Conditions: Hepatic Impairment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: yes

Brief summary:
The purpose of this study is to compare the pharmacokinetics (PK) of MK-8189 in participants with moderate hepatic impairment (based on the Child-Pugh classification) to healthy participants. This is Part 1 of the study; following review of the safety and PK data from Part 1, a decision will be made as to whether Part 2 of the study will be initiated. If done, Part 2 of the study will compare the PK of MK-8189 in participants with mild hepatic impairment to healthy participants.

Detailed description:

Arms:
arm 1: Participants with hepatic impairment will receive a single dose of MK-8189 4 mg orally on Day 1. arm 2: Healthy participants will receive a single dose of MK-8189 4 mg orally on Day 1.

Interventions: intervention 1: MK-8189
Intervention descriptions: intervention 1: Administered at a dose of 4 mg via oral tablet

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04676425 
Document Date: 
09-Feb-2021
A 2-part, open-label, single-dose study to investigate the influence 
of hepatic impairment on the pharmacokinetics of MK-8189


PRODUCT: MK-8189  
1
PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
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 2-part, open-label, single-dose study to investigate the influence of hepatic 
impairment on the pharmacokinetics of MK-8189
This protocol amendment is applicable only to the United States.
Protocol Number: 012-01
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 February 2021
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 012-01 
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09-FEB-2021
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  
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PROTOCOL/AMENDMENT NO.: 012-01 
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09-FEB-2021
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01/ 
Site 0001 Specific 
Amendment
09-FEB-2021
The protocol was amended to (1) include the site 0001-specific requirement of inclusion 
of the C-SSRS as required by the IRB for site 0001, (2) amend the Child-Pugh
classification of the severity of disease, and (3) clarify the primary endpoints of the trial. 
Changes to the contraceptive language and QTC interval criteria were also updated to 
align with FDA feedback on other MK8189 protocols.
Original Protocol
24-NOV-2020
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The protocol was amended to (1) include the site 0001-specific requirement of inclusion of the C-SSRS as required by the IRB for site 
0001, (2) amend the Child-Pugh classification  of the severity of disease, and (3) clarify the primary endpoints of the trial. Changes to 
the contraceptive language and QTC interval criteria were also updated to align with FDA feedback on other MK8189 protocols.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
3 Hypotheses, Objectives, 
and Endpoints
9.3 Hypotheses/Estimation

Primary endpoints were updated to 
include only AUC0-inf and Cmax

Estimation for primary endpoints updated 
to include only AUC0-inf and Cmax 

Exploratory PK objectives and endpoints 
( e.g. AUC0-24, C24, Tmax, CL/F, Vz/F 
and apparent terminal t½) were added 
While the other PK parameter values will be 
reported as exploratory endpoints, only AUC0-inf 
and Cmax are considered primary endpoints
5.1 Inclusion Criteria

Clarify language regarding WOCBP and 
abstinence
To align with FDA feedback on other MK-8189 
protocols
 
 
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Section # and Name
Description of Change 
Brief Rationale 
10.7 Appendix 7: 
Country/Site-specific 
Requirements

Added the C-SSRS - Baseline Version 
and C-SSRS - Since Last Assessment 
Version to the schedule of activities as 
well as further explanation of monitoring 
procedures. 

Exclusion criteria for healthy and 
hepatically impaired participants have 
both been updated for the standard C-
SSRS and suicidality related text. 

Added information on how safety data 
will be collected and reported based on 
addition of the standard C-SSRS.
Inclusion of site specific requirements for site 0001, 
per the request of IRB for site 0001 to include C-
SSRS to evaluate participant safety. Standard 
information surrounding the C-SSRS were added 
and updated as a result.
10.9 Appendix 9 12-Lead 
Electrocardiogram 
Abnormalities

Update QTc interval  criteria 
Update QTc interval criteria to align with exclusion 
criteria
10.11 Appendix 11 Child-
Pugh classification of the 
severity of liver disease  

Added a footnote to Child-Pugh
classification table in relation to 
assessment of ascites which indicates that
if a participant has ascites controlled by 2 
medications they may be assigned 2 
points.
When diuretics are used to control ascites it is 
common for a combination of a potassium sparing 
and potassium wasting diuretics to be used to 
mitigate issues with potassium imbalance, thus the 
use of 2 medications may not necessarily indicate 
more severe ascites and 2 points, as opposed to 3 
points, may be assigned based on  the modified 
Child-Pugh classification method.
10.12 Appendix 12: 
Abbreviations

Added C-SSRS as an abbreviation
Inclusion of the C-SSRS as a new abbreviation used 
throughout the document
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
1.3.1
Hepatic Impairment Participants..................................................................18
1.3.2
Healthy Matched Participants......................................................................22
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Preclinical and Clinical Studies ...................................................................26
2.2.2.1
Preclinical PK ....................................................................................26
2.2.2.2
Clinical Studies..................................................................................26
2.2.3
Ongoing Clinical Studies.............................................................................27
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................33
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Safety Endpoints................................................................................35
4.2.1.2
Pharmacokinetic Endpoints ...............................................................35
4.2.1.3
Planned Exploratory Biomarker Research.........................................35
4.2.1.3.1
Planned Genetic Analysis ........................................................35
4.2.1.4
Future Biomedical Research..............................................................35
4.3
Justification for Dose...........................................................................................36
4.3.1
Rationale for Dose Interval and Study Design ............................................36
4.4
Beginning and End of Study Definition .............................................................36
4.4.1
Clinical Criteria for Early Study Termination .............................................37
5
STUDY POPULATION ................................................................................................37
5.1
Inclusion Criteria.................................................................................................37
5.1.1
Inclusion Criteria for Healthy Participants ..................................................37
5.1.2
Inclusion Criteria for Hepatically Impaired Participants.............................39
 
