effect of a drug on 
cardiac repolarization can be measured as prolongation of the QT interval on ECG 
recordings. There is, in general, a qualitative relationship between substantial QT 
prolongation and the risk of TdP. The rationale for the endpoint is thus to demonstrate that 
MK-8189 does not meaningfully prolong (i.e. >10 msec) the QTc interval.
In Panel C, electrocardiogram data (eg, QT, QRS, RR and PR intervals) will be obtained with 
a digital Holter device on study days specified in the SoA.  A 24-hour Holter will also be 
conducted on Day -1 such that ECG data can be extracted at timepoints time-matched to 
post-dose assessments as specified in the SoA.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
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The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome CYP2C9 will specifically be 
investigated for association with the PK and PD endpoints 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.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR 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 FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
As the safety and tolerability profile is under continued evaluation and limited data is 
available at higher doses of MK-8189, a placebo-control will be included in this trial to 
ensure objective assessment of AEs. A placebo arm is also required to support the 
concentration-QTc analysis and helps to avoid false positive and false negative results; in
some instances study conditions have been found to prolong or shorten QT and placebo-
correction is required to determine the true effect of the drug.
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
As this is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
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regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.3.1
Starting Dose for This Study
In Panel A, A-1 and C, the starting dose will be MK-8189 48 mg/placebo.  A starting dose of 
24 mg/placebo was well tolerated in participants with schizophrenia in P011 (Section 2.2.3)
Multiple doses of 48 mg (3 consecutive days) have been evaluated in participants with 
schizophrenia in P007, a multiple ascending dose study. In P007, participants were titrated 
from 8 mg to 48 mg.  There were no clear trends for dose related increases in specific AEs 
and the 48 mg dose was found to be generally well tolerated. The majority of AEs were mild 
to moderate in severity.  Adverse events (n, %) occurring in more than one participant were 
dizziness (3, 27%), nausea (2, 18%) and anxiety (2, 18%).  One of the AEs of anxiety was 
considered severe and unrelated to study intervention. The AE began one day after the last 
dose of MK-8189 and resolved within the 3 days. Though this starting dose is 2-fold 
previously explored, enzyme occupancy of 
 
These data support the exploration of a 48 
mg starting dose in the current protocol. Panel C will only be conducted if the starting dose 
of 48 mg in Panel A is generally well tolerated.
Preliminary blinded data from Panel A demonstrated good tolerability of MK-8189 
48 mg/placebo administered on Day 1 and MK-8189 60 mg/placebo administered on Day 2. 
There were no deaths or SAEs. Four of the 11 participants reported 5 AEs of mild severity. 
The following treatment-related AEs (duration) were reported; discomfort (3 days), leg 
tremor (2.5 weeks) and headache (2 days). There were no trends for clinical meaningful 
changes in safety laboratory values, VS, or ECGs.
4.3.2
Maximum Dose/Exposure for This Study
The highest dose evaluated in this study will be 80 mg which will be administered for one 
day. In the current protocol, a single dose of 60 mg was found to be well tolerated as 
described above in Section 4.3.1.  Previously the highest dose evaluated in participants with 
schizophrenia was 48 mg which was found to be generally well tolerated as described in 
Section 4.3.1 above. In healthy participants the highest dose evaluated was 72 mg/placebo 
(n=8) in P016 (see section 2.2.3.6). Data from P016 are preliminary and blinded. In P016, 
poorer tolerability was observed in some participants at the 48 mg dose such that 4 of 12 
participants on MK-8189/placebo did not dose escalate above 48 mg). The tolerability issues 
may have been due to the rapid titration above 24 mg/placebo in Protocol 016.  Of the 8 
participants that dose escalated to 72 mg/placebo, 5 reported AEs.  The majority of AEs were 
mild in severity.  Adverse events included: nausea (n=2), nightmare (n=1), insomnia (n=1), 
tremor in legs (n=1), muscle twitches (n=1), dystonia (n=1), staring (n=1), decreased appetite 
(n=1), headache (n=2), xerostomia (n=1), hot flashes (n=1), closed eye hallucination (n=1), 
pyrosis (n=1), muscle spasms (n=1), emotional instability (n=1), globus pharynges (n=1), 
hoarseness (n=1), akathisia (n=1).  As all AEs are monitorable and reversible, escalating to 
80 mg under domiciled conditions where participants are closely supervised is supported.
CCI
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Moreover, across the multiple ascending dose studies (P003, P007 and P011), there was no 
dose relationship for specific AEs, including akathisia, somnolence, anxiety, nausea and 
vomiting.
The 80 mg dose was previously predicted to provide exposures 2-fold the high clinical 
exposure scenario (the highest possible clinical dose of MK-8189 coadministered with a 
strong CYP3A inhibitor) and support a concentration -QTc analysis that could negate the 
need for a much larger TQT study in patients. However, preliminary PK data from Panel A 
following a 60-mg dose of MK-8189 suggest that sufficient exposures may not be achieved 
following an 80-mg dose. However, exposures following an 80 mg, or lower dose if 80 mg is 
not generally well tolerated in Panel A-1, may be sufficient to support an integrated waiver 
assessment per ICH E14 &S7B Q&A [European Medicines Agency 2022].
The predicted exposure at 80 mg is 71.5 μM∙hr and the margin to the AUC0-24 for an 80 mg 
dose, as derived from the 6-Week and chronic toxicology studies, would be 5-12X and ~2 
fold, respectively, further supporting evaluation of this supratherapeutic dose.  Brief 
summaries of the 6-Week and chronic toxicology studies supporting dose escalation are 
provided below:
In the 6-Week rat study, doses of 25, 50 and 1000 mg/kg/day of MK-8189 were evaluated.  
