A Multiple-dose Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and QTc Effect of MK-8189 in Participants With Schizophrenia and Healthy Participants.
Phase: PHASE1
Conditions: Schizophrenia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03565068  
Document Date: 
09-SEP-2019
A Multiple-Dose Clinical Study to Evaluate the Safety, Tolerability,
Pharmacokinetics and QTc Effect of MK-8189 in Participants With 
Schizophrenia and Healthy Participants

PRODUCT: MK-8189  
1
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A multiple-dose clinical study to evaluate the safety, tolerability, 
pharmacokinetics and QTc effect of MK-8189 in participants with schizophrenia and healthy 
participants.
Protocol Number: 007-06
Compound Number: MK-8189
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
118,986
Approval Date: 09 September 2019
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
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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PRODUCT: MK-8189  
3
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 06
09-Sep-2019
Outdated protocol template language needed to be deleted from the contraception 
inclusion criteria to fix discrepancies and redundancies with the new language added in 
Amendment 05.
Amendment 05
15-Aug-2019
Updated Panel D to include 20 participants with schizophrenia, ECG Holter monitoring 
and an increase to a maximum dose of 48 mg. 
Amendment 04
27-Sep-2018
Addition of Panel D to evaluate the safety, tolerability and pharmacokinetics (PK) of MK-
8189 as monotherapy at doses up to 36 mg in healthy participants.
Amendment 03
06-Aug-2018
Addition of Panel C to evaluate the safety, tolerability and pharmacokinetics (PK) of MK-
8189 as add-on therapy.
Amendment 02
19-Jul-2018
The additional assessments included in Protocol 007 Amendment 02 are to enhance safety 
monitoring based on consultation with a health authority. Medications permitted during 
the antipsychotic washout period and trial were added and additional protocol 
clarifications were made throughout.
Amendment 01
28-Jun-2018
The protocol was amended to allow subjects to begin their washout as an outpatient if the 
investigator deems it appropriate for a participant, the caffeine consumption restriction 
was updated on PK/ECG Holter days as it is not considered to impact the QTc/PK 
analysis or the PK of MK-8189 and Panel B eligibility was updated to include evaluation 
of the screening laboratory values. Additional changes were included to improve study 
logistics, clarify protocol language and correct typographical errors.
Original Protocol
17-May-2018
Not applicable
 
 
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PRODUCT: MK-8189  
4
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
Outdated contraception protocol template language needed to be deleted from the inclusion criteria to fix discrepancies and
redundancies with the new language added in Amendment 05.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.1.2 Panel B, Panel 
C and Panel D 
(Participants with 
Schizophrenia) 
Inclusion Criteria
The following language was removed from inclusion #24: 
a.
If the participant is a female with reproductive potential, she must 
demonstrate a serum β-human chorionic gonadotropin (β-hCG) 
level consistent with the nongravid state at the prestudy (screening) 
visit and agree to use (and/or have their partner use) 2 acceptable 
methods of birth control beginning at the prestudy (screening) visit, 
throughout the study (including washout intervals between 
treatment periods/panels) and until 2 weeks after the last dose of 
study drug in the last treatment period. Acceptable methods of birth 
control are defined in Appendix 5.
b. If the participant is a postmenopausal female: she is without menses 
for at least 1 year and has a FSH value in the postmenopausal range 
upon prestudy (screening) evaluation.
c.
If the participant is a surgically sterile female: she is status post 
hysterectomy, oophorectomy or tubal ligation. Note: Information 
regarding the procedure may be based on the participant’s recall of 
her medical history, and details of the recall must be captured 
appropriately within the site's source documents.
This section contained language 
that was discrepant and redundant
to the updated contraception 
language presented in Appendix 5.
The contraception language in 
Appendix 5 is based upon Clinical
Trial Facilitation Group (CTFG)
recommendations and aligns with 
TransCelerate Common Protocol 
Template (CPT) guidelines for 
contraception which takes into 
account feedback from health 
authorities and regulators 
regarding acceptable contraception 
requirements.
 
 
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PRODUCT: MK-8189  
5
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Section # and Name
Description of Change 
Brief Rationale 
2.2.2. Preclinical and 
Clinical Studies
In the Clinical Study summary, the number of discontinuations due to 
AE in the Phase 1 studies was updated from 8 to 9.
The change reflects the true 
number of discontinuations 
throughout the Phase 1 program.
 
 
059Y88

PRODUCT: MK-8189  
6
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................29
Pharmaceutical and Therapeutic Background .............................................30
Preclinical and Clinical Studies ...................................................................30
Ongoing Clinical..........................................................................................35
2.3
Benefit/Risk Assessment......................................................................................37
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................38
4
STUDY DESIGN............................................................................................................39
4.1
Overall Design......................................................................................................39
4.2
Scientific Rationale for Study Design.................................................................41
Rationale for Endpoints ...............................................................................42
4.2.1.1
Safety Endpoints................................................................................42
4.2.1.2
Pharmacokinetic Endpoints ...............................................................43
4.2.1.3
Pharmacodynamic Endpoints.............................................................44
4.2.1.4
Planned Exploratory Biomarker Research.........................................44
4.2.1.4.1
Planned Genetic Analysis ........................................................44
4.2.1.5
Future Biomedical Research..............................................................45
Rationale for the Use of Comparator/Placebo .............................................45
Rationale for Suicidal Ideation and Behavior Monitoring...........................45
4.3
Justification for Dose...........................................................................................45
Starting Dose for This Study........................................................................46
Maximum Dose/Exposure for This Study ...................................................46
Rationale for Dose Interval and Study Design ............................................47
4.4
Beginning and End of Study Definition .............................................................48
Clinical Criteria for Early Study Termination .............................................49
5
STUDY POPULATION ................................................................................................49
5.1
Inclusion Criteria.................................................................................................49
Panel A (Healthy Participants) Inclusion Criteria .......................................49
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
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Panel B, Panel C and Panel D (Participants with Schizophrenia) 
Inclusion Criteria .........................................................................................51
5.2
Exclusion Criteria................................................................................................53
Panel A (Healthy Participants) Exclusion Criteria ......................................53
Panel B, Panel C, and Panel D (Participants with Schizophrenia) 
Exclusion Criteria ........................................................................................56
5.3
Lifestyle Considerations......................................................................................60
Meals and Dietary Restrictions....................................................................60
5.3.1.1
Diet Restrictions.................................................................................60
5.3.1.2
Fruit Juice Restrictions ......................................................................60
Caffeine, Alcohol, and Tobacco Restrictions ..............................................61
5.3.2.1
Caffeine Restrictions..........................................................................61
5.3.2.2
Alcohol Restrictions...........................................................................61
5.3.2.3
Tobacco Restrictions..........................................................................61
Activity Restrictions ....................................................................................61
5.4
Screen Failures.....................................................................................................62
5.5
Participant Replacement Strategy......................................................................62
6
STUDY INTERVENTION............................................................................................62
6.1
Study Intervention(s) Administered...................................................................63
6.2
Preparation/Handling/Storage/Accountability .................................................64
Handling, Storage, and Accountability........................................................64
6.3
Measures to Minimize Bias: Randomization and Blinding..............................65
Intervention Assignment..............................................................................65
Stratification.................................................................................................66
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................66
6.5
Concomitant Therapy..........................................................................................66
Rescue Medications and Supportive Care ...................................................67
6.6
Dose Modification (Escalation/Titration/Other)...............................................67
6.7
Intervention After the End of the Study............................................................68
6.8
Clinical Supplies Disclosure................................................................................68
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................68
7.1
Discontinuation of Study Intervention...............................................................68
7.2
Participant Withdrawal From the Study...........................................................69
7.3
Lost to Follow-up .................................................................................................69
8
STUDY ASSESSMENTS AND PROCEDURES........................................................70
8.1
Administrative and General Procedures ...........................................................71
 
 
059Y88

PRODUCT: MK-8189  
8
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Informed Consent.........................................................................................71
8.1.1.1
General Informed Consent.................................................................71
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................71
Inclusion/Exclusion Criteria ........................................................................71
Participant Identification Card.....................................................................72
Medical History ...........................................................................................72
Prior and Concomitant Medications Review...............................................72
8.1.5.1
Prior Medications...............................................................................72
8.1.5.2
Concomitant Medications..................................................................72
Washout from Antipsychotics......................................................................72
Assignment of Screening Number...............................................................73
Assignment of Treatment/Randomization Number.....................................73
Study Intervention Administration ..............................................................73
8.1.9.1
Timing of Dose Administration.........................................................73
Discontinuation and Withdrawal .................................................................73
8.1.10.1
Withdrawal From Future Biomedical Research ................................74
Participant Blinding/Unblinding..................................................................74
Domiciling ...................................................................................................75
Calibration of Equipment.............................................................................75
8.2
Efficacy/Immunogenicity Assessments ..............................................................75
8.3
Safety Assessments...............................................................................................75
Physical Examinations.................................................................................76
Body Mass Index (BMI) ..............................................................................76
Vital Signs....................................................................................................76
8.3.3.1
Resting Vital Signs ............................................................................76
8.3.3.2
Body Temperature .............................................................................76
8.3.3.3
Orthostatic Vital Signs.......................................................................77
Electrocardiograms ......................................................................................77
Pregnancy Testing........................................................................................78
Clinical Safety Laboratory Assessments .....................................................78
Suicidal Ideation and Behavior Monitoring.................................................79
8.3.7.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................79
Monitoring for Extrapyramidal Symptoms..................................................80
Assessment of Neuropsychological Effects.................................................80
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................80
 
 
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PRODUCT: MK-8189  
9
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................81
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......83
Follow-up of AE, SAE, and Other Reportable Safety Event Information...83
Regulatory Reporting Requirements for SAE .............................................83
Pregnancy and Exposure During Breastfeeding ..........................................83
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................84
Events of Clinical Interest (ECIs) ................................................................84
8.5
Treatment of Overdose........................................................................................85
8.6
Pharmacokinetics.................................................................................................85
Blood Collection for Plasma MK-8189 .......................................................85
Urine Collection for MK-8189 and metabolite profiling.............................85
8.7
Pharmacodynamics..............................................................................................85
8.8
Biomarkers ...........................................................................................................85
Planned Genetic Analysis Sample Collection..............................................85
8.9
Future Biomedical Research Sample Collection...............................................86
8.10
Visit Requirements...............................................................................................86
Screening......................................................................................................86
Treatment Period..........................................................................................86
Discontinued Participants Continuing to be Monitored in the Study ..........87
Poststudy......................................................................................................87
8.11
Critical Procedures Based on Study Objectives: Timing of Procedure..........87
8.12
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters ............................................................................................89
9
STATISTICAL ANALYSIS PLAN .............................................................................90
9.1
Statistical Analysis Plan Summary.....................................................................90
9.2
Responsibility for Analyses.................................................................................91
9.3
Hypotheses/Estimation ........................................................................................91
9.4
Analysis Endpoints...............................................................................................91
9.5
Analysis Populations............................................................................................92
9.6
Statistical Methods...............................................................................................92
9.7
Interim Analyses ..................................................................................................94
9.8
Multiplicity ...........................................................................................................94
9.9
Sample Size and Power Calculations .................................................................94
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................95
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........95
Code of Conduct for Clinical Trials.............................................................95
 