 
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5.2
Exclusion Criteria................................................................................................40
5.2.1
Exclusion Criteria for Healthy Participants.................................................40
5.2.2
Exclusion Criteria for Hepatically Impaired Participants............................43
5.3
Lifestyle Considerations......................................................................................45
5.3.1
Meals and Dietary Restrictions....................................................................45
5.3.1.1
Diet Restrictions.................................................................................45
5.3.1.2
Fruit Juice Restrictions ......................................................................46
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................46
5.3.2.1
Caffeine Restrictions..........................................................................46
5.3.2.2
Alcohol Restrictions...........................................................................46
5.3.2.3
Tobacco Restrictions..........................................................................46
5.3.3
Activity Restrictions ....................................................................................46
5.4
Screen Failures.....................................................................................................46
5.5
Participant Replacement Strategy......................................................................47
6
STUDY INTERVENTION............................................................................................47
6.1
Study Intervention(s) Administered...................................................................47
6.2
Preparation/Handling/Storage/Accountability .................................................49
6.2.1
Dose Preparation..........................................................................................49
6.2.2
Handling, Storage, and Accountability........................................................49
6.3
Measures to Minimize Bias: Randomization and Blinding..............................50
6.3.1
Intervention Assignment..............................................................................50
6.3.2
Stratification.................................................................................................50
6.3.3
Blinding........................................................................................................50
6.4
Study Intervention Compliance..........................................................................50
6.5
Concomitant Therapy..........................................................................................51
6.5.1
Rescue Medications and Supportive Care ...................................................51
6.6
Dose Modification ................................................................................................52
6.7
Intervention After the End of the Study............................................................52
6.8
Clinical Supplies Disclosure................................................................................52
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................52
7.1
Discontinuation of Study Intervention...............................................................52
7.2
Participant Withdrawal From the Study...........................................................52
7.3
Lost to Follow-up .................................................................................................53
8
STUDY ASSESSMENTS AND PROCEDURES........................................................53
8.1
Administrative and General Procedures ...........................................................54
8.1.1
Informed Consent.........................................................................................54
8.1.1.1
General Informed Consent.................................................................54
 
 
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................55
8.1.2
Inclusion/Exclusion Criteria ........................................................................55
8.1.3
Participant Identification Card.....................................................................55
8.1.4
Medical History ...........................................................................................55
8.1.5
Prior and Concomitant Medications Review...............................................55
8.1.5.1
Prior Medications...............................................................................55
8.1.5.2
Concomitant Medications..................................................................55
8.1.6
Assignment of Screening Number...............................................................55
8.1.7
Assignment of Treatment/Randomization Number.....................................56
8.1.8
Study Intervention Administration ..............................................................56
8.1.8.1
Timing of Dose Administration.........................................................56
8.1.9
Discontinuation and Withdrawal .................................................................56
8.1.9.1
Withdrawal From Future Biomedical Research ................................56
8.1.10
Participant Blinding/Unblinding..................................................................57
8.1.11
Domiciling ...................................................................................................57
8.1.12
Calibration of Equipment.............................................................................57
8.2
Efficacy/Immunogenicity Assessments ..............................................................57
8.3
Safety Assessments...............................................................................................57
8.3.1
Physical Examinations.................................................................................58
8.3.2
Vital Signs....................................................................................................58
8.3.2.1
Resting Vital Signs ............................................................................58
8.3.3
Electrocardiograms ......................................................................................59
8.3.4
Clinical Safety Laboratory Assessments .....................................................60
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................60
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................61
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...63
8.4.4
Regulatory Reporting Requirements for SAE .............................................63
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................63
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.4.7
Events of Clinical Interest............................................................................64
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................65
8.6.1
Blood Collection for Plasma MK-8189 .......................................................65
8.7
Pharmacodynamics..............................................................................................65
 
 
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PRODUCT: MK-8189  
9
PROTOCOL/AMENDMENT NO.: 012-01 
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8.8
Biomarkers ...........................................................................................................65
8.8.1
Planned Genetic Analysis Sample Collection..............................................65
8.9
Future Biomedical Research Sample Collection...............................................65
8.10
Visit Requirements...............................................................................................65
8.10.1
Screening......................................................................................................66
8.10.2
Treatment Period..........................................................................................66
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........66
8.10.4
Poststudy......................................................................................................66
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......66
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................67
9
STATISTICAL ANALYSIS PLAN .............................................................................68
9.1
Statistical Analysis Plan Summary.....................................................................68
9.2
Responsibility for Analyses.................................................................................68
9.3
Hypotheses/Estimation ........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.5
Analysis Populations............................................................................................69
9.6
Statistical Methods...............................................................................................69
9.7
Interim Analyses ..................................................................................................70
9.8
Multiplicity ...........................................................................................................71
9.9
Sample Size and Power Calculations .................................................................71
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................72
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........72
10.1.1
Code of Conduct for Clinical Trials.............................................................72
10.1.2
Financial Disclosure.....................................................................................74
10.1.3
Data Protection.............................................................................................74
10.1.3.1
Confidentiality of Data ......................................................................75
10.1.3.2
Confidentiality of Participant Records...............................................75
10.1.3.3
Confidentiality of IRB/IEC Information............................................75
10.1.4
Publication Policy........................................................................................75
10.1.5
Compliance with Study Registration and Results Posting Requirements ...76
10.1.6
Compliance with Law, Audit, and Debarment ............................................76
10.1.7
Data Quality Assurance ...............................................................................77
10.1.8
Source Documents .......................................................................................78
10.1.9
Study and Site Closure.................................................................................78
10.2
Appendix 2: Clinical Laboratory Tests..............................................................79
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................80
10.3.1
Definition of AE ..........................................................................................80
10.3.2
Definition of SAE ........................................................................................81
10.3.3
Additional Events Reported.........................................................................82
10.3.4
Recording AE and SAE ...............................................................................82
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................86
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................87
10.5
Appendix 5: Contraceptive Guidance................................................................88
10.5.1
Definitions....................................................................................................88
10.5.2
Contraception Requirements........................................................................89
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................90
10.7
Appendix 7: Country/Site-specific Requirements ............................................95
10.7.1
Site 0001-specific Requirements .................................................................95
10.8
Appendix 8: Blood Volume Table ......................................................................98
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................99
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...101
10.11 Appendix 11: Child-Pugh classification of the severity of liver disease........102
10.12 Appendix 12: Abbreviations .............................................................................103
11
REFERENCES.............................................................................................................105
 
 
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................48
Table 2
Allocation of Participants to Treatment...........................................................50
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................62
Table 4
Pharmacokinetic (Blood) Collection Windows ...............................................67
Table 5
Protocol-required Safety Laboratory Assessments..........................................79
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................17
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A 2-part, open-label, single-dose study to investigate the influence of hepatic 
impairment on the pharmacokinetics of MK-8189
Short Title: The effect of hepatic impairment on MK-8189 pharmacokinetics
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
The study population includes male and female participants with moderate and mild hepatic 
impairment between the ages of 18 and 75 (inclusive) and healthy controls.
Primary Objectives
Primary Endpoints
Part 1
- To compare MK-8189 pharmacokinetics 
after single dose administration of 4 mg MK-
8189 to participants with moderate hepatic 
impairment and healthy control participants.
- Estimation: The AUC0-inf and Cmax in 
participants with moderate hepatic 
impairment will be estimated and compared 
to those obtained from healthy control 
participants.
Part 2
- To compare MK-8189 pharmacokinetics 
after single dose administration of 4 mg MK-
8189 to participants with mild hepatic 
impairment and healthy control participants.
- Estimation: The AUC0-inf and Cmax in 
participants with mild hepatic impairment 
will be estimated and compared to those 
obtained from healthy control participants in 
Part 1.
Part 1 and Part 2
- AUC0-inf and Cmax
 