There were no adverse findings in the study; therefore, the no observed adverse effect level 
(NOAEL) was 1000 mg/kg/day (12-fold in females (AUC0-24hr = 822 ∙hour) and 9-fold in 
males (AUC0-24hr = 653 ∙hour) over the predicted supratherapeutic exposure of 71.5 μM∙hr 
at the 80 mg dose).  The functional observational battery (FOB) evaluation conducted on 
Study Day 1 showed findings at all dose levels that consisted of non dose-dependent 
decreases in the mean number of line crosses and rears, and very slight, dose-dependent 
CCI
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decreases in mean body temperature. In addition, an absence of motor activity (akinesis) was 
noted in 1 of the 6 high-dose animals tested. Collectively, these observations are consistent 
with mild sedation. Importantly, these animals retained normal ability to respond to external 
stimuli as evidenced by normal responses to the noise, touch and approach stimuli. These 
findings were considered transient as they were not present before the subsequent dose on 
Study Day 2.
In the 6-Week monkey study, doses of 10, 30 and 300 mg/kg/day were administered.  
Pharmacologically-mediated physical signs were observed across all dose groups and 
consisted of somnolence, increased/decreased activity, unsteady gait, increased 
licking/chewing/chomping motion, vocalization, intermitted recumbency, intermitted whole 
body trembling, and/or salivation.  These physical signs were considered transient, reversible 
and consistent with the expected pharmacology of PDE10A inhibition.  The NOAEL in this 
study was 300 mg/kg/day (AUC0-24hour = 333 ∙hour) providing an exposure margin of 5 
fold over the predicted supratherapeutic exposure of 71.5 μM∙hr at the 80 mg dose.    
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 (study week 13 and study 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 2-fold over the predicted 
supratherapeutic exposure of 71.5 μM∙hr at the 80 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. Similar to the 6-Week study, pharmacologically-mediated transient and 
reversible physical signs were observed in all dose groups in the study.  In addition, 
beginning in Study Week 8 of this study, reversible physical signs of uncoordinated 
movements were observed down to the low-dose level.  Due to the severity of the 
uncoordinated movements, the low-dose level had to be lowered (30 to 3 mg/kg/day) to 
increase tolerability of the test article.  Based on these findings, the NOAEL for physical 
signs was <3 mg/kg/day. 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 a 2-fold over the predicted supratherapeutic exposure of 71.5 μM∙hr at 
the 80 mg dose.
The effects of MK-8189 on measures of cardiac conduction and repolarization were assessed 
in both in vitro (hERG current [IKr] evaluation) and in vivo (anesthetized guinea pigs and 
conscious telemetered monkey models). MK-8189 inhibited hERG current with an IC50 
value of 81.9 μM, providing large margins (546-fold) to the projected median unbound Cmax 
at the supratherapeutic dose of 80 mg in humans (0.15 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 ~63-fold relative to the projected clinical Cmax at the 80 mg 
dose of 3.75 μM. In anesthetized rhesus monkeys, MK-8189 had no effect on CV parameters 
during rising IV doses up to a 27 μM plasma concentration (~7-fold above the projected 
clinical Cmax at 80 mg of 3.75 μM).
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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 (projected Cmax value of ~0.16 μM, estimated from a 6-week 
toxicity study [<1- fold of the projected clinical Cmax at 80 mg of 3.75 μM]). 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. 
Furthermore, a concentration-QTc analysis was conducted in P007 and as shown in Figure 4
there is no evidence for a relationship between concentration and QTc at MK 8189 exposures 
achieved with the 48 mg dose.  Therefore, preclinical and clinical data support dose 
escalation to 80 mg in the current study.  In addition, during the study safety and tolerability 
will be carefully assessed.  Dose escalation may be stopped within an individual or the study 
based on tolerability.
Figure 4
Predicted Mean ΔΔQTcF Versus the Observed Geometric Mean Cmax for Each 
Dose Level Along With 90% Confidence Band
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4.3.3
Rationale for Dose Interval and Study Design
MK-8189 is formulated as a controlled-release tablet intended for QD administration.  To 
date most multiple ascending dose studies have been conducted as a within participant 
titration.  The within participant titration was introduced based on results from the single-
ascending dose trial (P001) in healthy participants, where following treatment with the 3-mg 
and 6-mg IR formulation, dystonia was observed around the time of peak MK-8189 
concentration (See IB for details). One hypothesis for the observed acute dystonia is that the 
high MK-8189 IR formulation peak to trough ratio led to rapid-cycling of MK-8189 on and 
off the target enzyme, PDE10A. In addition to successfully reducing the peak-to-trough ratio 
through development of the CR formulation (4 with the IR vs 1.3 with the CR), a titration 
approach in the target patient population was implemented in the multiple ascending dose 
studies (P003 and P007) and the POC (P005) study, which significantly reduced the rate of 
observed EPS and dystonia and permitted evaluation of doses and exposures significantly 
greater than could be achieved tolerably with the IR formulation. Of note, in P007, where the 
highest likely clinical dose of 24 mg as well as supratherapeutic doses up to 48 mg have been 
evaluated, no MK-8189 -related dystonia has been reported in healthy participants or 
participants with schizophrenia. The peak concentration values at the 24-mg dose are ~1.7-
fold those observed following 6 mg of the IR formulation, suggesting the absolute 
concentration is not a driver of dystonia. Across P003 and P007 the starting dose of the CR 
formulation has increased from 2 mg to 4 mg to 8 mg without an increase in the incidence in 
dystonia. Furthermore, Part 1 of P011 was conducted to evaluate the need for titration in 
participants with schizophrenia. As described in section 2.2.3 (preliminary and blinded data), 
initiating dosing at 24 mg/placebo was generally well tolerated in participants with 
schizophrenia.  In this panel of participants, no AEs of EPS were reported. 
As this study continues to explore safety and tolerability of supratherapeutic doses to support 
the evaluation of concentration-QT effect, a titration approach will be implemented, though it 
will be more aggressive than earlier studies. 
In Panel A and Panel A-1 in participants with schizophrenia, participants will initiate dosing 
at MK-8189 48 mg mg/placebo (Day 1) and escalate to MK-8189 60 mg/placebo in Panel A 
(Day 2) and 80 mg in Panel A-1 (Day 2). If generally well tolerated, one of these regimens
would allow for rapid attainment of the necessary exposures to satisfy a TQT study and 
minimize MK-8189 exposure and shorten the duration of the TQT study. Additionally, if 
well tolerated, Panel C will be conducted to support an integrated (non-clinical and clinical)
concentration-QT analysis per ICH E14 & S7B Q&A [European Medicines Agency 2022]
where doses will be escalated to MK-8189 80 mg/Placebo to potentially negate the need for a 
TQT study.