 
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PRODUCT: MK-8189  
10
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Financial Disclosure.....................................................................................97
Data Protection.............................................................................................97
10.1.3.1
Confidentiality of Data ......................................................................98
10.1.3.2
Confidentiality of Participant Records...............................................98
10.1.3.3
Confidentiality of IRB/IEC Information............................................98
Publication Policy........................................................................................98
Compliance with Study Registration and Results Posting Requirements ...99
Compliance with Law, Audit, and Debarmen .............................................99
Data Quality Assurance .............................................................................100
Source Documents .....................................................................................100
Study and Site Closure...............................................................................101
10.2
Appendix 2: Clinical Laboratory Tests............................................................102
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................104
Definition of AE ........................................................................................104
Definition of SAE ......................................................................................105
Additional Events Reported in the Same Manner as SAE.........................106
Recording AE and SAE .............................................................................106
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................110
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................111
10.5
Appendix 5: Contraceptive Guidance..............................................................112
Definitions..................................................................................................112
Contraception Requirements......................................................................113
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................114
10.7
Appendix 7: Country-specific Requirements..................................................119
10.8
Appendix 8: 12-Lead Electrocardiogram Abnormality Criteria ..................120
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....122
10.10 Appendix 10: Blood Volume Table ..................................................................123
10.11 Appendix 11: General (Full) Neurological Exam ...........................................124
10.12 Appendix 12: Targeted Neurological Exam ....................................................131
10.13 Appendix 13: Abbreviations .............................................................................133
11
REFERENCES.............................................................................................................134
 
 
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PRODUCT: MK-8189  
11
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
LIST OF TABLES
Table 1
Study Interventions..........................................................................................63
Table 2
Panel A (healthy participants) and Panel B (participants with 
schizophrenia: monotherapy) Sample Allocation Schedule ............................65
Table 3
Panel C (participants with schizophrenia; add-on therapy) Sample 
Allocation Schedule.........................................................................................65
Table 4
Panel D (participants with schizophrenia: monotherapy) Sample 
Allocation Schedule.........................................................................................65
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................82
Table 6
Protocol-required Safety Laboratory Assessments........................................102
 
 
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PRODUCT: MK-8189  
12
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
LIST OF FIGURES
Figure 1
Study Schema Panel A: Healthy Participants (Japanese and non-Japanese)...17
Figure 2
Study Schema Panel B: Participants with Schizophrenia (monotherapy) .......17
Figure 3
Study Schema Panel C: Participants with Schizophrenia (add-on therapy) ....18
Figure 4
Study Schema Panel D: Participants with Schizophrenia (monotherapy) .......18
 
 
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PRODUCT: MK-8189  
13
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A multiple-dose clinical study to evaluate the safety, tolerability, 
pharmacokinetics and QTc effect of MK-8189 in participants with schizophrenia and healthy 
participants.
Short Title: MK-8189 multiple-dose clinical study in participants with schizophrenia and 
healthy participants.
Acronym: MDCS
Hypotheses, Objectives, and Endpoints:
The following objectives will be evaluated in participants with schizophrenia and healthy 
participants.
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 
rising multiple once-daily oral doses of MK-
8189 in participants with schizophrenia, as 
monotherapy and as add-on  therapy,  and 
healthy Japanese and non-Japanese 
participants 
- Adverse experiences, laboratory safety 
tests, ECGs, and vital signs 
Secondary Objectives
Secondary Endpoints
- To estimate the pharmacokinetics for MK-
8189 following multiple once-daily oral 
doses in participants with schizophrenia, as 
monotherapy and as add-on therapy, and in 
healthy Japanese and non-Japanese 
participants
- AUC0-24, Cmax, C24hr, Tmax, CL, Vd 
and apparent t1/2
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
- To evaluate the effect of MK-8189 
concentrations on QTc interval and other 
ECG parameters
- QTc, PR and RR intervals, heart rate, 
QRS duration, T wave morphology, 
presence of U waves and outlier 
assessment
 
 
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PRODUCT: MK-8189  
15
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Number of Participants:
Approximately 64 participants will be allocated/randomized.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Active
Panel A, 
Panel B
Panel C and 
Panel D
MK-
8189
4 mg
QD
Oral
Panels A, B and 
C:
1 tablet 
Days 1-3, 
2 tablets Days 4-
6, 
3 tablets Days 7-
9, 
4 tablets Days 10-
12, 5 tablets Days 
13-15, 6 tablets 
Days 16-18
Panel D:
2 tablets 
Days 1-3, 
4 tablets 
Day 4-6,
6 tablets 
Days 7-9,
9 tablets 
Days 10-12,
12 tablets 
Days 13-15
Experimental 
Treatment
Placebo
Panel A, 
Panel B
Panel C and 
Panel D
Placebo
0 mg
QD
Oral
Panels A, B and 
C:
1 tablet 
Days 1-3, 
2 tablets Days 4-
6, 
3 tablets Days 7-
9, 
4 tablets Days 10-
12, 5 tablets Days 
13-15, 6 tablets 
Days 16-18
Panel D:
2 tablets 
Days 1-3, 
4 tablets 
Day 4-6,
6 tablets 
Days 7-9,
9 tablets 
Days 10-12,
12 tablets 
Days 13-15
Placebo 
Matched to 
Experimental 
Treatment
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Total 
Number
2 intervention groups
Duration of 
Participation
Panel A (healthy Japanese and non-Japanese participants): Each participant 
will participate in the study for approximately 8 weeks from the time the 
participant signs the Informed Consent Form (ICF) through the final 
contact. After a screening phase of approximately 4 weeks, each participant 
will receive assigned intervention for approximately 18 days. After the end 
of treatment, each participant will be followed for 2 weeks.
Panel B and Panel C (participants with schizophrenia; monotherapy and 
add-on therapy, respectively): Each participant will participate in the study 
for approximately 8 weeks from the time the participant signs the ICF 
through the final contact. After a screening phase of approximately 4 weeks
(which may include a washout phase (Panel B only) of at least 5 days from 
the participant’s standard of care medication) each participant will receive
assigned intervention for approximately 18 days. After the end of treatment,
each participant will be followed for 2 weeks.
Panel D (participants with schizophrenia; monotherapy): Each participant 
will participate in the study for approximately 7.5 weeks from the time the 
participant signs the Informed Consent Form (ICF) through the final 
contact. After a screening phase of approximately 4 weeks (which may 
include a washout phase of at least 5 days from the participant’s standard of 
care medication), each participant will receive assigned intervention for 15
days. After the end of treatment, each participant will be followed for 2 
weeks.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 13.
 
 
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PRODUCT: MK-8189  
17
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
1.2
Schema
The study design is depicted in Figure 1, Figure 2, Figure 3 and Figure 4.
Figure 1
Study Schema Panel A: Healthy Participants (Japanese and non-Japanese)
Figure 2
Study Schema Panel B: Participants with Schizophrenia (monotherapy)
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Figure 3
Study Schema Panel C: Participants with Schizophrenia (add-on therapy)
Figure 4
Study Schema Panel D: Participants with Schizophrenia (monotherapy)
 
 
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PRODUCT: MK-8189  
19
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
1.3
Schedule of Activities (SoA)
Panels A, B and C
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening
-6 -2 -1 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 ~27
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Inclusion/Exclusion 
Criteria
X
Recheck 
clinical status 
before 1st dose 
of study 
intervention
Participant 
Identification Card
X
Medical History 
(includes psychiatric 
history and substance 
usage)
X
Substances: 
drugs, alcohol, 
tobacco (Panel 
A only), and 
caffeine
Prior/Concomitant 
Medication Review
       X------------------------------------------------------------------------------------------------------------------------------------X
Assignment of 
Screening Number
X
Washout from 
Antipsychotics – Panel 
B only
X
X
Discontinue 
medication at 
least 5 days or 
at least 3 half-
lives
(whichever is 
longer) prior 
to Day -1
 
 
059Y88

PRODUCT: MK-8189  
20
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panels A, B and C
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening
-6 -2 -1 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 ~27
Assignment of 
Allocation Number 
(Randomization)
X
May occur on 
Day -1 if 
required for 
Holter
MK-8189/Placebo 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See 
Sections 8.1.9 
and 6.3.1
Standard Mealsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confinement in Clinicb
X-------------------------------------------------------------------------------------------------------------X
Follow-up Phone Call –
Panel B only
X
May occur 5-7 
days after 
discharge.
Safety Procedures
Full Physical Exam
X
Xm
X
X
Height
X
Weight
X
Xm
X
X
Full Neurological Exam
X
Xm
Targeted Neurological 
Exam
X
X
X
X
X
X
X
X
Complete 
predose on 
dosing days or 
anytime on 
non-dosing
days;
Days 2, 5, 11: 
Panel A only
Vital Signs (heart rate, 
blood pressure)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Days 2, 5: 
Panel A only
Orthostatic Vital Signs 
(heart rate, blood 
pressure)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Days 2, 5: 
Panel A only
 
 
059Y88

PRODUCT: MK-8189  
21
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panels A, B and C
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening
-6 -2 -1 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 ~27
Vital Signs (respiratory 
rate, temperature)
X
X
X
X
X
X
Complete 
predose;
Day 5: 
Panel A only
12-lead Safety ECG
(Panels A and B only)e
X
X
X
X
X
X
X
X
X
X
Days 2, 5: 
Panel A only
24-hour Holter ECG & 
Extraction (Panels A 
and B only)f
X
X
X
X
X
X
X
12-lead Safety ECG 
(Panel C only)g
X
X
X
X
X
X
X
X
X
X
Serum β-Human 
Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
X
Urine Pregnancy test 
(WOCBP only)h
Xm
Serum Follicle 
Stimulating Hormone 
(FSH; WONCBP only)
X
HIV, hepatitis B and C 
Screen (per site SOP)
X
Urine Drug Screen 
(per site SOP)i
X
X
Laboratory Safety Tests 
(hematology, urinalysis,
chemistry)
X
Xm
X
X
X
X
Collected 
predose after 
~8 hour fast
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)-
Baseline Version
X
 
 
059Y88

PRODUCT: MK-8189  
22
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panels A, B and C
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening
-6 -2 -1 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 ~27
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)- Since Last 
Assessment Versionj
Xm
X
X
X
X
X
Complete 
predose
Barnes Akathisia 
Rating Scale (BARS)j, k
Xm
X
X
X
X
Complete 
predose
Abnormal Involuntary 
Movement Scale 
(AIMS) j, k
Xm
X
X
X
X
Complete 
predose
Simpson Angus Scale 
(SAS) j, k
Xm
X
X
X
X
Complete 
predose
Bond and Lader Visual 
Analog Scale (VAS)j
Xm
X
X
X
X
X
X
X
Days 2, 5, 11: 
Panel A only.
Complete 
predose
Brief Psychiatric Rating 
Scale (BPRS; 
Panels B and C only)j
X
Xm
X
X
X
X
Complete 
predose
AE/SAE review
     X-------------------------------------------------------------------------------------------------------------------------------------X
Biomarkers
Blood for Genetic 
Analysisn
X
Collect 
predose from 
enrolled 
participants 
only; See 
Section 8.8
Pharmacokinetics
Blood for Plasma 
MK-8189 and/or 
Metabolites assayl
X
X
X
X
X
X
X
X
X
X
 
 
059Y88

PRODUCT: MK-8189  
23
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
a. Meals should be given at approximately the same time every day starting on Day -1 (time-matched to postdose meals) through Day 20.  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. Panel A will be confined minimally from Day -2 through Day 21.  Panel B will be confined within a week of starting their antipsychotic washout period through Day 21; minimally subjects will be 
confined from Day -6 through Day 21. Panel C will be confined minimally from Day -1 through Day 21.
c. Single HR and BP measurements will be obtained at all postdose timepoints.  On the following days, specific timepoints are noted:   

Day -1:  Triplicate measurements time- matched to 8 hour post dose vital sign  

Day 2 and Day 5: 8 hours post-dose (Panel A only)

Day 8, Day 11, Day 14 and Day 17:  8 hours post-dose

Day 10, Day 12, Day 13, Day 15, Day 16 and Day 18: 10 and 16 hours postdose
d. Orthostatic assessments in HR and BP will follow semi recumbent vital sign assessments.  Subjects should be standing for approximately 3 minutes prior to the orthostatic assessments.   Orthostatic 
HR and BP measurements will be obtained on: 

Day -1: Time- matched to 8 hour post dose orthostatic vital sign.  

Day 2 and Day 5: 8 hours post-dose (Panel A only).