 
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Secondary Objectives
Secondary Endpoints
Part 1
- To evaluate the safety and tolerability of 
MK-8189 in patients with moderate hepatic 
impairment and in healthy control 
participants after single dose administration 
of 4 mg MK-8189.
Part 2
- To evaluate the safety and tolerability of 
MK-8189 in patients with mild hepatic 
impairment after single dose. administration 
of 4 mg MK-8189.
Part 1 and Part 2
•
Adverse experiences, laboratory safety 
tests, electrocardiograms and vital signs
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Part 1 and Part 2
- To investigate the relationship between 
CYP2C9 genetic polymorphisms and the PK 
of MK-8189. Genetic variation in CYP2C9 
may be analyzed for association with any 
laboratory or clinical data collected in this 
study.
- To explore the relationship between genetic 
variation and response to the treatment 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in this study.
- To compare additional MK-8189 
pharmacokinetic parameter values after 
single dose administration of 4 mg MK-8189 
to participants with moderate hepatic 
impairment, mild hepatic impairment, and  
healthy control participants.
Part 1 and Part 2
- Germline genetic variation in CYP2C9 
and association to clinical data collected in 
this study
- Germline genetic variation and 
association to clinical data collected in this 
study.
- AUC0-24, C24, Tmax, CL/F, Vz/F and 
apparent terminal t½
 
 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of schizophrenia
Population
Participants with hepatic impairment and healthy 
participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Healthy matched -control participants
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 16 participants will be allocated/randomized in Part 1; a minimum of 6 
participants with moderate hepatic impairment and 6 healthy participants will complete Part 
1. Approximately 8 participants will be randomized/allocated in Part 2.; a minimum of 6 
participants with mild hepatic impairment will complete Part 2.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Moderate 
Hepatic 
Impairment 
Group
MK-8189
4 mg 
Single dose
Oral
Part 1  Day 1
Experi
mental
Healthy 
Matched 
Control Group
MK-8189
4 mg 
Single dose
Oral
Part 1  Day 1
Experi
mental
Mild Hepatic 
Impairment 
Group
MK-8189
4 mg 
Single dose
Oral
Part 2 Day 1
Experi
mental
Total 
Number of 
Intervention 
Groups/ 
Arms
There will be up to 3 groups each containing up to 8 participants.  
Duration of 
Participation
Each participant will participate in the study for approximately 42 days,
from the time the participant signs the Informed Consent Form through the 
final contact. After a screening phase of 28 days, each participant will be 
receiving assigned intervention for approximately 1 day. After the end of 
treatment each participant will be followed for 14 days.
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 12.
 
 
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1.2
Schema
The study design is depicted in [Figure 1].
Figure 1
Study Design
 
 
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1.3
Schedule of Activities
1.3.1
Hepatic Impairment Participants
Study Period:
Screening
Intervention
Post-
study Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
4
5
5
6
14
Scheduled Hour
Screening
Check-
in
Pre-
dose
0
2
6
8
10 12 16 24 36 48 60 72
84
96
108
120
312
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Participant Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Includes 
substance use 
(drugs, alcohol, 
tobacco and 
caffeine)
Prior/Concomitant 
Medication Review
X
X
X--------------------------------------------------------------------------------------------X
Refer to Section 
8.1.5.
Assignment of Screening 
Number
X
Refer to Section 
8.1.6.
Assignment of Treatment 
Number
X
Refer to Section 
8.1.7
Domiciling
X-------------------------------------------------------------------------------------------------------X
Refer to Section 
8.1.11.
Outpatient Visit
X
X
MK-8189 Administration
X
To be dosed at 
approximately 8 
AM
 
 
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PRODUCT: MK-8189  
19
PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
Study Period:
Screening
Intervention
Post-
study Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
4
5
5
6
14
Scheduled Hour
Screening
Check-
in
Pre-
dose
0
2
6
8
10 12 16 24 36 48 60 72
84
96
108
120
312
Standard Meals
X-----------------------------------------X
Standard lunch 
and dinner will be 
provided at 
approximately 4 
and 9 hours 
postdose, 
respectively. A 
snack will also be
offered at 
approximately 12 
hours postdose.
Safety Procedures
Full physical examination
X
Xa
X
Directed PE may 
be performed at 
other times, at the 
Investigator’s 
discretion. Refer 
to Section 8.3.1.
Height
X
Refer to Section 
8.3.1.
Weight
X
BMI to be taken 
only at screening
Refer to Section 
8.3.1.
Vital Signs (heart rate, 
blood pressure)
X
X
X
X
X
Refer to Section 
8.3.2, Refer to 
Section 8.10.5 for 
timing
Respiratory Rate
X
X
Refer to Section 
8.3.2
Body Temperature
X
X
Refer to Section 
8.3.2
 
 
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PRODUCT: MK-8189  
20
PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
Study Period:
Screening
Intervention
Post-
study Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
4
5
5
6
14
Scheduled Hour
Screening
Check-
in
Pre-
dose
0
2
6
8
10 12 16 24 36 48 60 72
84
96
108
120
312
12-lead ECG
Xb
Xb
X
X
Refer to Section 
8.3.3, Refer to 
Section 8.10.5 for 
timing
Hepatitis B and C screen 
(per site SOP)
X
HIV-1, HIV-2 Screen
X
Serum/urine β-Human 
Chorionic Gonadotropin
(β-hCG; WOCBP only)
X
Xa
Required for 
WOCBP.  
Serum or urine β-
hCG at predose 
(per site SOP). 
Serum β-hCG 
required at 
Screening.  Refer 
to Section 10.2
Serum FSH - (WONCBP
only)
X
For WONCBP. 
Refer to Section 
10.2 and 10.5
Urine or Blood Drug 
Screen (UDS/BDS) (per 
site SOP)/alcohol screen
X
Xa
Any additional 
UDS/BDS and 
alcohol screen are 
conducted per site 
SOP.  Refer to 
Section 10.2
Hematology, urinalysis, 
and chemistry
X
Xa
X
X
X
Refer to Section 
8.3.4 and 10.2.
INR Assessment
X
Assessment of Liver 
Function using Child-
Pugh Classification
X
Refer to Section 
5.1.2 and 
Appendix 11
 