This study should define the highest tolerated dose that may be explored in a TQT study.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
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completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data are to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1.
Is in good health based on medical history, physical examination, VS measurements, 
and ECGs performed at the screening visit and/or prior to randomization.  The 
assessment prior to randomization is based on the mean of triplicate measures.  Note:  
TheQTcF-duration must be ≤450 msec, the QRS duration <120 msec and the PR 
interval <200 msec.  Repeat 12-lead safety ECGs may be performed in participants 
whose parameters are, per investigator discretion, minimally outside the designated 
range.
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2.
Have a normal resting blood pressure (systolic blood pressure is ≥90 mm Hg and ≤140 
mmHg; diastolic blood pressure is ≥60 mmHg and ≤90 mmHg) and normal resting 
heart rate (≥45 beats per minute [bpm] and ≤100 bpm) in the supine position at the pre-
trial (screening) visit and/or prior to randomization. Repeat evaluations may be done if 
the values for a participant are, per investigator discretion, minimally outside the 
designated range. The assessment prior to randomization is based on the mean of the 
triplicate measures. Participants may be included if values are outside the normal range 
but considered not clinically significant per investigator discretion.
3.
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.
4.
Have a Body Mass Index (BMI) > 18.5 and ≤ 40 kg/m2, inclusive, and total body 
weight of > 50 kg (110 lbs) at the screening visit. See Section 8.3.2 for criteria on 
rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
5.
Participants with hypothyroidism, diabetes, high blood pressure, 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 co-medication 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 
Diagnostic and Statistical Manual of Mental Disorders (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.
8.
Has a total Brief Psychiatric Rating Scale (BPRS) score of < 48 with a BPRS score < 4 
for #10 (hostility) and #14 (uncooperativeness) at the screening visit. 
9.
Is in the non-acute phase of their illness and clinically stable for 3 months prior to 
screening as demonstrated by:
a.
no clinically significant change in dose of prescribed antipsychotic medication, or 
clinically significant change in antipsychotic medication to treat symptoms of 
schizophrenia for two months prior to screening;
b. no increase in level of psychiatric care due to worsening of symptoms of 
schizophrenia for three months prior to screening.
Note: participants that are stable but not currently taking antipsychotic medications are 
eligible.
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10.
Has a history of receiving and tolerating antipsychotic medication within the usual dose 
range employed for schizophrenia. 
11.
Participant is able to discontinue the use of all antipsychotic medication at least 5 days 
or 3 half-lives (whichever is longer) prior to Day -1 and during the study period
Demographics
12.
Is male or female, from 18 years to 55 years of age inclusive, at the time of providing
informed consent. An attempt will be made to enroll approximately 40% of female 
participants.
Female Participants
13.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses 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. Contraceptive use by 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies
-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 72 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 
in Section 8.3.5 and Appendix 2.
Medical history, menstrual history, and recent sexual activity has been reviewed by the 
investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
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Informed Consent
14.
The participant has provided documented informed consent for the study. The 
participant may also provide consent for future biomedical research (FBR). However, 
the participant may participate in the study without participating in FBR.
Additional Categories
15.
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 meets any of the following 
criteria:
Medical Conditions
1.
Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, 
respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, 
immunological or cerebrovascular disease, malignance, allergic disease or other chronic 
and/or degenerative process at screening.
2.
Has any clinically significant abnormal laboratory, VS, physical examination, or 12-
lead safety ECG findings at screening or changes from baseline that may interfere with 
the interpretation of PK or safety parameters or, in the opinion of the investigator, 
would make the participant inappropriate for entry into this study.
3.
Is at imminent risk of self-harm, based on clinical interview and responses on the 
C-SSRS, or of harm to others in the opinion of the investigator.  Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method 
(eg, positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) 
in the past 2 months or suicidal behavior in  the past 6 months. 
4.
Is a WOCBP who has a positive serum pregnancy test at the screening visit or a urine 
pregnancy test within 72 hours before the first dose of study intervention. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
5.
Has a history of cancer (malignancy).
Exceptions: (1) Participants with adequately treated nonmelanomatous skin carcinoma 
or carcinoma in situ of the cervix may participate in the study; (2) Participants with 
other malignancies which have been successfully treated ≥10 years prior to the prestudy 
(screening) visit where, in the judgment of both the investigator and treating physician, 
appropriate follow-up has revealed no evidence of recurrence from the time of 
treatment through the time of the prestudy (screening) visit (except those cancers 
identified at the beginning of this exclusion criteria); or (3) Participants, who, in the 
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opinion of the study investigator, are highly unlikely to sustain a recurrence for the 
duration of the study
6.
Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than 
schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria within one 
month of screening.
7.
Has evidence or history of mental retardation, borderline personality disorder, or 
organic brain syndrome.
8.
Has a history of neuroleptic malignant syndrome or moderate to severe tardive 
dyskinesia.
9.
Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse. 
10.
Has a DSM-5 defined substance use disorder (excluding nicotine and caffeine) within 3 
months of screening.
11.
Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures. 
12.
Has a clinically significant history or presence of sick sinus syndrome, first, second, or 
third degree AV block, myocardial infarction, pulmonary congestion, cardiac 
arrhythmia, prolonged QTc interval, or conduction abnormalities.
13.
The participant meets any of the following cardiac parameters: a history of risk factors 
for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT 
syndrome), uncorrected hypokalemia or hypomagnesemia, or is taking concomitant 
medications that prolong the QT/QTc interval. Abnormal serum calcium at Screening 
or prior to dosing.
14.
Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
15.
Has a family history of cardiac sudden death
16.
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.
17.
Has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic 
allergic reaction) to prescription or non-prescription drugs or food.
18.
Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
19.
Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the prestudy (screening) visit.
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Prior/Concomitant Therapy
20.
Has received or is currently receiving treatment with clozapine (eg, for treatment of
schizophrenia) for any length of time. Has received treatment with monoamine oxidase 
inhibitors within 3 months of screening or cariprazine within 2 months of screening.