Day 8, Day 11, Day 14 and Day 17:  8 hours post-dose 

Day 10, Day 12, Day 13, Day 15, Day 16 and Day 18: 10 and 16 hours postdose 
e. For Panels A and B, single12-lead safety ECG measurements will be at all postdose timepoints. On the following days, specific timepoints are noted: 

Day 1: Triplicate measurements within 2 hours prior to dosing.

Day 2 and Day 5: 8 hours post-dose (Panel A only).

Day 8, Day 11, Day 14 and Day 17: 8, 10 and 16 hours post-dose
f. For Panels A and B, continuous (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: 2, 6, 8, 10, 12, 16 and 24 hours

Day 7, Day 10, Day 13 and Day 16: predose, 2, 6, 8, 10, 12, 16 and 24 hours post-dose.

Day 18: 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.

If a subject discontinues study treatment at a dose of 12 mg or higher, an attempt should be made to collect 24-hour Holter data through 48 hours following their last dose.
g. For Panel C, triplicate 12-lead safety ECG measurements will be taken 1-2 minutes apart at all timepoints.  On the following days, specific timepoints are noted:

Day 1: within 2 hours prior to dosing

Day 9, Day 12,  Day 13, Day 15, Day 16 and Day 18: 8, 10, 16 and 24 hours post-dose
h. In the event the urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required.
i. Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
j. Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.  
k. Additional BARS, AIMS and SAS assessments will be conducted when observed or reported complaints of dystonia and/or akathisia occur.
l. MK-8189 plasma PK sample collection (note: when time point coincides with Holter extraction, the PK sample will be collected as soon as possible after Holter extraction but must collected after any 
vital sign assessments): 

Panel A and B and C: Day 1 and Day 4:  pre-dose.  

Panel A and B: Day 7, Day 10, Day 13 and Day 16: predose, 2, 6, 8, 10, 12, 16 and 24 hours post-dose  

Panel C: Day 9, Day 12, Day 15; predose, 2, 6, 8, 10, 12, 16 and 24 hours post-dose. 

Panel A and B and C:  Day 18:  2, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose  

Optional sample when signs of dystonia and/or akathisia occur

If a subject discontinues study treatment at a dose of 12 mg or higher, an attempt should be made to collect PK samples through 48 hours following their last dose.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
m. In Panels A and B, assessments will be done on Day -2. In Panel C, assessments will be done on Day -1.
n. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does not approve of the planned analysis of the 
association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited to CYP2C9. Leftover extracted DNA will be stored for 
future biomedical research if the participant signs the future biomedical research consent.
 
 
059Y88

PRODUCT: MK-8189  
24
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panel D
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening -6 -2 -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
~24
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Inclusion/Exclusion 
Criteria
X
Recheck clinical status 
before 1st dose of study 
intervention
Participant 
Identification Card
X
Medical History 
(includes psychiatric 
history and substance 
usage)
X
Substances: drugs, alcohol,  
and caffeine
Prior/Concomitant 
Medication Review
X----------------------------------------------------------------------------------------------------------------------------X
Assignment of 
Screening Number
X
Washout from 
Antipsychotics
X
X
Discontinue medication at 
least 5 days or at least 3 
half-lives (whichever is 
longer) prior to Day -1
Assignment of 
Allocation Number 
(Randomization)
X
May occur on Day -1 if 
required for Holter
MK-8189/Placebo 
Administration
X X X X X X X X X
X
X
X
X
X
X
See 
Sections 8.1.9 and 6.3.1
Standard Mealsa
X X X X X X X X X X
X
X
X
X
X
X
X
X
Confinement in 
Clinicb
X-------------------------------------------------------------------------------------------X
Follow-up Phone Call
X
 
 
059Y88

PRODUCT: MK-8189  
25
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panel D
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening -6 -2 -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
~24
Safety Procedures
Full Physical Exam
X
X
X
X
Height
X
Weight
X
X
X
X
Full Neurological 
Exam
X
X
Targeted Neurological 
Examc
X
X
X
X
X
X
X
Vital Signs (heart rate, 
blood pressure)d
X
X X X X
X X X X X
X
X
X
X
X
X
X
X
X
Orthostatic Vital 
Signs (heart rate, 
blood pressure)e
X
X X X X
X X X X X
X
X
X
X
X
X
X
X
X
Vital Signs 
(respiratory rate, 
temperature)c
X
X
X
X
X
X
X
X
12-lead Safety ECGf
X
X X
X
X
X
X
X
X
24-hour Holter ECG 
& Extractiong
X X
X
X
X
X
X
X
Serum β-Human 
Chorionic 
Gonadotropin
(β-hCG; WOCBP 
only)
X
X
Urine Pregnancy test 
(WOCBP only)h
X
Serum Follicle 
Stimulating Hormone 
(FSH; WONCBP 
only)
X
HIV, hepatitis B and 
C Screen (per site 
SOP)
X
 
 
059Y88

PRODUCT: MK-8189  
26
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panel D
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening -6 -2 -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
~24
Urine Drug Screen 
(per site SOP)i
X
X
Laboratory Safety 
Tests (hematology, 
urinalysis, chemistry)c
X
X
X
X
X
X
X
Collected after ~8 hour 
fast
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)-
Baseline Version
X
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)- Since Last 
Assessment Versionc
X
X
X
X
X
X
Barnes Akathisia 
Rating Scale (BARS)c, 
X
X
X
X
X
X
Abnormal Involuntary 
Movement Scale 
(AIMS) c, j
X
X
X
X
X
X
Simpson Angus Scale 
(SAS) c, j
X
X
X
X
X
X
Bond and Lader 
Visual Analog Scale 
(VAS)c
X
X
X
X
X
X
X
Brief Psychiatric 
Rating Scale (BPRS)
X
X
X
X
X
X
X
AE/SAE review
X--------------------------------------------------------------------------------------------------------------------------X
 
 
059Y88

PRODUCT: MK-8189  
27
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panel D
Study Period
Screening Wash-
out
Post-
study
Notes
Scheduled Day
Screening -6 -2 -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
18
~24
Biomarkers
Blood for Genetic 
Analysism
X
Collect predose from 
enrolled participants only;
See Section 8.8
Pharmacokinetics
Blood for Plasma 
MK-8189  and/or 
Metabolites assayk
X
X
X
X
X
X
Urine for potential 
MK-8189 and 
metabolite profilingl
X
 
 
059Y88

PRODUCT: MK-8189  
28
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
a. Meals should be given at approximately the same time every day starting on Day -1 (time-matched to postdose meals) through Day 17.  Breakfast will be given at ~1 hour postdose, lunch given at ~4 
hours postdose, a snack given at ~8 hours postdose and dinner at ~12 hours postdose.  All meals will follow the completion of all specified procedures at that timepoint.
b. Participants will be confined minimally from Day -1 until Day 18 procedures are complete. 
c. Scheduled assessments are completed predose on dosing days and at any time on non-dosing days.  
d. Single HR and BP measurements will be obtained at all postdose timepoints.  On the following days, specific timepoints are noted:   

Day -1:  Triplicate measurements time- matched to 8, 10, 16 hours post dose vital sign  

Day 1, Day 2, Day 5, Day 8, Day 11, Day 14: 8 hours post-dose

Day 3, Day 6, Day 7, Day 9, Day 10, Day 12, Day 13, Day 15 and Day 17: 8, 10 and 16 hours postdose
e. Orthostatic assessments in HR and BP will follow semi-recumbent vital sign assessments.  Subjects should be standing for approximately 3 minutes prior to the orthostatic assessments.   Orthostatic 
HR and BP measurements will be obtained on: 

Day -1: Time- matched to 8, 10, 16 hours post dose orthostatic vital sign.  

Day 1, Day 2, Day 5, Day 8, Day 11, Day 14: 8 hours post-dose

Day 3, Day 6, Day 7, Day 9, Day 10, Day 12, Day 13, Day 15 and Day 17: 8, 10 and 16 hours postdose
f. Single 12-lead safety ECG measurements will be taken at all postdose timepoints.  On the following days, specific timepoints are noted:

Day 1: Triplicate measurements within 2 hours of dosing

Day 2, Day 5, Day 8, Day 11, and Day 14: 8, 10, 16 and 24 hours post-dose
g. Continuous (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: 2, 6, 8, 10, 12, 16 and 24 hours

Day 1, Day 4, Day 7, Day 10 and Day 13: predose, 2, 6, 8, 10, 12, 16 and 24 hours post-dose.

Day 15: 2, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.

If a subject discontinues study treatment at a dose of 16 mg or higher, an attempt should be made to collect 24-hour Holter data through 48 hours following their last dose.
h. In the event the urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required.
i. Screening UDS is mandatory; any additional UDS are conducted per site SOP. UDS prior to randomization will be done on the day of admission.
j. Additional BARS, AIMS and SAS assessments will be conducted when observed or reported complaints of dystonia and/or akathisia occur. 
k. MK-8189 plasma PK sample collection: 

Day 1, Day 4, Day 7, Day 10 and Day 13: predose, 2, 6, 8, 10, 12, 16 and 24 hours post-dose. 

Day 15:  2, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose  

Optional sample when signs of dystonia and/or akathisia occur.

If a subject discontinues study treatment at a dose of 16 mg or higher, an attempt should be made to collect PK samples through 48 hours following their last dose.

Leftover main study plasma will be stored for future biomedical research if the participant consents to future biomedical research.
l. Spot collection between 8-12 hr postdose at the 48 mg dose only.  Participants should void prior to dose administration.
m. This sample will be drawn for CYP2C9 and for planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does not approve of the planned analysis of 
the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited to CYP2C9. Leftover extracted DNA will be 
stored for future biomedical research if the participant signs the future biomedical research consent.
 
 
059Y88

PRODUCT: MK-8189  
29
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
2
INTRODUCTION
2.1
Study Rationale
This study will evaluate safety, tolerability and pharmacokinetics (PK) of multiple oral doses 
of MK-8189, an inhibitor of phosphodiesterase 10A (PDE10A), in healthy participants and 
participants with schizophrenia at doses that are higher than those explored in the previous 
multiple-ascending dose study (MK-8189 PN003-06).  Initially this protocol was intended to 
evaluate doses up to and including doses of 24 mg.  However, doses up to 24 mg have been 
generally well tolerated in Panel A and B, and thus this amendment will allow the safety and 
tolerability assessment of doses up to and including 48 mg.  This study will also evaluate the 
effect of MK-8189 on QTc.  
The clinical dose of MK-8189 is currently unknown; however, 12 mg has demonstrated 
antipsychotic activity in acute exacerbation of schizophrenia and was generally well 
tolerated.  Based on data from the current protocol as well as the potential for increased 
efficacy at higher doses of MK-8189, doses of MK-8189 as high as 24 mg are being 
considered for evaluation in Phase 2. Therefore, the current study, which will evaluate doses 
up to 48 mg of MK-8189 as monotherapy and up to 24 mg of MK-8189 as add-on therapy, 
would support safety and tolerability margins for doses as high as 24 mg or 16 mg, when 
given as monotherapy or as adjunct therapy, respectively.   Therefore, these data would 
potentially support dosing in the presence of intrinsic and extrinsic factors which may 
increase MK-8189 exposure (e.g. CYP3A inhibition).  In addition, if titration to 
supratherapeutic doses is achievable, this trial could support robust characterization of the 
effect of MK-8189 on QTc, which would depend on determination of the final clinical dose. 
Inclusion of healthy Japanese subjects will support the global clinical development in Japan.
It is recognized that an undesirable property of some non-antiarrhythmic drugs is their ability 
to delay cardiac repolarization leading to increased risk of development of life-threatening 
cardiac arrhythmias such as Torsade de Pointes (TdP) and possibly other ventricular 
tachyarrhythmias. 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 current trial will 
evaluate in a rigorous manner the impact of administration of MK-8189 on the QTc interval,
to determine the risk of cardiac repolarization prolongation. While MK-8189 data to date do 
not suggest a QT prolongation risk, in fact, many antipsychotics are known to prolong QT. 
As MK-8189 is expected to be used as adjunct therapy, the QTc effect of MK-8189 will be 
an important assessment in the present study.
2.2
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8189.
 