 
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PRODUCT: MK-8189  
21
PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
Study Period:
Screening
Intervention
Post-
study Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
4
5
5
6
14
Scheduled Hour
Screening
Check-
in
Pre-
dose
0
2
6
8
10 12 16 24 36 48 60 72
84
96
108
120
312
Creatinine Clearance 
Assessment
X
X
Refer to Section 
5.2.2
AE/SAE review
X-----------------------------------------------------------------------------------------------------------------------------X
Refer to Section 
8.4.
Pharmacokinetics
Blood Collection for 
Plasma MK-8189
Xc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Refer to Section 
8.6.1
Blood Collection for 
Plasma Protein Binding
Xc
Refer to Section 
4.2.1.2
Biomarkers
Blood for Genetic 
Analysis 
X
Collect predose 
from enrolled 
participants only.
Refer to Section 
8.8
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; FBR=future biomedical research; FSH=follicle stimulating hormone;
ID=identification; SAE=serious adverse event; SOP=standard operating procedure; UDS=Urine Drug Screen
a. Pre-dose PE, urine drug screen, safety labs and pregnancy screen can be conducted/collected within 24 hours prior to study drug administration.  Predose labs should be taken 
after an 8 hour fast. Results from predose safety labs and drug/alcohol screen must be reviewed prior to treatment allocation.
b. ECG measurements obtained in triplicate during Screening Visit and Day 1 pre-dose. All other measurements will be single measurements
c. Plasma for MK-8189 PK and plasma protein binding to be collected within 60 minutes prior to study drug administration.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
1.3.2
Healthy Matched Participants
Study Period:
Screening
Intervention
Post-
study
Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
4
5
14
Scheduled Hour.
Screening
Check
-in
Pre-
dose
0
2
6
8
10
12
16
24
36
48
72
96
312
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Includes substance use 
(drugs, alcohol, tobacco 
and caffeine)
Prior/Concomitant Medication 
Review
X
X
X----------------------------------------------------------------------X
Refer to Section 8.1.5.
Assignment of Screening Number
X
Refer to Section 8.1.6.
Assignment of Treatment Number
X
Refer to Section 8.1.7.
Domiciling
X-----------------------------------------------------------------X
Refer to Section 8.1.11.
Outpatient Vist
X
X
X
X
MK-8189 Administration
X
To be dosed at 
approximately 8 AM
Standard Meals
X-------------------------------------------------------X
Standard lunch and 
dinner will
be provided at 
approximately 4 and 9 
hours postdose,
respectively. A snack will 
also be offered at 
approximately 12 hours 
postdose.
 
 
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PRODUCT: MK-8189  
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PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
Study Period:
Screening
Intervention
Post-
study
Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
4
5
14
Scheduled Hour.
Screening
Check
-in
Pre-
dose
0
2
6
8
10
12
16
24
36
48
72
96
312
Safety Procedures
Full physical examination
X
Xa
X
Directed PE may be 
performed at other times, 
at the Investigator’s 
discretion. Refer to 
Section 8.3.1.
Height
X
Refer to Section 8.3.1.
Weight
X
BMI to be taken only oat 
screening Refer to Section 
8.3.1.
Vital Signs (heart rate, blood 
pressure)
X
X
X
X
X
Refer to Section 8.3.2, 
Refer to Section 8.10.5 
for timing
Respiratory Rate
X
X
Refer to Section 8.3.2
Body Temperature
X
X
Refer to Section 8.3.2
12-lead ECG
Xb
Xb
X
X
Refer to Section 8.3.3, 
Refer to Section 8.10.5 
for timing
Hepatitis B and C screen (per site 
SOP)
X
HIV-1, HIV-2 Screen
X
Serum/urine β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
X
Xa
Required for WOCBP.  
Serum or urine β-hCG at 
predose (per site SOP). 
Serum β-hCG required at 
Screening.  Refer to 
Section 10.2
Serum FSH - (WONCBP only)
X
For WONCBP. Refer to 
Section 10.2 and 10.5
 
 
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PRODUCT: MK-8189  
24
PROTOCOL/AMENDMENT NO.: 012-01 
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
Study Period:
Screening
Intervention
Post-
study
Notes
Scheduled Day
-1
1
1
1
1
1
1
1
1
2
2
3
4
5
14
Scheduled Hour.
Screening
Check
-in
Pre-
dose
0
2
6
8
10
12
16
24
36
48
72
96
312
Urine or Blood Drug Screen 
(UDS/BDS) (per site SOP)/alcohol 
screen
X
Xa
Any additional UDS/BDS 
and alcohol screen are 
conducted per site SOP.  
Refer to Section 10.2
Hematology, urinalysis, and 
chemistry
X
Xa
X
X
Refer to Section 8.3.4 and 
10.2.
Creatinine Clearance Assessment
X
X
Refer to Section 5.2.1
AE/SAE review
X-----------------------------------------------------------------------------------------------------X
Refer to Section 8.4.
Pharmacokinetics
Blood Collection for Plasma MK-
8189
Xc
X
X
X
X
X
X
X
X
X
X
X
Refer to Section 8.6.1
Blood Collection for Plasma Protein 
Binding
Xc
Refer to Section 4.2.1.2
Biomarkers
Blood for Genetic Analysis 
X
Collect predose from 
enrolled participants only.
Refer to Section 8.8
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; FBR=future biomedical research; FSH=follicle stimulating hormone; ID=identification; 
SAE=serious adverse event; SOP=standard operating procedure; UDS=Urine Drug Screen
a. Pre-dose PE, urine drug screen, safety labs and pregnancy screen can be conducted/collected within 24 hours prior to study drug administration.  Predose labs should be taken 
after an 8 hour fast. Results from predose safety labs and drug/alcohol screen must be reviewed prior to treatment allocation.
b. ECG measurements obtained in triplicate during Screening Visit and Day 1 pre-dose. All other measurements will be single measurements
c. Plasma for MK-8189 PK and plasma protein binding to be collected within 60 minutes prior to study drug administration.
 