21.
Is unable to be washed off their parenteral depot antipsychotic medication prior to
screening or requires a dose of a parenteral depot antipsychotic medication during the
study.
22.
Is unable to refrain from the use of co-medication that is a moderate or strong inhibitor
or inducer of CYP3A or moderate or strong inducer of CYP2C9 beginning 
approximately 2 weeks or 5 half-lives, whichever is longer, prior to administration of 
the initial dose of trial drug and throughout the trial. (see Section 6.5).
23.
Has received any nonlive vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any nonlive vaccine through 30 days following study intervention. 
Exception: COVID-19 vaccine may be administered. Study intervention must be given 
at least 72 hours following or at least 48 hours prior to any COVID-19 vaccination.  
Investigational COVID-19 vaccines (i.e., those not licensed or approved for Emergency 
Use) are not allowed.
Prior/Concurrent Clinical Study Experience
24.
Participated in another investigational study within 4 weeks (or 5 half-lives, whichever 
is greater) prior to the prestudy (screening) visit. The window will be derived from the 
date of the last visit in the previous study.
Diagnostic Assessments
Not applicable.
Other Exclusions
25.
Under the age of legal consent.
26.
Is a smoker that does not agree to follow the smoking restrictions as defined by the 
CRU.
27.
Consumes greater than 3 servings of alcoholic beverages (1 serving is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume 4 servings of alcoholic 
beverages per day may be enrolled at the discretion of the investigator.
28.
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.
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29.
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.
30.
The investigator has any concern regarding safe participation in the study or for any 
other reason the investigator considers the participant inappropriate for participation in 
the study.
31.
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
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.
During the study participants will fast from all food and drinks, except water, for at least 8
hours before study and during intervention administration. Participants will fast from all food 
and drinks, except water, between study intervention administration until 1 hour post dose.
Meals and snack(s) will be provided by the investigator at time points indicated in the SoA. 
Participants will fast from all food and drinks, except water, between meals and snacks. For 
multicenter studies the meal content should be consistent within a given clinical site. Meals 
and snacks will be served after any coinciding Holter and/or PK procedure.  
The caloric content and composition of meals will be the same. After the 24-hour postdose 
procedures have been completed in Panels A and A-1, subsequent meals and snacks will be 
unrestricted in caloric content, composition and timing.
Water will be provided during study intervention administration. Water will be restricted 
1 hour before and 1 hour after study intervention administration.
Meal and water restrictions on Day -1 will be time-matched to those timepoints on 24-hour 
Holter/PK days when treatment is administered.  Similarly, during intermediate days and the 
days following the last scheduled dose, meal and water restrictions will be time-matched to 
24-hour Holter/PK days when treatment is administered.
Each study intervention administration will need to be taken with water. Water will be 
restricted 1 hour before and 1 hour after study intervention administration.
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5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention, throughout the study and until the poststudy visit.
On full PK sampling days (ie, Panels A and A-1 Days 1-2, Panel C Days 1-3), participants 
will refrain from the consumption of all fruit juices 24 hours before study intervention
administration and during the entire day.
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 before the prestudy and poststudy visits. On full PK sampling days 
(ie, Panel A and A-1 Days 1-2) and 24-hour Holter monitoring days (ie, Panel C Days 1-3),
participants will be permitted to consume approximately 2 units of caffeinated beverages or 
xanthine-containing products only between 1 hour and 2 hours post dose. Otherwise, 
participants will refrain from consumption of such products 8 hours prior to study drug 
administration until the 24- hour postdose ECG/PK assessment is complete.
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before the prestudy and 
poststudy visits. During the in-house period, consumption of alcohol is not allowed. At all 
other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent servings (1 serving is approximately equivalent to: beer 
[354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking restrictions (and if applicable, the use of nicotine/nicotine-containing products) 
defined by the CRU will be followed during the study.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods) and until the poststudy visit.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered 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 replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study intervention(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Panel A 
Active
Experimental
MK-8189
Drug
Tablet
12 mg
48 mg
60 mg
Oral
Panel A
Test 
Product
IMP
Provided 
centrally
Panel 
A-1 
Active
Experimental
MK-8189
Drug
Tablet
12 mg
4 mg
48 mg
80 mg
Oral
Panel A-1
Test 
Product
IMP
Provided 
centrally
Panel C 
Active
Experimental
MK-8189
Drug
Tablet
12 mg
4 mg
48 mg
80 mg
Oral
Panel C
Test 
Product
IMP
Provided 
centrally
Placebo
Placebo 
Comparator
MK-8189
Drug
Tablet
0 mg
All 
dosage 
levels
Oral
All Panels
Placebo
IMP
Provided 
centrally
IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area 
(EEA). Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation schedules are provided in Table 2 (Panel A), Table 3 (Panel A-1), 
Table 4 (Panel C).
Table 2
Panel A Schizophrenic Sample Allocation Schedule
na
Day 
1
Day 
2
9
48 mg
60 mg
3
PBO
PBO
a An attempt will be made to enroll approximately 40% female participants
Note: The allocation scheduled will be stratified to females and males. 
Female participants will be assigned the low allocation range and male 
participants will be assigned the upper allocation range.
Table 3
Panel A-1 Schizophrenic Sample Allocation Schedule
na
Day 
1
Day 
2
9
48 mg
80 mg
3
PBO
PBO
a An attempt will be made to enroll approximately 40% female participants
Note: The allocation scheduled will be stratified to females and males. 
Female participants will be assigned the low allocation range and male 
participants will be assigned the upper allocation range.
Table 4
Panel C Schizophrenic Sample Allocation Schedule
na
Day 
1
Day 
2
Day
3
18
48 mg
48 mg
80 mg
12
PBO
PBO
PBO
a An attempt will be made to enroll approximately 40% female participants
Note: The allocation scheduled will be stratified to females and males. 
Female participants will be assigned the low allocation range and male 
participants will be assigned the upper allocation range.
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6.3.2
Stratification
The allocation schedules will be stratified to females and males. Female participants will be 
assigned the low allocation range and male participants will be assigned the upper allocation 
range to attempt to ensure approximately 40% of females.