 
059Y88

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PRODUCT: MK-8189  
39
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
4
STUDY DESIGN
4.1
Overall Design
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
This is a four-panel, randomized, placebo-controlled, parallel-group, multiple-dose, double-
blinded, safety, tolerability, PK and QTc study of MK-8189 in participants with 
schizophrenia and healthy participants. 
Panel A will enroll up to 16 healthy participants (8 Japanese and 8 non-Japanese) and 
Panel B will enroll up to 16 participants with schizophrenia or schizoaffective disorder to 
ensure at least 12 completers per group.  Panel C will enroll up to 12 participants with 
schizophrenia/schizoaffective disorder and Panel D will enroll up to 20 participants with 
schizophrenia; participants may be replaced at the discretion of the Sponsor in consultation 
with the principal investigator.  Participants will be randomized to MK-8189 or matched-
placebo in a ratio of 3:1 (Panels A, B and C) and 3:2 (Panel D) according to a computer
generated allocation schedule; within Panel A, 6 Japanese and 6 non-Japanese will be 
randomized to MK-8189 and 2 Japanese and 2 non-Japanese will be randomized to receive 
placebo according to the computer generated allocation schedule.  
Participants with schizophrenia in Panel B and Panel D will be washed off their antipsychotic 
medication.  The washout may start with a down titration of the antipsychotic treatment 
during the screening phase per direction of the investigator.  Participants in Panel B and 
Panel D should not receive antipsychotics for at least 5 days or 3 half-lives (whichever is 
longer) prior to Day -1 Holter assessments. If deemed appropriate by the investigator, a 
participant may begin their washout as an outpatient, but should be confined within a week of 
starting the washout and minimally beginning on Day -6.  In Panel C, participants with 
schizophrenia will remain on their study permitted atypical antipsychotic (AAP).
Panels A, B and C: Beginning on Day 1, participants randomized to MK-8189 will begin to 
receive MK-8189 QD and will be titrated from 4 mg to 24 mg over the course of an 18 day 
treatment period as follows: 1 x 4 mg tablet Days 1-3,  2 x 4 mg tablets Days 4-6, 3 x 4 mg 
tablets Days 7-9, 4 x 4 mg tablets Days 10-12, 5 x 4 mg tablets Days 13-15 and 6 x 4 tablets 
Days 16-18. Participants randomized to placebo will receive the same number of tablets 
matching the 4 mg tablet of MK-8189 as the active group. Dose titration decisions for each 
participant will occur, after 3 days of dosing per dose level, jointly between the investigator 
and Sponsor. 
Panel D: Beginning on Day 1, participants randomized to MK-8189 will begin to receive  
MK-8189 QD and will be titrated from 8 mg to 48 mg over the course of a 15 day treatment 
period as follows: 2 x 4 mg tablets Days 1-3, 4 x 4 mg tablets Days 4-6, 6 x 4 mg tablets 
Days 7-9, 9 x 4 mg tablets Days 10-12 and 12 x 4 mg tablets Days 13-15.  Participants 
randomized to placebo will receive the same number of tablets matching the 4 mg tablet of 
 
 
059Y88

PRODUCT: MK-8189  
40
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
MK-8189 as the active group. Dose titration decisions for each participant will occur, after 3 
days of dosing per dose level, jointly between the investigator and Sponsor.
In Panel D, a small cohort (n=4) will initially be dosed with 8 mg to confirm tolerability prior 
to dosing the remainder of the cohort.  Tolerability will be assessed following the second 
dose of 8 mg before the remainder of the panel is dosed; depending on tolerability, the 
remainder of the panel may i) be dosed starting with 8 mg, ii) a small cohort of the remainder 
of the panel may be dosed starting with 8 mg, or iii) the starting dose may be adjusted 
downward to 4 mg. The decision on how to proceed will be made by the principal
investigator jointly with the Sponsor and documented in a protocol clarification letter.  If any 
of the panel begins dosing at 4 mg, the following titration schedule may be followed: 
1 x 4 mg tablets Days 1-3, 2 x 4 mg tablets Days 4-6, 4 x 4 mg tablets Days 7-9, 6 x 4 mg 
tablets Days 10-12 and 12 x 4 mg tablets Day 13-15.    
If a participant does not tolerate escalation to the next dose, the participant may be titrated 
down to the previous dose (Panel A, B, C or D) or intermediate dose (Panel D). In addition, 
as discussed above, if the initial dosing cohort of Panel D or subsequent dosing cohort(s) 
does not tolerate the starting dose of 8 mg, subjects may be down-titrated to 4 mg.  If 
appropriate medical care necessitates a down-dose, the investigator may do so independent of 
consultation with the Sponsor. If the participant tolerates continued dosing following down-
titration, the participant may continue in the trial at that dose until study completion or may 
be re-challenged at a higher dose. Re-challenges  are only to occur on regularly scheduled 
dose titration days, i.e. Day 4, Day 7, Day 10, etc. and will not extend the participant’s time 
in the study. Participants will be followed for approximately 2 weeks after the last study 
treatment dose.
Panel A, healthy participants, will be confined to the clinical research unit (CRU) beginning 
on Day -2 through Day 21.
Participants with schizophrenia in Panel B and Panel D have a risk to experience 
exacerbations in psychotic symptoms both during the washout period as well as during the 
MK-8189 treatment period. To mitigate this risk, only participants with schizophrenia in the 
non-acute phase of their illness, with the onset of the first episode being no less than 2 years 
prior to study entry, will be recruited for study. 
Panel B and Panel D, participants with schizophrenia, will be confined to the CRU within a 
week of beginning their antipsychotic medication washout and for at least the last 5 days of 
their washout (i.e. confinement will begin on Day -6 or earlier) and during the MK-8189 
treatment to provide an enhanced level of participant supervision. If needed, rescue 
medication will be provided to treat withdrawal symptoms (see Section 6.5.1). Participants
showing exacerbations in psychotic symptoms during the washout period will be 
re-evaluated for participation and referred for additional treatment as indicated.
Panel C, participants with schizophrenia, will be confined to the CRU beginning on Day -1 
through Day 21.
 
 
059Y88

PRODUCT: MK-8189  
41
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
The safety and tolerability of MK-8189 will be monitored by clinical assessment of AE, 
repeated measurements of ECGs and VS, physical and neurological examinations, and 
standard laboratory tests (hematology, chemistry, urinalysis). In addition, extrapyramidal 
symptoms (EPS) of dystonia and akathisia will be monitored along with psychological 
effects using rating scales.
All participants in Panels A, B and D will have 24-hour Holter recordings on Day -1, which 
will be considered baseline, and throughout the dosing period as specified in the SoA.  Blood 
sampling for PK will follow each ECG extraction time.  In addition, 24-hour Holter 
recordings and blood sampling for PK will be conducted for 2 additional days following the 
participant’s last dose.   In the case a participant has down-dosed or does not dose escalate 
and continues in the study, the participant will not repeat the 24-hour Holter monitoring and 
PK sampling at the given dose level. In the case of participant discontinuation at a dose of 
12 mg or higher, an attempt should be made to collect 24-Holter and matched PK 
measurements for 48 hours following the participant’s last dose.  Panel C will not have 
Holter assessments but will have 12-lead ECG evaluations with coinciding PK samples at 
specified timepoints as per the SoA.
After completion of the MK-8189 treatment, participants with schizophrenia in Panel B and 
Panel D will resume the use of their own antipsychotic medication following collection of the
last PK sample; Panel B: Day 18, 48- hour postdose PK sample (Day 20) and Panel D: the
Day 15, 48- hour postdose PK sample (Day 17).  Participants in Panels B and D will remain 
domiciled through Day 21 (Panel B) and Day 18 (Panel D)  All participants will be followed 
for approximately 2 weeks after the last study treatment dose.
Because this is a Phase 1 assessment of MK-8189 in humans, the pharmacokinetic (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 8.12 for examples of modifications permitted within 
the protocol parameters.
4.2
Scientific Rationale for Study Design
Initially a 3-Panel design was selected such that MK-8189 could be evaluated in both healthy 
Japanese and non-Japanese participants (Panel A) and participants with schizophrenia as 
monotherapy (Panel B) and as add-on therapy (Panel C). At the time of study initiation, 
12 mg was considered the likely clinical dose and characterization of higher dose (>12 mg)
safety, tolerability and PK of MK-8189 in healthy participants could enable a determination 
of the safety/tolerability margin in this population, which is needed to understand the 
potential for healthy participants to participate in future Phase 1 clinical studies that require 
supratherapeutic doses or exposure.  However, if dose escalation above 12 mg in healthy 
participants was poorly tolerated, high dose safety data in participants with schizophrenia 
would be used to understand the safety/tolerability margin in the target population, including 
evaluation of the effect of higher doses of MK-8189 on QTc. Panel C of this study will 
provide safety data in a small number of participants to support the evaluation of doses 
higher than 12 mg of MK-8189 in the setting of add-on therapy in a planned Phase 2 study.
 
 
059Y88

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CCI

PRODUCT: MK-8189  
43
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
As EPS are associated with antipsychotics and have been observed in the MK-8189 clinical 
program, the Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement 
Scale (AIMS) and Simpson Angus Scale (SAS) will be used to quantify any EPS observed in 
the trial. The BARS is an akathisia rating scale with objective and subjective measures and 
an overall rating from 0 to 5. A score of 0 presents no evidence for akathisia, a score of 3 is 
moderate akathisia and a score of 5 is severe akathisia. The AIMS evaluates 12 items and 
uses a 5-point scale to assess abnormal movement in 3 areas (orofacial, extremities, trunk).
The SAS evaluates 10 items and uses a 5-point scale to measure symptoms of parkinsonism 
or parkinsonian side effects (including rigidity, tremor, akinesia, and salivation).  
In case moderate EPS symptoms in an individual participant persist, the dose will not be 
further up titrated for this participant. Participants with severe EPS symptoms will be 
discontinued if not attenuated with dose reduction, dose titration and/or medical 
management. 
To monitor the psychological well-being, the Bond and Lader Visual Analogue Scale (VAS) 
will be used in all participants. In participants with schizophrenia, the Brief Psychiatric 
Rating Scale (BPRS) will be used.  The BPRS is rating scale to measure psychiatric 
symptoms such as depression, anxiety, hallucinations and unusual behavior in a range of 
psychotic and affective symptoms. 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 20-30 minutes 
for the interview and scoring. The rater should enter a number ranging from 1 (not present) to 
7 (extremely severe). 0 is entered if the item is not assessed. Participants who experience 
severe psychosis during the study will be discontinued and referred for additional treatment 
as indicated.
The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered to monitor 
mood and suicidal ideation and behavior in all trial participants (see Section 4.2.3).
All dose titration decisions will be made jointly by the investigator and the Sponsor. Each 
dose titration decision for each individual participant will occur after 3 days of dosing per 
dose level. However, if a participant needs to be discontinued or have a dose reduction based 
on safety/tolerability, the principal investigator may do so independent of consultation with 
the Sponsor.
4.2.1.2
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189, particularly at higher doses 
which have not been previously evaluated. Therefore, individual plasma concentration and 
actual sample collection times of MK-8189 will be used to drive the PK parameter values 
AUC0-24, Cmax, Tmax, C24hr, CL, Vd and apparent t1/2.
 
 
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PRODUCT: MK-8189  
45
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
Rationale for the Use of Comparator/Placebo
A matched placebo-control will be included to reduce bias with regards to the participant
reporting and investigator assessment of AEs.  In addition, inclusion of a placebo cohort will 
also control for potential bias introduced by study procedures and to increase the power to 
exclude modest QTc effects in a study with a relatively small sample size.
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 trials conducted under Investigational 
New Drug (IND) applications and trials that are intended for submission in a New Drug 
Application to the Neurology or Psychiatry Divisions of the FDA or biologics license 
application, as well as assessment in trials that fall within the guidance for other reasons 
(e.g., central nervous system active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
The methods used in calculating doses and estimated exposures are detailed in Sections 4.3.1 
and 4.3.2.
 