 
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PRODUCT:  MK-8189  
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PROTOCOL/AMENDMENT NO.:  012-01  
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
2
INTRODUCTION
2.1
Study Rationale
The liver is involved in the clearance of many drugs through a variety of oxidative and
conjugative metabolic pathways and/or through biliary excretion of the unchanged drug or
metabolites. Alterations of these excretory and metabolic activities by hepatic impairment
can lead to drug accumulation. Hepatic disease can alter the absorption and disposition of
drugs as well as their efficacy and safety.
Patients with schizophrenia have a higher incidence of co-morbid conditions and are at 
greater risk for multiple co-morbidities as compared to individuals without schizophrenia.  
Liver disease is among the co-morbidities for which there is increased prevalence in the 
schizophrenia population.  In fact, it has been reported in the literature that the co-morbidity 
with the highest OR is viral hepatitis (OR 3.98, 95% CI 2.81 to 5.64), which can lead to 
hepatic impairment.   Consistent with this, the OR for liver disease in patients with 
schizophrenia compared to controls is also significant (OR 1.66, 95% CI  1.19 to 2.31)
[Smith, D. J., et al 2013].
MK-8189 undergoes oxidative metabolism primarily via CYP3A4, with a lesser contribution 
by CYP2C9 and a minor contribution from CYP1A2. A human absorption, metabolism and 
excretion study has not yet been conducted.  However, in both rats and monkeys, 
biotransformation was the major mechanism of elimination with only trace levels of 
unchanged parent compound detected in the excreta. Since hepatic metabolism plays an 
important role in the elimination of MK-8189, and hepatic impairment may affect the PK of 
MK-8189, it is appropriate to evaluate the effect of hepatic impairment on the PK of MK-
8189.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-8189
2.2.1
Pharmaceutical and Therapeutic Background
MK-8189 is a potent and selective inhibitor of PDE10A that is being developed as a novel 
therapeutic for the treatment of schizophrenia. The PDE10A enzyme metabolically 
inactivates the ubiquitous second messengers, cAMP and cGMP [Bender, A. T. and Beavo, J. 
A. 2006] and is highly expressed in the target nucleus of the corticostriatal pathway, the 
striatum [Seeger, T. F., et al 2003]. Preclinical pharmacology studies demonstrate that 
PDE10A inhibition increases cAMP/cGMP signaling in pathways that have been associated 
with underlying pathology (glutamate) as well as clinically validated therapeutics (dopamine 
D2 receptor antagonists) for schizophrenia. Enhanced signaling in these pathways is 
hypothesized to restore behavioral inhibition that is impaired in schizophrenia [Grauer, S. M., 
et al 2009] [Schmidt, C. J., et al 2008]. PDE10A inhibitors may potentially be an alternative 
treatment as monotherapy and/or adjunct treatment in schizophrenia patients who have 
inadequate response to first line AAP treatment.
 
 
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PRODUCT:  MK-8189  
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PROTOCOL/AMENDMENT NO.:  012-01  
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
2.2.2
Preclinical and Clinical Studies
Preclinical and clinical study information can be found in the MK-8189 IB.
2.2.2.1
Preclinical PK
MK-8189 exhibited low to moderate plasma clearance in rats (21.3 mL/min/kg) and monkeys
(9.3 mL/min/kg). In both species, the terminal half-life in plasma was approximately 4 hrs
and the oral bioavailability ranged from 41 to 46%. MK-8189 was significantly bound to
plasma proteins in rat, monkey, and human with unbound fraction (expressed as percent) as
8.2, 8.7, and 4.0%, respectively. The compound did not preferentially distribute to red blood
cells from any of the three species. In both rats and monkeys, the major mechanism of 
elimination is biotransformation with oxidation as the dominant pathway.  Oxidative 
metabolism of MK-8189 is catalyzed primarily via CYP3A, with a lesser contribution by 
CYP2C9 and a minor contribution from CYP1A2.
2.2.2.2
Clinical Studies
To date, completed studies in the Phase 1 program include 3 single-dose clinical studies, 1 
DDI study and 1 multiple-dose clinical study conducted with MK-8189. A total of 104 
participants were enrolled in the Phase 1 studies with 59 healthy participants and 33 
participants with schizophrenia receiving at least 1 dose of MK-8189. Twelve participants 
received placebo. Single doses up to 6 mg (IR formulation) and multiple increasing doses up 
to 16 mg (CR formulation) over 14 days have been administered to date in these completed 
studies.
Overall, single and multiple doses of MK-8189 were generally well tolerated. The most 
frequently (≥5%) reported treatment emergent AEs following administration of MK-8189 
(across all completed 5 Phase 1 studies) were headache, somnolence, fatigue, dystonia 
(includes dystonia, torticollis, oromandibular dystonia, spasmodic dysphonia and 
blepharospasm), diarrhea, akathisia, anxiety, dizziness, insomnia, nausea and decreased 
appetite. No deaths occurred in any of the 5 Phase 1 trials. A total of 9 participants were 
discontinued due to AEs.  No treatment-related SAEs were reported across these studies.
There were no clinically meaningful changes in laboratory investigations, ECGs or VS 
related to MK-8189.
In a Phase 2 POC trial (P005), MK-8189 was generally well tolerated up to 12 mg QD. 
Adverse Events that occurred in ≥5% of participants in the MK-8189 intervention group and 
had greater incidence than placebo were diarrhea, nausea, vomiting, decreased appetite, 
akathisia, dystonia, headache, sedation, somnolence, anxiety, and insomnia. No deaths were 
reported in the P005 study. No SAEs were reported for participants on MK-8189.
In P005, for the primary endpoint of PANSS total score change from baseline at Week 4, 
although the MK-8189 group showed meaningful improvement in symptoms, the 
improvement missed statistical significance (difference [95% CI] in LS mean change was -
4.7 [-9.8, 0.5]; p=0.074). Risperidone was superior to placebo with respect to this endpoint 
 
 
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PRODUCT:  MK-8189  
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PROTOCOL/AMENDMENT NO.:  012-01  
MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
(difference [95% CI] in LS mean change was -7.3 [-14.0, -0.6]; p=0.033). There was no 
difference in magnitude of effect between MK-8189 and risperidone (difference [95% CI] in 
LS mean change was 2.6 [-4.0, 9.2]; p=0.440). For the exploratory endpoint of PANSS 
positive subscale score at Week 4, both MK-8189 and risperidone were superior to placebo. 
There was no significant difference in effect between MK-8189 and risperidone. Neither 
risperidone nor MK-8189 demonstrated significant improvement in the CGI-S.
Following multiple doses of the controlled release formulation, MK-8189 exposure increased 
approximately proportionally with dose over the range of doses tested (2 to 16 mg) in all 
populations. Median Tmax of MK-8189 as monotherapy ranged from 10 to 20 hours with a 
t1/2 of approximately 8.4 hours (37.8% GCV). 
Based on completed studies, data suggest that the exposures at steady state for a given dose 
are generally comparable between healthy participants and participants with schizophrenia 
administered MK-8189 as monotherapy. 
In a DDI study (P006) the coadministration of extended release 240-mg diltiazem increased 
MK-8189 AUC and Cmax by approximately 2-fold and 1.3-fold, respectively, confirming 
that MK-8189 is a CYP3A substrate.
2.2.3
Ongoing Clinical Studies
P007 is a 4- panel (A, B, C and D) randomized (3:1), placebo-controlled, multiple-dose 
safety, tolerability and PK study of MK-8189 monotherapy in participants with schizophrenia 
and healthy participants. The study is clinically complete and data are unblinded. In this 
study, 16 healthy participants (Japanese and non-Japanese) were enrolled in Panel A and 16 
participants with schizophrenia were enrolled in Panel B. Participants were washed off their 
standard of care during screening.  The treatment regimen for Panel A and Panel B was as 
follows: MK-8189 4- mg/placebo Days 1-3, MK-8189 8- mg/placebo Days 4-6, MK-8189 
12- mg/placebo Days 7-9, MK-8189 16- mg/placebo Days 10-12, MK-8189 20- mg/placebo 
Days 13-15 and MK-8189 24- mg/Days 16-18.
Safety data from Panel A and Panel B indicated that MK-8189 at doses up to and including 
24 mg were generally well tolerated and tolerability was similar across the populations 
(healthy Japanese, healthy non-Japanese and participants with schizophrenia). No SAEs or 
deaths were reported and no AEs of dystonia were reported.
In Panel A, of the 16 participants enrolled, 14 completed treatment and 2 discontinued due to 
an AE: 1 Japanese participant discontinued due to a treatment-related headache of moderate 
intensity following administration of the MK-8189 16 mg dose and 1 Japanese participant 
discontinued due to treatment-related  exacerbation of a preexisting motor tic disorder of 
moderate severity. The AE began following administration of the 4 mg dose and the 
participant was discontinued following treatment with MK- 8189 8 mg x 2 days. This AE 
resolved approximately 3 weeks following cessation of therapy. This participant was also
reported to have moderate akathisia at the MK-8189 4-mg dose which resolved 1 day 
following discontinuation of drug. 
 