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 and the investigator who is involved in the study intervention administration 
or clinical evaluation of the participants are unaware of the group assignments.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified 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
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
Paracetamol/acetaminophen (up to 4 g per day) and ibuprofen (up to 1.2g per day) and 
antacids (eg, magnesium hydroxide) may be used for minor ailments without prior 
consultation with the Sponsor.
For participants with schizophrenia, 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 moderate or strong inducers of CYP2C9 are not allowed.  
In addition, the following concomitant medications/vaccinations are permitted:
•
Nonlive vaccines may only be administered in consultation with the Sponsor prior to or 
following the receipt of study intervention according to the time frames specified in 
Exclusion Criteria (Section 5.2).
Exception: COVID-19 vaccine may be administered. Study intervention must be given at 
least 72 hours following or at least 48 hours prior to any COVID-19 vaccination.
Investigational COVID-19 vaccines (i.e., those not licensed or approved for Emergency Use) 
are not allowed. The Sponsor Clinical Director should be contacted if there are any questions 
regarding concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
For the treatment of EPS, such as acute dystonia, all participants may be treated with an 
anticholinergic. If the symptoms are unresponsive to anticholinergic treatment or not 
recommended based on a participant’s medical history/concomitant medication, a 
benzodiazepine can be used.
In case the participant presents with signs of akathisia without signs of dystonia, the 
participant can be treated with a β-adrenergic blocker. If symptoms do not disappear with the 
β-adrenergic blocker, treatment with an anticholinergic may be used.  An anticholinergic may 
be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred 
treatment based on a participant’s medical history and/or concomitant medication.
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Anticholinergics benzodiazepines and β-adrenergic blockers are often used in the treatment 
of EPS and are considered standard practice. Oral anticholinergic treatment is also used as 
concomitant medication to prevent EPS symptom with antipsychotic medication.
Participants with schizophrenia will be washed off from their antipsychotic treatment.  The 
duration of washout period should be at least 5 days or cover at least 3 half-lives of the drug 
(whichever is longer) prior to Day -1 assessments (this includes any rescue medication given 
during the washout period).  During the washout and treatment period, a benzodiazepine and 
zolpidem may be used to treat withdrawal symptoms. The drugs indicated above should not 
be moderate or strong inhibitors or inducers of CYP3A or moderate or strong inducers of 
CYP2C9 (see Section 6.5 for further details), thus no effect on the PK of MK-8189 would be 
expected during co-administration.
6.6
Dose Modification (Escalation/Titration/Other)
If, as judged by the Sponsor and/or 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
•
Dosing may be stopped 
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 after 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.
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6.9
Standard Policies
Not applicable
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.As 
certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if 
the participant has discontinued study intervention. Therefore, all participants who 
discontinue study intervention before completion of the protocol-specified treatment 
period/vaccination 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.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
Participants with severe EPS symptoms will be discontinued if not attenuated with dose 
reduction, titration, or medical management.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive UDS at any time during the course of the study. The drug 
screen can be confirmed by a recheck at the discretion of the investigator after discussion 
with the Sponsor.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
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.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 225 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 informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
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and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
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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 of 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.
Washout from Antipsychotics:
All participants will be washed out from their antipsychotic medication prior to Day -1 
Holter assessment. The washout may start with a down titration of the antipsychotic 
treatment during the screening phase.
Participants may restart their antipsychotic therapy following completion of the 72 hour post 
last dose study procedures.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are 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 allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff. Participants 
will fast from all food and drinks, except water, for at least 8 hours prior to all doses of 
MK-8189. Approximately 240 mL of water will be provided during study drug 
administration, but will be restricted 1 hour prior to and 1 hour post dose. Site staff will 
ensure that participants have swallowed study treatment.
8.1.8.1
Timing of Dose Administration
Participants will be dosed according to the SoA (Section 1.3). MK-8189 Treatment 
administration will be in the AM at approximately the same time each day (within a 30 
minute window) and will occur after an 8-hour overnight fast. Participants will fast from all 
food and drinks, except water, between study intervention administration and the first 
scheduled meal. Participants will receive each oral dose of MK-8189/placebo with ~240mL 
of 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 8.11.4 to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a follow-
up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any AEs 
have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
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information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the
intensityof the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.11
Domiciling
Participants in Panel A and Panel A-1 will be domiciled in the study unit minimally from 
Day -1 until Day 5 procedures are complete. Participants in Panel C will be domiciled in the
study unit minimally from Day -2 until Day 6 procedures are complete.
For any participant who is required to wash off antipsychotic therapy, domiciling will begin 
on Day -6. At the discretion of the investigator, participants may be requested to remain in 
the CRU longer.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
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calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
There are no direct efficacy assessments in this study; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Complete physical examinations will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. at prespecified 
timepoints noted in the SoA (Section 1.3). Height and weight will also be measured and 
recorded.
Brief directed physical examinations will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard at 
prespecified timepoints noted in the SoA (Section 1.3).
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed at 
prespecified timepoints noted in the SoA (Section 1.3). 
•
BP and heart rate measurements will be assessed in a supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
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8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a supine position for at 
least 10 minutes before having VS measurements obtained. Supine VS will include HR, 
systolic and diastolic BP, RR, and body temperature at timepoints indicated in the SoA. The 
correct size of the BP cuff and the correct positioning on the 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 at the 9 hour post dose equivalent timepoint on Day -1. The mean of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). Postdose VS measurements will be single 
measurements.
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 within a given clinical 
site
8.3.2.2
Orthostatic Vital Signs
During Panels A-1 and C, orthostatic VS (HR and systolic and diastolic BP) will also be 
obtained following resting HR and BP measurements. Participants should be supine for at 
least 10 minutes and then stand upright for 2 minutes prior to measurement of orthostatic VS.
8.3.3
Electrocardiograms
Triplicate 12-lead ECG on Day -1 will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
[QTc] intervals. Refer to Inclusion/Exclusion criteria and Appendix 9 for eligibility 
assessment and potentially significant findings.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the supine for at least 10 minutes before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
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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.