 
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CCI

PRODUCT: MK-8189  
49
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy Japanese and non-Japanese and schizophrenic male and female participants, with an 
attempt to enroll approximately 40% of female participants (in each panel), between the ages 
of 18 and 60 years (inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Panel A (Healthy Participants) Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Is in good health based on medical history, physical examination, vital sign (VS) 
measurements and 12-lead safety ECGs performed prior to randomization. Appendix 8
provides a table of the 12-Lead Electrocardiogram Abnormality Criteria.
2. 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 9 
provides an algorithm for the assessment of out of range laboratory values.
3. Have a Body Mass Index (BMI) > 18.5 and ≤ 35 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.
4. Have no clinically significant abnormality on the 12-lead safety ECG performed at the 
pre-trial (screening) visit and/or prior to randomization. The assessment prior to 
randomization is based on the mean of the triplicate measures. Note:  The QTcF duration 
must be <450 msec for males and <470 msec for females, 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. Appendix 8 provides a table of the 12-Lead Electrocardiogram 
Abnormality Criteria.
5. 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 semi-recumbent position at 
the pre-trial (screening) visit and/or prior to randomization (up to the time-matched 
8 hour assessment). 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.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
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Demographics
6. Participant is Male or Female.
7. Participant is from 18 years to 60 years of age inclusive, at the time of signing the 
informed consent.
     Female Participants
d. If the participant is a female with reproductive potential, she must demonstrate a 
serum β-human chorionic gonadotropin (β-hCG) level consistent with the nongravid 
state at the prestudy (screening) visit and agree to use (and/or have their partner use) 
2 acceptable methods of birth control beginning at the prestudy (screening) visit, 
throughout the study (including washout intervals between treatment periods/panels) 
and until 2 weeks after the last dose of study drug in the last treatment period. 
Acceptable methods of birth control are defined in Section 5.3.1.
e.
If the participant is a postmenopausal female: she is without menses for at least 1 year 
and have a follicle stimulating hormone (FSH) value in the postmenopausal range 
upon prestudy (screening) evaluation.
f.
If the participant is a surgically sterile female: she is status post hysterectomy, 
oophorectomy or tubal ligation. Note: Information regarding the procedure may be 
based on the participant’s recall of her medical history, and details of the recall must 
be captured appropriately within the site's source documents.
Japanese Participants
a.
If the participant is of Japanese descent, both biological parents and all biological 
grandparents must be born in Japan.  Adequate documentation to verify the descent 
should be obtained and kept with source documents.  While 2nd and 3rd generation 
Japanese are acceptable for enrollment, preference should be given to enrollment of 
subjects who were born in Japan.
Informed Consent
8. The participant provides written informed consent for the study. The participant may also 
provide consent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
Additional Categories
9. Is willing to comply with the study restrictions (see Section 5.3 for a complete summary 
of study restrictions).
 
 
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PRODUCT: MK-8189  
51
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Panel B, Panel C and Panel D (Participants with Schizophrenia) Inclusion 
Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
10. 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 9 
provides an algorithm for the assessment of out of range laboratory values.
11. 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.
12. Have no clinically significant abnormality on 12-lead safety ECG performed at the pre-
trial (screening) visit and/or prior to randomization. The assessment prior to 
randomization is based on the mean of the triplicate measures. Note:  The QTcF duration 
must be <450 msec for males and <470 msec for females, 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. Appendix 8 provides a table of the 12-Lead Electrocardiogram 
Abnormality Criteria.
13. 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 semi-recumbent 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. For Panel C and Panel D, participants may be included if values are 
outside the normal range but considered not clinically significant per investigator 
discretion.
14. 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.
15. 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.
16. 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;
 
 
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PRODUCT: MK-8189  
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MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
b. no increase in level of psychiatric care due to worsening of symptoms of 
schizophrenia for three months prior to screening.
17. Has a history of receiving and tolerating antipsychotic medication within the usual dose 
range employed for schizophrenia.
18. Has a stable living situation in which the patient or a contact person can be reached by 
the investigator if there is a need for follow up.
19. 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. 
20. Has regular bowel movements and, in the opinion of the investigator, no clinically 
significant diarrhea or constipation.
21. Panels B and D: Participant is able to discontinue the use of all antipsychotic medication 
at least 5 days prior to the start of the treatment period and during the study period. 
Demographics
22. Participant is Male or Female.
23. Participant is from 18 years to 60 years of age inclusive, at the time of signing the 
informed consent.
Female Participants
24.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, 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.
•
A WOCBP must have a negative highly sensitive pregnancy test (serum as required by 
local regulations) within 24 hours before the first dose of study intervention.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
25. The participant provides written informed consent for the study. The participant may also 
provide consent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
Additional Categories
26. Is willing to comply with the study restrictions (see Section 5.3 for a complete summary 
of study restrictions).
5.2
Exclusion Criteria
Panel A (Healthy Participants) Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history of clinically diagnosed depression, anxiety disorder, or any history of 
psychiatric disorders having required drug treatment or hospitalization. Participants who 
have had situational depression more than 5 years before the start of the study may be 
enrolled in the study at the discretion of the investigator. 
2. Has a history of stroke, chronic seizures, or major neurological disorder. 
3. Has a history of dystonic reaction to antipsychotic, anti-emetic or related medication
4. 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 
(e.g., positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) 
in the past 5 years or suicidal behavior in  their lifetime. 
5. Is a woman of childbearing potential (WOCBP) who has a positive serum pregnancy test 
at the screening visit or a positive urine pregnancy test within 48 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. 
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
6. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (e.g., uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
7. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
8. Has any clinically significant abnormal laboratory, VS, physical examination, or 12-lead 
safety ECG findings at screening or changes from baseline that may interfere with the 
interpretation of PK or safety parameters or, in the opinion of the investigator, would 
make the participant inappropriate for entry into this study.
9. Has a history of cancer (malignancy).
Exceptions: (1) 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 opinion of the study 
investigator, are highly unlikely to sustain a recurrence for the duration of the study.
10. Has a clinically significant history or presence of sick sinus syndrome, first, second, or
third degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, 
cardiac arrhythmia, prolonged QTc interval, or conduction abnormalities.
11. Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
12. Has a family history of sudden death.
13. Has a history of any illness that, in the opinion of the study investigator, might confound 
the results of the study or poses an additional risk to the participant by their participation 
in the study.
14. Participant has an estimated creatinine clearance (CrCl) ≤ 80 mL/min based on the 
Cockcroft-Gault (CG) Equation.
Cockcroft-Gault Equation: 
ClCr = (140-age[yr])(body wt [kg])
(72)(serum creat [mg/dL])
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
When creatinine is measured in micromole/litre, use this formula:
ClCr = (140-age[yr])(body wt[kg])
(72)(serum creatinine [micromol/L] x 0.0113)
For females, multiple the result by 0.85.
At the discretion of the investigator a measured creatinine clearance, as determined by a 
24-hour urine collection, may be used in place of, or in conjunction with, the estimate of 
the creatinine clearance.
Participants who have a measured creatinine clearance of up to 10% below 80 mL/min 
may be enrolled in the study at the discretion of the investigator.
15. Has a history of significant multiple and/or severe allergies (e.g., 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.
16. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
17. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
18. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies, beginning approximately 2 weeks (or 5 
half-lives) prior to administration of the initial dose of study drug, throughout the study 
(including washout intervals between treatment periods), until the poststudy visit. There 
may be certain medications that are permitted (see Section 6.5).
Prior/Concurrent Clinical Study Experience
19. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
20. Has history or presence of risk factors for TdP (e.g., cardiac disease, heart failure, 
hypokalaemia or hypomagnesaemia, hypertrophy, cardiomyopathy, or family history of
long QT syndrome).  For Panel A, plasma calcium must be within normal limits at 
screening and serum calcium must be within normal limits prior to dosing.
Other Exclusions 
21. Is a smoker and/or has used nicotine or nicotine-containing products (e.g., nicotine patch 
and electronic cigarette) within 3 months of screening.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
22. Is under the age of legal consent.
23. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
24. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
25. 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 urine drug screen 
(UDS) prior to randomization.
26. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
27. 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.
Panel B, Panel C, and Panel D (Participants with Schizophrenia) Exclusion 
Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
28. 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.
29. Has evidence or history of mental retardation, borderline personality disorder, anxiety 
disorder, or organic brain syndrome.
30. Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia 
(TD).
31. Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse. 
32. Has a DSM-5 defined substance abuse or dependence disorder (excluding nicotine and 
caffeine) within three months of screening.
33. Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures. 
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
34. 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.
35. 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.
36. 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 
(e.g., 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.
37. Is a WOCBP who has a positive serum pregnancy test at the screening visit or a urine 
pregnancy test within 48 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. 
38. 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 opinion of the study 
investigator, are highly unlikely to sustain a recurrence for the duration of the study.
39. Has a clinically significant history or presence of sick sinus syndrome, first, second, or 
third degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, 
cardiac arrhythmia, prolonged QTc interval, or conduction abnormalities.
40. Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
41. Has a family history of sudden death.
42. 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.
 
 
059Y88

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CCI
CCI

PRODUCT: MK-8189  
59
PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Prior/Concurrent Clinical Study Experience
50. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
51. Has history or presence of risk factors for TdP (e.g., cardiac disease, heart failure, 
hypokalaemia or hypomagnesaemia, hypertrophy, cardiomyopathy, or family history of 
long QT syndrome).  Plasma calcium must be in within normal limits at screening and 
serum calcium must be within normal limits prior to dosing.
Other Exclusions 
52. Is under the age of legal consent.
53. Has been in incarceration or imprisonment within three months prior to screening.
54. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
55. 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.
56. 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 prior to 
randomization.
57. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
58. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
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09-SEP-2019
5.3
Lifestyle Considerations
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 Section 8.0.
Each study drug administration will need to be taken with 240 mL of water after an 8 hour 
fast. Water will be restricted 1 hour prior to and 1 hour after study drug administration.  
Subjects will remain fasting until 1 hour post dose.
On full PK sampling days and/or 24-hour Holter monitoring days, participants will fast from 
all food and drinks, except water, for at least 8 hours prior to study drug administration until 
1 hour post-dose. Participants will fast from all food and drinks except water between study 
drug administration and the first scheduled meal. Meals and snack(s) will be provided by the 
investigator at time points indicated in the SoA. Participants will fast from all food and 
drinks except water between meals and snacks. The caloric content and composition of meals 
will be the same on each full PK sampling and/or Holter evaluation day in each panel.  Meals 
and snacks will be served after any coinciding Holter and/or PK procedure. After the Day 15 
(Panel D) or Day 18 (Panel A, Panel B and Panel C) 48-hour post-dose procedures have been 
completed (Day 17 or Day 20, respectively for Panel D or Panel A, Panel B, Panel C), 
subsequent meals and snacks will be unrestricted in caloric content, composition and timing.
Meal and water restrictions on Day -1 (Panels A, B and D only) will be time-matched to 
those timepoints on 24-hour Holter/PK days when treatment is administered.  Similarly, meal 
and water restrictions will be time-matched on Day 19 and Day 20 (Panel A and B) and Day 
16 and Day 17 (Panel D) to 24-hour Holter/PK days when treatment is administered.
On intermediate days, participants will fast from all food and drinks, except water, for at least 
8 hours prior to study drug administration.  Participants will remain fasted until 1 hour
post-dose.  Meals and snacks should be standardized for caloric content, composition and 
timing.  Meals and snacks should be served after any scheduled ECG procedure.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study until 48 hours following last dose administration.
On full PK sampling and/or Holter days, participants will refrain from the consumption of all 
fruit juices 24 hours prior to study drug administration.
On intermediate days, the consumption of all fruits and fruit juices (except for grapefruit, 
grapefruit juices, and grapefruit products) is allowed.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 007-06 
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits. 
On full PK sampling and/or Holter days (Panels A and B: Day -1, Day 7, Day 10, Day 13, 
Day 16, Day 18 and Day 19; Panel C: Day 9, Day 12, Day 15 and Day 18; Panel D: Day -1, 
Day 1, Day 4, Day 7, Day 10, Day 13, Day 15 and Day 16), 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.
On intermediate days, caffeinated beverages or xanthine-containing products will be limited 
to no more than 6 units per day amounts (>6 units: 1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits. During the in-house period, consumption of alcohol is not allowed.  At all 
other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], 
wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
For Panel A (healthy participants), smoking (and/or the use of nicotine/nicotine-containing 
products) is not permitted during the study.
For Panel B, Panel C and Panel D (participants with schizophrenia), smoking restrictions 
(and if applicable, the use of nicotine/nicotine-containing products) defined by the CRU will 
be followed during the study.
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
 