 
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Ten of 12 (83.3%) and 3 of 4 (75%) participants reported at least 1 AE following treatment 
with MK-8189 and placebo, respectively. The most common AEs (reported by ≥2 
participants) following treatment with MK-8189, regardless of causality, were headache 
(n=6, 50% vs. placebo n=1, 25%), dizziness (n=4, 33% vs placebo n=0), decreased appetite 
(n=3, 25% vs placebo n=1, 25%), insomnia (n=3, 25% vs placebo n=0), anxiety (n=2, 16.7%
vs placebo n=1, 25%), restlessness (n=2, 16.7% vs. placebo n=0), and abdominal discomfort 
(n=2, 16.7% vs placebo n=0). 
In Panel B, of the 16 participants enrolled, 3 participants discontinued due to AEs; 1 
participant discontinued after administration of placebo due to a psychotic disorder. The 
participant was reported to have mild psychosis prior to dosing and the AE of moderate 
psychosis began following administration of placebo on Day 4. The AE resolved within 4
weeks. Another participant was discontinued due to a panic attack, psychosis and 
dissociation following administration of MK-8189 16 mg which were all assessed as severe 
in intensity and treatment-related. The participant was restarted on their antipsychotic 
medication, and within 15 hours the intensity of these AEs abated and was considered mild.  
The psychosis and panic attack resolved within 6 days and the dissociation resolved within 
1.3 weeks. In addition, 1 participant discontinued due to mild dyspepsia, considered 
unrelated to treatment, following administration of MK-8189 4 mg.
Ten of 12 participants (93.8%) and 4 of 4 participants (100%) reported at least 1 AE
following treatment with MK-8189 and placebo, respectively. The most common AEs 
(reported by ≥2 participants) regardless of causality were headache (n=7, 58.3% vs placebo 
n=1, 25%), constipation (n=5, 41.7%, vs placebo n=1, 25%), dyspepsia (n=3, 25% vs placebo 
n=0),  anxiety (n=3, 25% vs placebo n=0), neck pain (n=3, 25% vs placebo n=0), nausea 
(n=2, 16.7 % vs placebo n=1, 25%), and insomnia (n=2, 16.7% vs placebo n=1, 25%). 
Panel C was conducted to evaluate the multiple-dose safety, tolerability and PK of MK-8189 
as add-on therapy in participants with schizophrenia. Participants were randomized to MK-
8189 or placebo (3:1) and titrated up to doses of 24 mg while remaining on their 
antipsychotic standard of care. The titration schedule was the same as that evaluated in Panel 
A and Panel B. Seventeen participants were enrolled in Panel C and safety data suggest that 
MK-8189 was generally well tolerated up to including doses of 24 mg when administered as 
add-on therapy. No SAEs or deaths occurred, and 1 AE of dystonia considered unrelated to 
treatment was reported and is described as part of the safety summary below.
In Panel C, 10 participants completed study treatment and 7 discontinued treatment. One 
participant withdrew consent and one participant was discontinued from treatment for a 
protocol deviation, as the participant had a history of seizures (exclusion criteria) not 
disclosed during Screening. Five participants discontinued due to an AE:  One participant 
discontinued due to moderate treatment-related akathisia following administration of MK-
8189 8-mg.  One participant discontinued due to treatment-related mild nausea and moderate 
vomiting which began following treatment with the MK-8189 12 mg and treatment-related 
mild headache and moderate hypertension which began following treatment with MK-8189 
16 mg.  One participant discontinued due to treatment-related moderate abdominal pain and 
muscles spasms following treatment with MK-8189 4 mg.  One participant discontinued due 
to mild treatment-related chest pain following treatment with MK-8189 12 mg.  One 
 