Predose ECGs will be obtained per the schedule of activities on Day -1. These measurements 
will be used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed).
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 (Day -1) 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.
During each treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The mean value of the QTc 
interval from the 3 ECGs will represent the value at that time point. If the mean QTc interval 
is ≥500 msec, the Sponsor should be notified and the ECGs should be reviewed by a 
cardiologist. The participant should be telemetry monitored (until the QTc is <500 msec) or 
should be considered for transfer to a location where closer monitoring and definitive care 
(eg, a CCU or ICU) is available.
If at any time the QRS duration is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc 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.
24-Hour Holter Assessment
For the entire 24-hour Holter recording duration, participants should not wear metal jewelry 
such as watches, necklaces, and/or bracelets from the waist up. Participants must also not use 
electronic devices such as cell phones, computers/laptops, MP3 players, etc. during Holter 
recording. Holter recording will be turned on approximately 30 minutes prior to trial drug 
administration. Participants will not be allowed to shower/bath for the duration of the 24-
hour Holter assessment. 
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Holter data will be extracted (in triplicate) and analyzed using automated and semi-
automated methods by a blinded core ECG laboratory according to a pre-specified algorithm. 
To minimize artifacts, participants must rest quietly in a supine position for ~10 minutes
prior to the time points specified for extraction. The extraction window will be 10 minutes. 
No other study assessments or procedures should occur during the resting period. 
Holters may be removed and reapplied (same Holter used by the same participant) per the 
instructions in the Acquisition Guide for Holter-recordings provided by the ECG vendor.  
Lead placement must be marked anytime electrodes are removed.  
See the Acquisition Guide provided by the ECG vendor for specific instructions.
Procedures for transfer, archiving, and review of ECGs will be specified by the ECG vendor.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
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8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness. If the C-SSRS is administered 
by someone other than the investigator, consider providing the completed C-SSRS to the 
investigator for review, before their assessment of the participant and to further inform their 
evaluation. The C-SSRS is not explicit about whether the participant specifically has ideation 
at the time of screening. If a participant reports a prior history of ideation/behavior at 
screening, the assessor should also inquire and document if this is also present at the time of 
the Screening Visit.
8.3.6.2
Monitoring for Extrapyramidal Symptoms
The investigator or qualified designee will complete the BARS, AIMS and SAS at times 
specified in the SoA. Additional assessments at unscheduled times outside of the SoA will be 
conducted by study staff, as soon as reasonably possible, if it is observed or a participant 
reports complaints of dystonia and/or akathisia. 
8.3.7
Assessment of Neuropsychological Effects
A general (full) Neurological Exam will be performed at the Screening visit, Baseline and 
prior to discharge. A targeted Neurological Exam will be administered at times specified in 
the SoA. 
A BPRS evaluation will be performed at Screening, Baseline and will also be completed at 
times specified in the SoA.
The General and Targeted Neurological Exams are contained in Appendix 11.
8.3.8
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption or rash occurrence in determining etiology and drug relationship.
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.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators need to document if an AE and/or SAE was associated with a medication error, 
misuse, or abuse. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation/randomization through 14 days after cessation of 
intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
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Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
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)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable 
event.
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (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
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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:
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
(unless serious)
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 24 hours 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; 
SAE=serious adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized] participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities 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.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of 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.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Disease-related Events and/or Disease-related Outcomes not qualifying as AEs or SAEs are 
not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
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and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3. Severe EPS or EPS leading to study discontinuation
4. Treatment-emergent adverse event of new or worsening tardive dyskinesia
5. Suicidal ideation, suicidal behavior 
6. Moderate or severe depression
7. Moderate or severe mood swings
8. Dystonia
8.4.8
Medical Device and Drug-device Combination Products - PQCs/Malfunctions
Not applicable
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations/Laboratory Manual.
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8.7
Pharmacodynamics
ECG parameter values are extracted from 24-hour Holter monitoring per the SoA.
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 FBR if the participant 
provides documented informed consent for FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
•
Leftover main study plasma from MK-8189 and/or metabolites assay stored for future 
research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Within approximately 6 weeks before intervention allocation/randomization, potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
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 since
there are Day -1 procedures planned per protocol.
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8.10.2
Treatment Period
Participants with schizophrenia that meet selection criteria for enrollment will participate, up 
to 12 participants in each of Panels A, and A-1, and up to 30 participants in Panel C. 
Participants must be washed out from any antipsychotic therapy for at least 5 days or cover at 
least 3 half-lives of the drug (whichever is longer) prior to Day -1. Participants will report to 
the CRU on Day -6 to start their washout period. However, if participants are not currently 
being treated with antipsychotic medications and therefore do not require a washout, they 
may be domiciled on Day -2 in Panel C, or Day -1 in Panels A and A-1.
On treatment days participants will be dosed once daily with MK-8189/placebo and have 
procedures completed per the SoA. Participants will remain in the unit through 72 hours post 
last dose and completion of all procedures and will be discharged at the discretion of the 
investigator.
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.10.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the ECG parameter values extracted from the 24-hour Holter collection and 
time-matched blood samples for MK-8189 are the critical procedures for Panel C.
At any time point, these assessments need to be collected as close to the exact time point as 
possible. The PK sample should follow immediately after the Holter extraction window is 
complete.  All other procedures should be completed as close to the prescribed/scheduled 
time as possible. Study procedures can be performed before or after the prescribed/scheduled 
time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
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Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
1. Holter ECG assessment (extraction period)
2. 12-Lead Safety ECG
3. Resting Blood Pressure and Heart Rate
4. Blood for MK-8189
5. Neurological exams, C-CSSRS, BPRS, BARS, AIMS, SAS
The following variance in procedure collection times will be permitted.
•
PK Collection of samples which are not time-matched to Holter ECG assessments as 
outlined in Table 6.