 
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PROTOCOL/AMENDMENT NO.: 007-06 
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09-SEP-2019
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the electronic case report forms (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
A participant who discontinues from study intervention or withdraws from the study in 
Panel A or Panel B will not be replaced.
If a participant discontinues from study intervention or withdraws from the study in Panel C
or Panel D, a replacement participant may be enrolled if deemed appropriate by the 
investigator and Sponsor. The replacement participant will generally receive the same 
intervention or intervention sequence (as appropriate) as the participant being replaced. The 
replacement participant will be assigned a unique treatment/randomization number. The 
study site should contact the Sponsor for the replacement participant’s 
treatment/randomization number.
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 , MK-8189 and matching placebo, will be packaged to support enrollment . 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
Table 1
Study Interventions
Arm 
Name
Arm Type
Inter-
vention 
Name
Type
Dose 
Form
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen 
Use
IMP/
NIMP
Sourcing
Active
Experimental
MK-8189
Drug
Tablet
4 mg
All 
dosage 
levels
Oral
Panels A, B and 
C: Titration 
period, days 1-
18
Panel D: 
Titration period, 
days 1-15
Experimental
IMP
Provided 
centrally
Placebo
Placebo 
Comparator
MK-8189
Drug
Tablet
0 mg
All 
dosage 
levels
Oral
Panels A, B and 
C: Titration 
period, days 1-
18
Panel D: 
Titration period, 
days 1-15
Experimental
IMP
Provided 
centrally
 
 
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PRODUCT:  MK-8189  
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PROTOCOL/AMENDMENT NO.:  007-06  
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09-SEP-2019
All supplies indicated in Table 1 will be provided per the "Sourcing" row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product per local guidelines 
unless otherwise instructed by the Sponsor.
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
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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PRODUCT:  MK-8189  
65
PROTOCOL/AMENDMENT NO.:  007-06  
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09-SEP-2019
6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule in a 3:1 ratio within each Panel. The sample allocation schedules are provided in 
Table 2, Table 3 and Table 4.
Table 2
Panel A (healthy participants) and Panel B (participants with schizophrenia:
monotherapy) Sample Allocation Schedule
Panel
n
Days
1-3
Days
4-6
Days
7-9
Days
10-12
Days 
13-15
Days 
16-18
Aa
12
4 mg
8 mg
12 mg
16 mg
20 mg
24 mg
4
PBO
PBO
PBO
PBO
PBO
PBO
Bb
12
4 mg
8 mg
12 mg
16 mg
20 mg
24 mg
4
PBO
PBO
PBO
PBO
PBO
PBO
a.
Panel A allocation schedule will be stratified to Japanese and non-Japanese participants.  Japanese participants will 
be assigned the lower allocation range (first 8 numbers) and non-Japanese will be assigned the upper allocation 
range (last 8 numbers).  This will allow an equal number of active and placebo within the Japanese and non-Japanese 
participants.
b.
Panel B allocation schedule will not be stratified
Table 3
Panel C (participants with schizophrenia; add-on therapy) Sample Allocation 
Schedule
Panel
n
Days
1-3
Days
4-6
Days
7-9
Days
10-12
Days 
13-15
Days 
16-18
C
9
4 mg
8 mg
12 mg
16 mg
20 mg
24 mg
C
3
PBO
PBO
PBO
PBO
PBO
PBO
Table 4
Panel D (participants with schizophrenia: monotherapy) Sample Allocation 
Schedule
Panel
n
Days 1-3
Days 4-6
Days 7-9
Days 10-12
Days 13-15
D
12
8 mg
16 mg
24 mg
36 mg
48 mg
D
8
PBO
PBO
PBO
PBO
PBO
 
 
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CCI
CCI
CCI
CCI
CCI
CCI

PRODUCT:  MK-8189  
67
PROTOCOL/AMENDMENT NO.:  007-06  
MK-8189-007-06 FINAL PROTOCOL
09-SEP-2019
For healthy participants (Panel A), no concomitant medication/vaccinations are permitted, 
except for the necessary treatment of AEs (see also Section 6.5.1 on rescue medication).
Rescue Medications and Supportive Care
For the treatment of EPS, such as acute dystonia, all participants may be treated with an
anticholinergic. If the symptoms are unresponsive to anticholinergic treatment, a
benzodiazepine can be used.
In case the participant presents with signs of akathisia without signs of dystonia, the
participant can be treated with a β-adrenergic blocker. If symptoms do not disappear with
the β-adrenergic blocker, treatment with an anticholinergic may be used.  An anticholinergic 
may be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred 
treatment based on a participant’s medical history and/or concomitant medication.
Anticholinergics benzodiazepines and β-adrenergic blockers are often used in the treatment
of EPS and are considered standard practice. Oral anticholinergic treatment is also used as
concomitant medication to prevent EPS symptom with antipsychotic medication.
Panel B and Panel D participants 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 inhibitors or inducers of CYP3A and CYP2C9 (see Section 6.5 for further details), thus no 
effect on the PK of MK-8189 would be expected during co-administration.  
6.6
Dose Modification (Escalation/Titration/Other)
All dose titration decisions will be made jointly by the investigator and the Sponsor. Each 
dose titration decision for each individual participant will occur after 3 days of dosing per 
dose level.
Dose titration decisions for each participant will be based on available (as per the SoA) 
safety variables: VS, 12-lead safety ECG, laboratory safety tests, AEs, C-SSRS, BPRS, and 
EPS evaluations from the previous dose levels. Pharmacokinetic and pharmacodynamic data 
may be included in the dose titration decisions.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose titration, the dose will not be increased as planned. Instead, participants may:

Skip a single dose and dosing may continue at the same dose level or adjusted 
downwards 

Receive the same dose level to further explore safety and tolerability at that level

Receive a lower dose of the study intervention
 
 
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
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 following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity . The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.11). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
This  study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.10, 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 8.1.10.
 
 
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A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant 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 treatment.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen at any time during the course of the 
study.
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 8.1.10, or if available, a protocol 
clarification letter.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. 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.
 
 
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•
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 or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed 500 mL (Appendix 10).
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
 
 
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8.1
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant prior to participating in a clinical 
study or future biomedical research .If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent form or addendum to 
the original consent form that captures the participant’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
 
 
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Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/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.
Medical History
A medical history will be obtained by the investigator or qualified designee. This should also 
include any psychiatric history of the participant.
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 14 days before starting the study for Panel A (healthy participants) and within 
3 months of starting the study for Panel B, Panel C and Panel D (participants with 
schizophrenia).  Use of any prescription or nonprescription medication during the washout 
period of Panel B and Panel D 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.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Washout from Antipsychotics
All participants in Panel B and Panel D 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.
 
 
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Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.10.1.
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 re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
8.1.9.1
Timing of Dose Administration
MK-8189/placebo dosing will occur once daily in the morning following an 8 hour fast.  
Participants will receive each oral dose of MK-8189 /placebo with ~240 mL water.
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 post-study visit (approximately 14 days 
after the last dose of study intervention is given) 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 14 days after the last dose of study intervention is given, the investigator 
should perform a follow-up telephone call 14 days after the last dose of study intervention  to 
determine if any AEs have occurred since the post-study clinic visit. Any AEs that are 
present at the time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4.
 
 
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8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
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 drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the intensity
of the AEs observed, the relation to study drug, the reason thereof, etc., in the medical chart. 
If it is not possible to record this assessment in the chart prior to the unblinding, the 
unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
 
 
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Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Domiciling
Participants in Panel A will report to the CRU on Day -2 prior to the scheduled day of study 
intervention administration on Day 1. Participants in Panel B and Panel D will be confined to 
the CRU within a week of beginning their antipsychotic washout and at least 6 days prior to 
treatment with MK-8189 on Day 1. Participants in Panel C will report to the CRU on Day -1
prior to the scheduled day of study intervention administration on Day 1. All participants in 
Panel A, Panel B and Panel C will remain in the CRU until Day 21 (72 hours following the 
last dose). Participants in Panel D will remain in the CRU until Day 18 (72 hours following 
the last dose). At the discretion of the investigator, participants may be requested to remain in 
the CRU longer.
Participants may be permitted to leave the unit, for emergency situations only, during the 
domiciling period at the discretion of the investigator after discussion with the Sponsor. The 
decision how to monitor the participant will be at the discretion of the investigator after 
discussion with the Sponsor.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy or immunogenicity assessments in this study. 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Section 10.10.
Planned time points for all safety assessments are provided in the SoA.
 
 
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Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI)
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1-0.4 round down and 0.5-0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
Vital Signs
•
Oral temperature, pulse rate, respiratory rate, and BP will be assessed at prespecified 
timepoints noted in the SoA (Section 1.3).
•
Blood pressure and pulse measurements will be assessed semi-recumbent with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
8.3.3.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a semi-recumbent for at least 10 minutes prior to having VS 
measurements obtained. Semi-recumbent will include HR and BP. 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 in triplicate measurements, obtained at least 1-2 
minutes apart on Day -1 as per the SoA. 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.
8.3.3.2
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.
 
 
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8.3.3.3
Orthostatic Vital Signs
Orthostatic VS (HR and BP) will also be obtained. Participants should be semi-recumbent for 
at least 10 minutes and then stand upright after the resting vitals for approximately 3 minutes 
prior to measurement of orthostatic VS.
Electrocardiograms
12-Lead Safety Electrocardiogram
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent for at least 10 minutes prior to each 
ECG measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
In all Panels, baseline (prior to Day 1 dosing) ECGs will be obtained in triplicate at least
1-2 minutes apart as per the SoA. The mean of these measurements will be used as the 
baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed). 
In Panels A, B and D, postdose ECG measurements will be single measurements. In Panel C, 
postdose ECG measurements will be obtained in triplicate at least 1-2 minutes apart as per 
the SoA.
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 10 minutes (applies to Panels A, B and D only as Panel C will have triplicate post 
dose ECG evaluations). The mean value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the mean QTc interval increase from baseline for any postdose 
time point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study cardiologist 
may be appropriate and the Sponsor should be notified.
If the 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 (e.g., a cardiac or intensive care unit) is available.
 
 
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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 study cardiologist will be consulted by the Principal Investigator as needed to review ECG 
tracings with abnormalities.
24-Hour Holter Assessment (Panel A ,Panel B and Panel D only)
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 in each trial period. Participants will not be allowed to shower/bath for the 
duration of the 24-hour Holter assessment.
Holter data will be extracted (in triplicate) and analyzed by a blinded core ECG laboratory 
according to a pre-specified algorithm. To minimize artifacts, participants must rest quietly in 
a semi-recumbent position for ~10 minutes prior to the time points specified for extraction. 
No other study assessments or procedures should occur during the resting period.
Please see Trial Procedures Manual for Holter-specific procedures provided by the ECG
vendor.
Procedures for transfer, archiving, and review of ECGs will be specified by the ECG vendor.
Pregnancy Testing
Female subjects of childbearing potential will be tested for serum and/or urine β-hCG at 
specific timepoints outlined in the SoA.  In the case of a positive or borderline serum β-hCG 
pregnancy test at the pre-trial (screening) visit, the subject must not enter the trial; in the case 
of a positive or borderline urine β-hCG pregnancy test during the trial, a serum β-hCG
pregnancy test will be required.  If the pregnancy has been confirmed the subject must be 
discontinued from the trial immediately and the pregnancy must be reported to the Sponsor 
as outlined in Section 8.4.5.   
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.
 