 
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participant discontinued due to treatment-related mild palpitations following treatment with 
MK-8189 12 mg. 
One participant experienced dystonia following treatment with MK-8189 4 mg. The AE of 
dystonia was considered unrelated as it was determined the participant had previously 
experienced dystonia while taking lurasidone, which had been reinitiated during the trial. 
This participant was discontinued for failure to disclose a history of seizures as mentioned 
above.
In Panel C, 13 of 13 participants (100%) and 1 of 4 (25%) participants experienced at least 1 
adverse event following MK-8189 and placebo, respectively.  The most common AEs (≥2 
participants) regardless of causality were decreased appetite (n=5, 38.5% vs placebo, n=0), 
dizziness (n=4, 30.8% vs placebo n=1, 25%), headache (n=4, 30.8% vs placebo n=0)  nausea 
( n=3, 23.1% vs placebo n=0), vomiting (n=3, 23.1% vs placebo. n=0), abdominal pain upper 
(n=2, 15.4% vs placebo n=0), anxiety (n=2, 15.4% vs placebo n=0), constipation (n=2, 
15.4% vs. placebo n=0), and restlessness (n=2, 15.4% vs placebo n=0).  
Panel D was conducted to evaluate the multiple-dose safety, tolerability and PK of 
supratherapeutic doses of MK-8189 monotherapy in participants with schizophrenia. The 
planned enrollment for Panel D was 20 participants with schizophrenia or schizoaffective 
disorder. Participants were washed off their antipsychotic medication during the screening 
phase. During the treatment period, participants were titrated up to 48 mg or received placebo 
in a ratio of 3:2. The titration regimen was MK-8189 8-mg/placebo Days 1-3, MK-8189 16
mg/placebo Days 4-6, MK-8189 24 mg/placebo Days 7-9, MK-8189 36 mg/placebo Days 
10-12 and MK-8189 48-mg/placebo Days 13-15. 
Safety data from Panel D indicate that MK-8189 at doses up to and including 48 mg is 
generally well tolerated. No deaths have been reported and 1 SAE of treatment-related 
psychotic disorder was reported. This SAE is described below as part of the AE summary. In 
addition, two participants experienced dystonia. However, as dystonia occurred following 
cessation of MK-8189 dosing and following re-initiation of the participants pre-trial atypical 
antipsychotic treatment, these AEs were not considered related to MK-8189.
Twenty-six (26) participants were enrolled in Panel D. Eighteen of 26 participants completed 
study treatment and 8 participants discontinued treatment; six discontinuations were due to 
adverse events and 2 participants withdrew consent. One participant discontinued due to a 
treatment-related SAE of increased psychosis which resulted in hospitalization. The SAE 
occurred following treatment with the MK-8189 36 mg dose.  The AE was considered severe 
and had a duration of 6 days. The SAE resolved following initiation of an antipsychotic and 
benzodiazepine.  No other AEs were reported by this participant.  In addition, one participant 
discontinued due to an AE of moderate psychosis on Day 14 following treatment with 
placebo; one participant discontinued due to AEs of moderate psychosis and severe anxiety 
following treatment with MK-8189 16 mg and neither AE was considered related to 
treatment; one participant was discontinued due to an AE of treatment-related, mild 
asymptomatic and intermittent atrial fibrillation following treatment with placebo; one 
participant discontinued due to mild treatment-related anxiety following treatment with MK-
8189 16 mg.  One participant discontinued due to several AEs following treatment with MK-
 
 
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PRODUCT:  MK-8189  
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MK-8189-012-01 FINAL PROTOCOL
09-FEB-2021
8189 including (dose at which AE began) moderate anxiety (16 mg), mild somnolence (8 
mg), mild flank pain (16 mg), mild skin lesion (16 mg), mild vulvovaginal pruritis (16 mg), 
mild dermatitis (16 mg), and mild contact dermatitis (8 mg).  Only somnolence and 
dermatitis were considered related to treatment.  
In Panel D, 14 of 17 participants (82.4%) and 9 of 9 participants (100%) reported at least one 
AE following treatment with MK-8189 or placebo, respectively. The most common AEs 
(reported by ≥2 participants), regardless of causality, were anxiety (n=7, 41.2% vs. placebo 
n=1, 11.1%), headache (n=5, 29.4% vs. placebo n=2, 22.2%), nausea (n=5, 29.4 vs placebo 
n=1, 11.1%%), somnolence (n=4, 23.5% vs placebo n=1, 11.1%), back pain (n=3, 17.6%, vs 
placebo n=2, 22.2%), contact dermatitis (n=2, 11.8% vs placebo n=3, 33.3%), insomnia (n=2, 
11.8% vs placebo n=1, 11.1%), psychotic disorder (n=2, 11.8% vs placebo n=1, 11.1%), 
dizziness (n=3, 17.6%, vs placebo n=0), decreased appetite (n=2, 11.8% vs placebo n=0), 
vomiting (n=2, 11.8% vs placebo n=0) and palpitations (n=2 (11.8% vs placebo n=0). 
The observed proportion of participants reporting AEs was higher following the 48 mg dose 
(72.7%, n=8 of 11) when compared to the 8 mg ( 47.1%, n=8 of 17), 16 mg (50.0%, n=8 of 
16), 24 mg (33.3%, n=5 of 15) and 36 mg (38.5%, n=5 of 13) dose groups. It should be noted 
that 11 participants (42.3%) reported at least one AE during screening. In general, there were 
no clear dose-related increases in specific AEs. However, all three participants with AEs of 
dizziness occurred at the 48 mg dose.
Overall, across P007 there were no clinically relevant trends for changes from baseline in 
vital signs, ECGs, or safety laboratory parameters. In Panel C, increases in ventricular 
rate/heart rate, appeared to be greater in the MK-8189 group when compared to placebo.  In 
Panel D, while a few parameters such as ventricular rate/heart rate, resting diastolic blood 
pressure, and resting systolic blood pressure appeared to have some greater changes towards 
the end of dosing, these changes were within the range of changes observed 48 hours 
following completion of dosing (Day 17) when MK-8189 concentrations are expected to be 
significantly diminished, based on a half-life in participants with schizophrenia of 
approximately 8-11 hours.
In P007, at the same doses (16 mg and 24 mg), preliminary data from Panels A (healthy 
participants) and B (participants with schizophrenia) suggest that MK-8189 exposure 
appeared to be greater in participants with schizophrenia when compared with healthy 
participants; 1.6 - 2-fold and 1.5 - 1.7-fold  for AUC0-24 and Cmax values, respectively at 
the 16 and 24 mg dose. However, when PK data from participants with schizophrenia dosed 
in Panel C (add-on therapy) and Panel D (monotherapy) were compared with Panel A, PK 
data were similar between healthy participants and participants with schizophrenia; the 
reason for the higher exposure observed in Panel B is currently unknown.  CL/F (CV%) was 
found to be 3.65 L/hr (67%) with half-life (CV%) found to be 8.33 hr (21%).
2.3
Benefit/Risk Assessment
Healthy participants and participants with hepatic impairment in this trial will not receive 
direct benefit from treatment during participation as clinical studies are designed to provide 
information about the safety and effectiveness of an investigational medicine.
 