Table 6
Pharmacokinetic (Blood) Collection Windows for samples not time-matched to 
Holter ECG assessments
PK Collection
PK Collection Window
0 to <1 h
5 min
1 to <24 h
15 min
24 to <48 h
1 h
48 to 168 h
2 h
˃168 h
24 h
•
Predose standard safety evaluations: VS and ECG triplicate measurements on Day -1 
time matched to the 9 hour post-dose equivalent timepoint within 1 hour; physical exam 
within 24 hours and laboratory safety tests within 48 hours prior to dosing.
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam:
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time
-
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
-
From 48-hours to 168-hours postdose may be obtained within 2 hours of the 
theoretical sampling time
•
Study intervention administration (multiple dose studies only): at 30 minutes.
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8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose and/or titration steps of the study intervention 
administered panel
•
Repeat of a panel at the same dose regimen or more conservative dose regimen.
•
Entire period(s) or panel(s) may be omitted
•
Decrease in the duration of study intervention administration (eg, number of days)
•
Adjustment of the dosing interval (eg, divided doses [bid to qd, qd to bid, tid, or vice 
versa])
•
Addition of PK pause
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
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additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Section 9.2).
9.1
Statistical Analysis Plan Summary
Safety: Adverse experiences and discontinuation of study intervention due to adverse events 
will be tabulated. Separately for each panel, 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). Day -1 or Day -
2 readings will serve as baseline for laboratory parameters. Day -1 9-hour reading will serve 
as time-matched baseline for the corresponding post-dose 12-lead ECG and vital sign 
readings.
Summary statistics and plots will be generated for BPRS, BARS, AIMS, SAS, as well as for 
change from baseline. The difference from baseline will be computed on the original scale 
(raw change from baseline). Responses to the C-SSRS will be listed. The Columbia Suicide 
Severity Rating Scale (C-SSRS) will be used to systematically and prospectively ascertain 
and document the occurrence of suicidal events (i.e., ideation and behavior).
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
Medicine 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
The objectives are listed in section 3.0.
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9.4
Analysis Endpoints
Primary Endpoints
Safety endpoints will include adverse experiences and discontinuation of study intervention 
due to adverse events.
Exploratory Endpoints
Safety: Laboratory safety tests, 12-lead ECGs, and VS. Baseline is defined as Day -1 or Day 
-2 readings for laboratory safety tests. Day-1 9-hour reading will serve as time-matched 
baseline for the corresponding postdose 12-lead ECG and vital sign readings.
BPRS, BARS, AIMS, SAS for all participants. The Columbia Suicide Severity Rating Scale 
(C-SSRS) will be used to systematically and prospectively ascertain and document the 
occurrence of suicidal events (i.e., ideation and behavior). 
PK variables: AUC0-24, Cmax, C24, AUC0-inf, Tmax, CL/F, Vz/F, and apparent t1/2.
Cardiodynamics (Panel C only): QTc change from baseline (Holter ECGs), HR, RR interval, 
PR interval, and QRS duration. U and T wave morphology.
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 major protocol deviations.  Major 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 and 
Concentration-QTc analyses.
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9.6
Statistical Methods
Safety
Adverse experiences and discontinuation of study intervention due to adverse events will be 
tabulated. 
Separately for each panel, summary statistics and plots will be generated for raw laboratory 
safety tests, 12-lead ECGs, and VS as well as for change from baseline, as deemed clinically 
appropriate. Depending on the safety parameter, the difference from baseline will either be 
computed on the original scale (raw change from baseline) or on the log scale and back
transformed for reporting (percent change from baseline). Day -1 or Day -2 readings will 
serve as baseline for laboratory parameters. Day -1 9-hour reading will serve as time-
matched baseline for the corresponding post-dose ECG and vital sign readings.
Summary statistics and plots will be generated for BPRS, BARS, AIMS, SAS as well as for 
change from baseline. The difference from baseline will be computed on the original scale 
(raw change from baseline). Responses to the C-SSRS will be listed. The Columbia Suicide 
Severity Rating Scale (C-SSRS) will be used to systematically and prospectively ascertain 
and document the occurrence of suicidal events (i.e., ideation and behavior). Responses on 
the C-SSRS are classified according to 11 prespecified categories. The most severe 
treatment-emergent event within each of three broad categories (suicidal ideation, suicidal 
behavior, and non-suicidal self-injurious behavior) reported at a visit will be used for analysis 
and reporting. An event is considered treatment-emergent during the assessment phase if it is 
either newly emerged or is more severe than the most severe event reported to have occurred 
in the trial-defined pre-treatment reference period. Individual C-SSRS listings will be 
provided.
Pharmacokinetics
Model-Based PK Summary
Separately for each panel and separately for each PK parameter, individual values of AUC0-
24, Cmax, and C24 at each dose level will be natural log-transformed and evaluated with a 
linear mixed effects model containing a fixed effect for dose, day (where applicable), and a 
random effect for subject. Kenward and Roger's method will be used to calculate the 
denominator degrees of freedom for the fixed effects. Ninety-five percent confidence 
intervals (CIs) for the least squares means for each dose will be constructed on the natural log 
scale and will reference the t-distribution. Exponentiating the least-squares means, and lower 
and upper limits of these CIs will yield estimates for the population GMs and 95% CIs about 
the GMs on the original scale.
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Descriptive Statistics 
For each panel individual values will be listed for each PK parameter 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).
Cardiodynamics:
The exploratory objective pertaining to QTc will be evaluated through development of a 
model describing the relationship between MK-8189 plasma concentrations and QTc change 
from baseline in participants with schizophrenia (Panel C). Details of the concentration-QTc 
analysis will be specified in a separate modeling analysis plan (MAP). This MAP will be 
completed prior to unblinding and database lock. Results of this analysis will be reported 
separately from the CSR.
9.7
Interim Analyses
No interim analysis is planned.
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. For evaluation of the 
relationship between QTc and plasma concentrations, the number of dose levels being 
evaluated and the number of participants on each treatment is consistent with those deemed 
to be adequate in the white paper [Mehrotra, D. V., et al 2017].
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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 LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
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 and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
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underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
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, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
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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.