 
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•
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 case report form 
(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 procedures 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.
Suicidal Ideation and Behavior Monitoring
8.3.7.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the 
C-SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff
should review the contents of the C-SSRS for completeness. If the C-SSRS is administered 
by someone other than the investigator, consider providing the completed C-SSRS to the 
investigator for review, prior to their assessment of the participant and to further inform their 
evaluation. The C-SSRS is not explicit about whether the participant specifically has ideation 
at the time of screening. If a participant reports a prior history of ideation/behavior at 
screening, the assessor should also inquire and document if this is also present at the time of 
the screening visit.
Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an adverse event, either between visits or during visit interviews, must be 
assessed by the Investigator.  Participants who report suicidal ideation with intent, with or 
without a plan or method (i.e., a positive response to items 4 or 5 in the assessment of 
suicidal ideation on the C-SSRS) or suicidal behavior must be evaluated that day by a 
psychiatrist or other trained mental health professional who is a licensed psychologist, social 
worker or mental health nurse practitioner (or comparable professional qualification in 
countries outside of the United States).  Only participants whose suicidal ideation is passive, 
who expressly deny any intent to act, and who, after evaluation, are not judged to be at 
 
 
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serious risk for self-harm during the course of the study may continue in the study; others 
must be discontinued from study participation and receive appropriate clinical follow-up care 
to ensure their safety.  In addition, all AEs of suicidal ideation or behavior must be recorded 
as an Event of Clinical Interest (see Section 8.4.7).  Sites are to designate which health care 
professionals are to be responsible for acute care on-site and to specify referral center(s) to be 
used for further evaluation.
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 if it is observed or a participant reports complaints of 
dystonia and or akathisia.
Assessment of Neuropsychological Effects
For the assessment of the psychological effects, all participants will complete the VAS
at times specified in SoA. Prior to the initial administration of the VAS participants will be 
trained by study staff and will practice the assessment.
In addition, participants with schizophrenia will also complete the BPRS at times specified in 
SoA.
A General Neurological Exam will be performed at the Screening and Baseline visits for all
participants. A targeted Neurological Exam will be administered at times specified in the 
SoA. Details of the neurological examinations are in Appendix 11 and Appendix 12.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, 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.
 
 
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Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization, must be reported by the investigator for 
randomized participants only if the event is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment, or a procedure.
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
 
 
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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
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Non-Serious 
Adverse Event 
(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
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
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:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
Event of Clinical 
Interest (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
 
 
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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.
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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
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.
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. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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. 
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs 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, that is not associated 
with clinical symptoms or abnormal laboratory results.
2.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3.
Suicidal ideation and/or suicidal behavior as reported in the C-SSRS scores, TEAEs 
or any self-injurious behavior
4.
Dystonia
5.
New or worsening tardive dyskinesia
6.
QTcF interval of ≥500 msec (the average of the three QTcFs will be used)
 
 
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8.5
Treatment of Overdose
The participant has taken (accidentally or intentionally) any drug administered as part of the 
protocol that exceeds the dose as 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.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of PK/PD
will be collaboratively determined by the Sponsor (e.g., samples at lower doses may not be 
assayed if samples at higher doses reveal undetectable drug concentrations). If indicated, 
these samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional PD markers.
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the procedures manual.
Urine Collection for MK-8189 and metabolite profiling
Sample collection, storage, and shipment instructions for urine samples will be provided in 
the procedures manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters, other than QTc and other ECG parameters, will not be 
evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:

Blood for Genetic Analysis
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for CYP2C9 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CYP2C9. Leftover extracted DNA will be stored for future biomedical 
research if the participant signs the future biomedical research consent.
 
 
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Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the procedures manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research 
•
Leftover main study plasma from MK-8189 and/or metabolites assay stored for future 
research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
Screening
Within approximately 4 weeks prior to treatment allocation/randomization, potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Sections 5.1 and 5.2.
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 treatment allocation/randomization if there 
are Day -1 procedures planned per protocol.
Treatment Period
Panel A: Healthy participants that meet selection criteria for enrollment will participate in 
Panel A, 16 participants in total. Participants will report to the CRU on Day -2 to undergo 
procedures in SoA.  
Panel B and Panel D: Participants with schizophrenia that meet selection criteria for
enrollment will participate in Panel B or Panel D, 16 participants or 20 participants, 
respectively, in total. Participants must be washed out from their antipsychotic medication
for at least 5 days prior to the Day -1 Holter assessment. Participants will report to the CRU
within a week of the start of their washout, minimally on Day -6.
Panel C: Participants with schizophrenia that meet selection criteria for enrollment will
participate in Panel C, 12 participants in total. Participants will report to the CRU on Day -1
to undergo procedures in SoA.  
On treatment days between Day 1 and Day 18 (Panel A, B and C) or Day 1 and Day 15
(Panel D), participants will be dosed once daily with MK-8189/placebo and have procedures 
 
 
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completed per the SoA.  Participants will remain in the unit through Day 21 (Panel A, B, C) 
or Day 18 (Panel D) procedures and discharged at the discretion of the investigator.
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
Poststudy
After completion of treatment, participants in Panel B and Panel D will resume the use of
their own antipsychotic medication after the Day 18, 48 hour post-dose (Day 20 - Panel B) or 
Day 15, 48 hour post-dose (Day 17 - Panel D) PK sample has been collected. A phone call 
should occur after 5-7 days after CRU discharge to check for any side effects and medication 
compliance.
All participants will be required to return to clinic approximately 14 days after the last dose 
of study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days 
after the last dose of study intervention, a subsequent follow-up telephone call should be 
made at 14 days post the last dose of study intervention to determine if any AEs have 
occurred since the poststudy clinic visit.
8.11
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the timing of the ECG extraction from the 24-hour Holter recording, and 
blood sample for MK-8189 and ECG collection are the critical procedures. At any postdose 
time point, these assessments will be collected close to the exact time point as possible. The 
PK sample should follow immediately after the Holter extraction is complete.
These procedures will be performed in the following order (below) with regard to the 
prescribed time.  These procedures can be done prior to or after the time point.
1.
Holter ECG assessment (extraction period)
2.
Resting VS
3.
Orthostatic VS
4.
Blood for MK-8189
As a blood sample for assessment of MK-8189 plasma concentration, 12-lead safety ECGs, 
and resting and orthostatic VS are planned at the same timepoint, the order of execution is as 
follows:
1.
12-lead safety ECG
 
 
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2.
Resting VS
3.
Orthostatic VS
4.
Blood for MK-8189
All other procedures should be completed as close to the prescribed/scheduled time as 
possible. Study procedures can be performed prior or after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
Predose standard safety evaluations: 12-lead safety ECGs within 2 hours prior to dosing; 
laboratory safety tests within approximately 48 hrs prior to dosing
•
Postdose standard safety evaluations: 12-lead safety ECG, and VS
a.
Day 1 postdose through Day 18 (Panels A, B and C) postdose or Day 1 postdose 
through Day 15 (Panel D) postdose may be obtained +/- 15 min of the theoretical 
sampling time
b. Day 19 postdose through Day 21 (Panels A, B and C) or Day 16 postdose through Day 
18 (Panel D) may be obtained +/- 30 min of the theoretical sampling time
•
Postdose laboratory safety tests on Days 1 through 18 may be obtained:
a.
For blood: within -90 minutes from the theoretical sampling time
b. For urine: within -120 minutes from the theoretical sampling time.
•
Predose and Postdose ECG Holter extractions may be obtained -15/+5 minutes from the 
theoretical sampling time.
•
PK collections: 
a.
May be obtained -5/+10 minutes from the theoretical sampling time.
b. Must be obtained no more than +10 minutes after the end of the ECG Holter extraction
window at each theoretical timepoint.
c.
Must NOT be taken prior to the end of the ECG Holter extraction window.
 
 
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d. Must be obtained no more than +15 minutes after the 12-lead safety ECG at each 
theoretical timepoint and must be collected following vital sign assessments. 
•
Study intervention administration: +/- 30 mins
8.12
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8189 in humans, and the PK, PD, and safety profiles of 
the compound are still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase 1 clinical studies. Modifications to the 
dose, dosing regimen, and/or clinical or laboratory procedures currently outlined may be 
required to achieve the scientific goals of the study objectives and/or to ensure appropriate 
safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.

Repeat of or decrease in the dose and/or titration steps of the study intervention 
administered in any given day/panel.

Entire panel may be omitted.

Adjustment of the dosing interval (e.g., divided doses [BID to QD, QD to BID, TID, or 
vice versa]).

Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data.

Modification of the PK/PD sample processing and shipping details based on newly 
available data.

A single dose may be skipped, and dosing may continue at the same dose level or 
adjusted downwards. 
The PK/PD sampling scheme currently outlined in the protocol may be modified during the 
study based on newly available PK or PD data (e.g., 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 PD markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or PD analyses. The total 
blood volume withdrawn from any single participant will not exceed the maximum allowable 
volume during his/her participation in the entire study (Section 10.10).
The timing of procedures for assessment of safety procedures (e.g., VS, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
 
 
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Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 9.2).
Safety: Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead 
ECGs, and/or VS as well as for change from baseline, as deemed clinically appropriate.  
Depending on the safety parameter, the difference from baseline will either be computed on 
the original scale (raw change from baseline) or on the log scale and back-transformed for 
reporting (percent change from baseline). For Panels A, B, and C, Day -1 8hr serves as a 
baseline for post-dose vital sign readings. For Panel D, Day -1 8 hr, 10 hr, and 16 hr readings 
will serve as time-matched baselines for the corresponding post-dose vital sign readings.
For all panels, summary statistics and plots will be generated for Barnes Akathisia Rating 
Scale (BARS), Abnormal Involuntary Movement Scale (AIMS) and Simpson Angus Scale 
(SAS), Bond and Leader Visual Analogue Scale (VAS), and Brief Psychiatric Rating Scale 
(BPRS) as well as for change from baseline.  The difference from baseline will be computed 
on the original scale (raw change from baseline). Responses to the C-SSRS will be listed.
PK Summary: 
Panel A (healthy participants: Japanese and non-Japanese) : Separately for each PK 
parameter, individual values of AUC0-24hr, Cmax, and C24hr at each dose level (and day 
where applicable) will be natural log-transformed and evaluated with a linear mixed effects 
model containing a fixed effect for dose, population (Japanese, Non-Japanese), and 
population by dose and a random effect for subject. 
Panels B and D (schizophrenia participants: monotherapy), Panel C (schizophrenia 
participants: add-on therapy),: Separately for each panel and PK parameter, individual values 
of AUC0-24hr, Cmax, and C24hr at each dose level (and day where applicable) will be 
natural log-transformed and evaluated with a linear mixed effects model containing a fixed 
effect for dose and a random effect for subject.  
For each population and PK parameter, geometric means (GM) and corresponding 
ninety-five percent confidence intervals (CI) for each dose will be provided.
 
 
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Cardiodynamic Analysis:  
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.  Separate models may be evaluated for each population. 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.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Objectives:
To evaluate the safety and tolerability of rising multiple once-daily oral doses of MK-8189 in 
participants with schizophrenia (monotherapy and add-on) and healthy Japanese and non-
Japanese participants
To estimate the pharmacokinetics for MK-8189 following multiple once-daily oral doses in 
participants with schizophrenia (monotherapy and add-on) and in healthy Japanese and 
non-Japanese participants
To evaluate the effect of MK-8189 concentrations on QTc interval and other ECG 
parameters
9.4
Analysis Endpoints
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse experiences, in addition to 
laboratory safety tests, 12-lead ECGs, and VS. Baseline is defined as day 1 predose (Day -1 
for VS) reading. 
BARS, AIMS, SAS, VAS and BPRS 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). Responses on the 
C-SSRS are classified according to 11 prespecified categories as described in procedure 
manual. The most severe treatment-emergent ideation and behavior event reported at a visit 
 
 
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will be used for analysis and reporting. An event is considered treatment-emergent during the 
assessment phase if it newly emerged or is more severe compared to recent history (i.e., 
protocol-defined recent history prior to entering the trial as stated in the Inclusion/Exclusion 
criteria for suicidal ideation/behavior, up to and including the randomization visit).
Secondary Endpoints
Pharmacokinetics: The PK variables MK-8189 (AUC0-24hr, Cmax, C24hr, Tmax, CL, Vd 
and t1/2) are of secondary interest.
Exploratory Endpoints
Cardiodynamics: QTc change from baseline (Holter ECGs for Panels A, B, and D and 
triplicate 12-lead safety ECG measurements for Panel C), HR, RR interval, PR interval, and 
QRS duration. U and T wave morphology are of exploratory interest
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data.  All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received. 
All Participants as Treated (APasT): The All Participants as Treated Population consists of 
all participants who received at least one dose of treatment.  This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of participants who comply with the protocol sufficiently to ensure that these data will 
be likely to exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
measurements and absence of important protocol deviations.  Important protocol deviations 
will be identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation.  Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.  
At the end of the study, all participants who are compliant with the study procedure as 
aforementioned and have available data from at least one treatment (dose level) will be 
included in the Per-Protocol dataset. This population will be used for the PK and 
Concentration-QTc analyses.
9.6
Statistical Methods
Safety 
Summary statistics and plots will be generated for raw laboratory safety tests, 12-lead ECGs, 
and/or VS as well as for change from baseline, as deemed clinically appropriate.  Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline). 
 
 
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For all panels, summary statistics and plots will be generated for BARS, AIMS, SAS, VAS, 
and BPRS as well as for change from baseline.  The difference from baseline will be 
computed on the original scale (raw change from baseline). Responses to the C-SSRS will be 
listed.
Pharmacokinetics
Model-Based PK Summary 
The PK parameters in healthy (Panel A), and schizophrenia (Panels B, C, and D), will be 
evaluated separately as variability in PK parameters in schizophrenia participants may differ 
from those in the healthy participants and these panels also differ in the day when the PK are 
collected. Furthermore, the PK parameters in Panel B and D will be evaluated separately as 
these panels differ in the day when the PK data are collected.
Panel A (healthy participants: Japanese and non-Japanese): Separately for each PK 
parameter, individual values of AUC0-24hr, Cmax, and C24hr at each dose level (and day 
where applicable) will be natural log-transformed and evaluated with a linear mixed effects 
model containing a fixed effect for dose, population (Japanese, Non-Japanese), and 
population by dose and a random effect for subject. Kenward and Roger's method will be 
used to calculate the denominator degrees of freedom for the fixed effects.  For each 
population, ninety-five percent 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 CIs about the GMs on the original scale.
Panels B and D (schizophrenia participants: monotherapy), Panel C (schizophrenia 
participants: add-on therapy), ): Separately for each panel and PK parameter, individual 
values of AUC0-24hr, Cmax, and C24hr at each dose level (and day where applicable) will 
be natural log-transformed and evaluated with a linear mixed effects model containing a 
fixed effect for dose, and a random effect for subject.  Geometric means (GM) and 
corresponding 95% CIs for each dose will be provided.
Descriptive Statistics 
For each panel individual values will be listed for each PK parameter AUC0-24hr, Cmax, 
C24hr, Tmax, CL, Vd, and t1/2 by dose (and day where applicable), and the following (non-
model-based) descriptive statistics will be provided: N (number of participants with non-
missing data), arithmetic mean, standard deviation, arithmetic  percent CV (calculated as 
100 x standard deviation/arithmetic mean), median, minimum, maximum, GM, and 
geometric percent CV (calculated as  100 x sqrt(exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale).
 
 
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General
For the above PK analyses, data will be examined for departures from the assumptions of the 
statistical model(s) as appropriate; e.g., heteroscedasticity, nonnormality of the error terms.  
Distribution-free methods may be used if a serious departure from the assumptions of the 
models(s) is observed, or suitable data transformations may be applied.
Cardiodynamic Analysis 
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.  Separate models may be evaluated for each population. 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 subjects on each treatment is consistent with those deemed to be 
adequate in the Scientific White Paper on Concentration-QTc Modeling [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
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, 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 (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), 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 to identify potentially eligible participants.
 
 
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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 (eg, 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.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
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.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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 International Committee 
of Medical Journal Editors authorship requirements.
 
 
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Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
Compliance with Law, Audit, and Debarmen
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); 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 Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
 
 
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Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
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.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
 
 
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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 will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
• The tests detailed in Table 6 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.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception 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 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline phosphatase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
Microscopic examination (if blood or protein is abnormal)
 
 
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
Follicle-stimulating hormone (as needed in women of nonchildbearing potential 
only)
Urine alcohol, cotinine (Panel A only) and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines; If 
the clinical site's drug screen evaluation routinely detects additional agents, the 
relevance of positive findings for exclusion will be discussed with the Sponsor.)
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed 
for WOCBP)
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) 
• WBC Differential: absolute or % acceptable per institutional standard.
• Creatinine: GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
NOTES:
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
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, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, 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, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
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.
 
 
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•
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
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
 
 
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•
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.
(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 
 
 
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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 case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
 
 
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•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, 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 electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study and if HRT use is permitted per protocol. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
 
 
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
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.
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
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to the hormonal contraception.
d
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 condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d.
DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.
Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
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b.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.
Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13.
References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: 12-Lead Electrocardiogram Abnormality Criteria
If criteria listed in table below differ from inclusion/exclusion criteria, the most conservative 
criteria should be used.
12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant Post-
Randomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 beats per minute 
(bpm)
HR >110 bpm  and HR increase of ≥ 25 
bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of ≥5 bpm 
from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial premature complex
1 beat
≥3 beats
Ventricular premature complex
All
≥3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with 
HR <40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB with Left Anterior 
Hemiblock (LAHB)
New onset LAHB
Right Axis Deviation
RBBB with Left Posterior 
Hemiblock (LPHB)
New onset LPHB
CONDUCTION
1st degree A-V Block
PR ≥230 ms
PR ≥230 ms + increase of 15 ms; or PR 
increase of >25%
2nd degree A-V Block
Mobitz Type II
Mobitz Type II
3rd degree A-V Block
All
All
LBBB   
All
All
RBBB   
RBBB with LAHB/LPHB 
as defined above
New onset RBBB (not including rate-
related)
 
 
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12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant Post-
Randomization Findings 
(clarification on action to take)
Incomplete Right BBB 
(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
MYOCARDIAL  INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST elevation suggestive of 
Myocardial Injury 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST depression suggestive of
Myocardial Ischaemia 
In 2 or more contiguous  
leads
In 2 or more contiguous  leads
T-wave Inversions suggestive of  
Myocardial Ischaemia 
In 2 or more contiguous  
leads
In 2 or more contiguous leads
Non-specific ST-T changes 
(In 2 or more leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1
ms=milliseconds, mm=millimeter
 
 
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10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The participant may be excluded from the study;
2. The participant may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (e.g., elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in question. If 
such diseases can be ruled out, and if the abnormal laboratory value is not clinically 
relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.10 Appendix 10: Blood Volume Table
All Panels
Pre-trial
Treatment 
Period
Post-trial
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory safety tests
(included FSH and 
β-hCG)
1
4
1
6
12.5
75.0
HIV/Hepatitis Screen 
(at the discretion of 
the investigator)
1
1
8.5
8.5
Blood for Planned 
Genetic Analysis  
1
1
8.5
8.5
Blood for MK-8189
(Panels A and B)
43
43
4.0
172.0
Blood for MK-8189 
(Panel C)
35
35
4.0
140.0
Blood for MK-8189 
(Panel D)
49
49
4.0
196.0
Total Blood Volume Participant (Panels A and B)† 264.0 mL
Total Blood Volume Participant (Panel C)† 232.0 mL
Total Blood Volume Participant (Panel D) † 288.0 mL
† If additional PK and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained.  
 
 
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10.11 Appendix 11: General (Full) Neurological Exam
The General Neurological Examination includes all the modules listed below and is 
intended to be a general screening examination.
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal: Generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention.
B. Thought Processes and Language: Generally assess logic, relevance, organization and 
coherence of volunteer’s use of language throughout the interview.
C. Orientation (time, place, person)
D. Attention/Concentration
Ask the subject to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite months 
backwards or spell a 5 unique letter word (e.g. “WORLD”) backwards.  
Note: to avoid learning effects, switch between tests throughout the study
E. Memory:   Test registration of 3 objects; then test immediate recall 5 minutes later.
Grade: 
NORMAL or IMPAIRED and describe abnormality (for each, A to E, 
above).  Normal performance on Serial 7’s is getting to 65 with no more than one error. 
 
 
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MODULE 2 – CRANIAL NERVE ASSESSMENT
A. II – Visual Fields and acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of gaze 
or other oculomotor changes (mild nystagmus at extremes of gaze is normal). Note 
direction of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test e.g. by rubbing fingers 
on each side of subject’s head or by whispering numbers)
G. IX – Gag reflex
H. X – Swallow 
I. XI – Shoulder shrug
J. Tongue Protrusion (midline)
Score: left and right (except for G, H, J)
Grade: NORMAL or IMPAIRED and describe abnormality
 
 
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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
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
 
 
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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.
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
 
 
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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
 
 
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MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible. 
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the subject will be asked to 
strike his hand on the thigh, raise the hand, turn it over and then strike the back of the 
hand down on the same place.  (This test is impaired in cerebellar disease, extra 
pyramidal disease and upper MN weakness.)
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)
 
 
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10.12 Appendix 12: Targeted Neurological Exam
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal: Generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example difficulty remembering or following  
instructions or distractibility may be signs of inattention)
MODULE 2 – CRANIAL NERVE ASSESSMENT
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is 
normal). Note direction of nystagmus
MODULE 3 - MOTOR SYSTEM
B. Muscle Tone
1. Ask the volunteer to relax.
2. Flex and extend the volunteer’s elbows (may also move wrists simultaneously) and at 
the knees (bilaterally). When testing the upper limbs, do this again while the subject 
makes large repetitive movements with the opposite arm (e.g. patting the palm of the 
hand on the knee).
3. There is a small, continuous resistance to passive movement.
Score:  left and right
Grade: NORMAL, IMPAIRED, or DECREASED and describe abnormality
 
 
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MODULE 5 - COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible. 
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the subject will be asked to 
strike his hand on the thigh, raise the hand, turn it over and then strike the back of the 
hand down on the same place.  (This test is impaired in cerebellar disease, extra 
pyramidal disease and upper MN weakness.)
D. Gait
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally.
 
 
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
AAP
atypical anti-psychotics
AE
adverse event 
AIMS
Abnormal Involuntary Movement Scale
BARS
Barnes Akathisia Rating Scale
BPRS
Brief Psychiatric Rating Scale
CRF
case report form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EPS
extrapyramidal symptoms
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
NOAEL
no observed adverse effect level 
PANSS
positive and negative symptoms scale
PK
pharmacokinetic
RNA
ribonucleic acid
SAE
serious adverse event 
SAS
Simpson Angus Scale
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
UDS
urine drug screen
VAS
Visual Analogue Scale
WONCBP
woman/women of non-childbearing potential
WOCBP
woman/women of childbearing potential 
 
 
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11
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