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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical 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 trials 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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
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completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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 7 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 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN)
Albumin
Bicarbonate or CO2
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose [ fasting]
Calcium
Alkaline 
phosphatase
Magnesium
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) if applicable]
•
Serology [(HIV antibody, HBsAg, and hepatitis C virus antibody
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; [HBsAg=hepatitis B surface antigen]; hCG=human chorionic gonadotropin; 
[HIV=human immunodeficiency virus]; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular 
volume; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-
pyruvic transaminase; ULN=upper limit of normal; WBC=white blood cell; WOCBP=women of 
childbearing potential; WONCBP=women of nonchildbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (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.
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•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category used for rating the intensity of an 
event; and both AE and SAE can be assessed as severe (for pediatric studies, extremely 
distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
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•
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 
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.
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(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?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a 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.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
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The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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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: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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 
non-hormonal 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 for a male participant 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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
•
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).
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 female participant hormonal contraception.
d
If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited 
to those which inhibit ovulation.
e
IUS is a progestin releasing IUD.
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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will 
be used in various experiments to understand:
    The biology of how drugs/vaccines work
    Biomarkers responsible for how a drug/vaccine enters and is removed by the body
    Other pathways with which drugs/vaccines may interact
    The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
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3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. 
In fact, little or no research can be conducted without connecting the clinical study data 
to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes 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 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers 
will appear on the specimen tube.
5.
Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to 
the specific scope of analysis outlined in future biomedical research protocol and 
consent. Future biomedical research specimens remaining with the third party after 
specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be 
removed from the biorepository and destroyed. Documentation will be sent to the 
investigator confirming withdrawal and/or destruction, if applicable. It is the 
responsibility of the investigator to inform the participant of completion of the 
withdrawal and/or destruction, if applicable. Any analyses in progress at the time of 
request for withdrawal/destruction or already performed before the request being 
received by the Sponsor will continue to be used as part of the overall research study 
data and results. No new analyses would be generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
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particular study, the study site will ship directly to the Sponsor-designated 
biorepository. The specimens will be stored under strict supervision in a limited access 
facility which operates to assure the integrity of the specimens. Specimens will be 
destroyed according to Sponsor policies and procedures and this destruction will be 
documented in the biorepository database.
8.
Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address 
participant data privacy concerns. Data privacy risks are largely limited to rare 
situations involving possible breach of confidentiality. In this highly unlikely situation, 
there is risk that the information, like all medical information, may be misused.
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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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
Panels A, A-1, and C
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ Test
Laboratory Safety Tests
including serum β-hCG
(WOCBP) or serum FSH
(WONCBP) and BDS
3
2
1
6
12
72
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
1
4.5
4.5
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for MK-8189 Panel A
19
19
4
76
Blood for MK-8189 Panel A-1
19
19
4
76
Blood for MK-8189 Panel C
34
34
4
136
Total Blood Volume per Participant for Panel Aa
161 mL
Total Blood Volume per Participant for Panel A-1a
161 mL
Total Blood Volume per Participant for Panel Ca
221 mL
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more than 
50 mL in total) may be obtained.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
If criteria diverges from inclusion/exclusion criteria, more conservative criteria should 
be used.
Screen Failure Criteria
Potentially Significant 
Postrandomization 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 LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other 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
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
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
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch 
block; LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; 
mm=millimeter; ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT 
correction using Fredericia formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside 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:
a.
The participant may be excluded from the study;
b. 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).
c.
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
d. 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: Neurological Exam
The following assessments are provided as an example of what will be collected at the 
appropriate time points in the SoA, Section 1.3.  
The general (full) neurological exam and targeted neurological exam may be used for 
patient/subject assessment.  
10.11.1
General (Full) Neurological Exam
See SoA, Section 1.3 for specific timepoints.
The General 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 (eg, “WORLD”) backwards.  
Note: to avoid learning effects, switch between tests throughout the study
E. Memory:   Test registration of 3 objects; then test immediate recall 5 minutes later.
Grade: 
NORMAL or IMPAIRED and describe abnormality (for each, A to E, 
above).  Normal performance on Serial 7’s is getting to 65 with no more than 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
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.
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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
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MODULE 6 - SENSORY
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
D. Vibration:  tuning fork vibration detection in hands, feet bilaterally.
E. Position sense:  perception of thumb and toe movement, bilaterally.
F. Stereognosis:  (identify common objects placed in hand, e.g., coin, key).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
10.11.2
Targeted Neurological Exam
See SoA, Section 1.3 for specific timepoints.
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
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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
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
ACCP
American College of Chest Physicians
ADA
anti drug antibodies
ADL
activities of daily living  
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
AIMS
abnormal involuntary movement scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti retroviral therapy
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
BARS
Barnes Akathisia Rating Scale
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
bid
twice daily
BMI
body mass index
BP
blood pressure
BPRS
Brief Psychiatric Rating Scale
CAC
Clinical Adjudication Committee
CCU
Cardiac care unit
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale 
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Abbreviation
Expanded Term
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
CYP
cytochrome P450
DAIDS
Division of AIDS
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic patient-reported outcomes
E-R
exposure response
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
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Abbreviation
Expanded Term
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HSSB
Hepatic-specific Safety Board
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWG
International Working Group
IWRS
integrated web response system
JAPIC-CTI
Japan Pharmaceutical Information Center Clinical Trials Information
KPS
Karnofsky performance status
LAM
lactational amenorrhea method
LCQ
Leicester Cough Questionnaire
LLN
lower limit of normal
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Expanded Term
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
noneosinophilic bronchitis
NSCLC
non–small cell lung cancer
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over-the-counter
PBPK
physiologically-based PK
PCL
Protocol Clarification Letter
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
quality of life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RCC
refractory chronic cough
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SAS
Simpson Angus Scale
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Abbreviation
Expanded Term
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transminase
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
STING
stimulator of interferon genes
SUSAR
suspected unexpected serious adverse reaction
SVR12
sustained viral response
TEA
Treatment Eligibility Assessment (form)
Tmax
Time to maximum plasma concentration
TMDD
target-mediated drug disposition
t1/2
half life
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
ULN
upper limit of normal
URTI
upper respiratory tract infection
UTN
Universal Trial Number
Vd 
volume of distribution
VS
vital signs
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
ZAP70
zeta-chain-associated protein kinase
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11
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