 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The study population includes male and female participants with moderate and mild hepatic 
impairment between the ages of 18 and 75 (inclusive) and healthy controls.
Objectives
Endpoints
Primary
Part 1
•
To compare MK-8189 pharmacokinetics 
after single dose administration of 4 mg 
MK-8189 to participants with moderate 
hepatic impairment and healthy control 
participants.
•
Estimation: The AUC0-inf and Cmax in 
participants with moderate hepatic 
impairment will be estimated and 
compared to those obtained from healthy 
control participants.
Part 2
•
To compare MK-8189 pharmacokinetics 
after single dose administration of 4 mg 
MK-8189 to participants with mild
hepatic impairment and healthy control 
participants.
•
Estimation: The AUC0-inf and Cmax in 
participants with mild hepatic impairment 
will be estimated and compared to those 
obtained from healthy control participants
in Part 1.
Part 1 and Part 2
•
AUC0-inf and Cmax
 
 
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Objectives
Endpoints
Secondary
Part 1
•
To evaluate the safety and tolerability of 
MK-8189 in patients with moderate 
hepatic impairment and in healthy control 
participants after single dose 
administration of 4 mg MK-8189.
Part 2
•
To evaluate the safety and tolerability of 
MK-8189 in patients with mild hepatic 
impairment after single dose.
administration of 4 mg MK-8189.
Part 1 and Part 2
•
Adverse experiences, laboratory safety 
tests, electrocardiograms and vital signs
Tertiary/Exploratory
Part 1 and Part 2
•
To investigate the relationship between 
CYP2C9 genetic polymorphisms and the 
PK of MK-8189. Genetic variation in 
CYP2C9 may be analyzed for association 
with any laboratory or clinical data 
collected in this study.
•
To explore the relationship between 
genetic variation and response to the 
treatment administered, and mechanisms 
of disease. Variation across the human 
genome may be analyzed for association 
with clinical data collected in this study.
•
To compare additional MK-8189 
pharmacokinetic parameter values after 
single dose administration of 4 mg MK-
8189 to participants with moderate 
hepatic impairment, mild hepatic 
impairment, and  healthy control 
participants.
Part 1 and Part 2
•
Germline genetic variation in CYP2C9 
and association to clinical data 
collected in this study
•
Germline genetic variation and 
association to clinical data collected in 
this study.
•
AUC0-24, C24, Tmax, CL/F, Vz/F and 
apparent terminal t½
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a 2-part, non-randomized, open-label, single-dose study to compare, in Part 1, the PK
of MK-8189 in participants with moderate hepatic impairment (based on the Child-Pugh 
classification) to healthy control participants reasonably matched to the demographics (age, 
weight, sex) of the group with hepatic impairment. Following a review of the safety and PK
data from Part 1, a decision will be made as to whether Part 2 will be initiated; if there is a 
clinically meaningful higher exposure of MK-8189 in participants with hepatic impairment 
as compared to healthy participants, Part 2 will be conducted. Part 2 of the study will 
compare the PK of MK-8189 in participants with mild hepatic impairment to the healthy 
participants enrolled in Part 1. On Day 1, a single oral dose of MK-8189 will be 
administered and followed by PK sampling for 96 hours in the healthy control participants 
and for 120 hours in the mild and moderate hepatic impaired participants. Safety will be 
monitored through physical examination, vital signs, 12-lead electrocardiograms (ECGs), 
adverse events and clinical laboratory tests. 
The clinic will attempt to contact participants (including participants who terminate the study 
early) using their standard procedures approximately 14 days after study drug administration 
to determine if any adverse events have occurred since dosing.
In Part 1, a total of up to 16 adults male and female participants will be enrolled. Up to 8
participants with moderate hepatic impairment (a score of 7 to 9, on the Child-Pugh scale) 
and up to 8 healthy control participants matched to the mean demographic of the moderate 
hepatic impairment group (see Section 5 for matching criteria) .
In Part 2, up to 8 participants with mild hepatic impairment (a score of 5 to 6 on the Child-
Pugh scale) will be enrolled. The healthy control group in Part 1 will be used for the PK
comparison in Part 2.
Because this is a Phase 1 assessment of MK-8189 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
A 2-part, open-label study design has been selected to evaluate the effect of hepatic
impairment on the PK of MK-8189. Though hepatic elimination may be important for MK-
8189, the magnitude of the preclinical and clinical safety margins support a reduced design 
with an evaluation of participants with moderate hepatic impairment first; in the clinic a 
 
 
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starting dose 2-fold and a top dose 12-fold the proposed dose have been evaluated and found 
to be generally well tolerated (Panel D, P007). It has been recognized that, in general, low 
clearance compounds (CL < 20 L/h) are less affected by hepatic impairment [Heimbach, T., 
et al 2020].Though MK-8189 is primarily eliminated through hepatic metabolism, the low 
clearance of MK-8189 (CL/F < 5 L/hr) may limit the effect of moderate hepatic impairment 
on MK-8189 PK.
Following a review of the safety and PK data from moderately hepatic impaired patients and 
healthy control participants (Part 1), a decision will be made by the Sponsor whether to 
conduct Part 2 in mildly hepatic impaired participants. If a clinically meaningful increase in 
MK-8189 exposure is observed in participants with moderate hepatic impairment (Part 1)
when compared to healthy participants, Part 2 will be initiated. The effect of mild hepatic 
impairment on MK-8189 PK will not need to be assessed if a clinically meaningful increase 
in MK-8189 exposure is not observed in moderate hepatic impairment patients. Following
enrollment of the moderate hepatic cohort, a control group will be enrolled with
demographics which are reasonably matched to the mean demographic parameters to control 
for the influence of covariates. The Child-Pugh classification will be used to categorize 
hepatic impairment due to its widespread use and acceptance by regulatory agencies 
including the U.S. Food and Drug Administration [S 2003] and the European Committee for 
Medicinal Products for Human Use). [Guideline on the evaluation of... 2005]
The Child classification, which should only be applied to patients with a diagnosis of hepatic 
cirrhosis, was initially used to assess the preoperative risk of patients with hepatic cirrhosis. 
The Child scale, as modified by Pugh, et al [Pugh, R. N. H., et al 1973] has been 
subsequently found useful in classifying a patient’s level of hepatic impairment for PK
studies. The Child-Pugh scale has been shown to correlate with hepatic (i.e., metabolic) 
clearance for several compounds. [S 2003]
In the current study, patients with chronic, stable hepatic impairment due to any etiology will 
be enrolled, and the Child-Pugh scale will be used to classify the severity of liver disease (see 
Child-Pugh classification of the severity of liver disease presented in Appendix 10.11).  The
Child-Pugh scale used in this trial takes into account the medications/treatments being used 
to treat complications of cirrhosis, in order to accurately describe the severity of 
encephalopathy and ascites [Garcia-Tsao, G., et al 2007].  Patients’ scores of 5 to 6, 7 to 9, 
and 10 to 15 on this scale are classified as having mild, moderate, and severe hepatic failure, 
respectively.
In addition, as the laboratory parameters specified in the Child-Pugh scale (e.g., reduced 
serum albumin, increased serum bilirubin, and increased INR) may be better associated with 
the capacity of the liver to eliminate drugs, in comparison to ascites and encephalopathy,
[Guideline on the evaluation of... 2005] at least four (4) patients with moderate hepatic 
impairment (Part 1 only) will be required to have a score of at least 2 on one of the laboratory 
parameters on the Child-Pugh scale.
 
 
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4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of physical and 12 lead ECGs, VS, and 
laboratory safety tests. 
4.2.1.2
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189 in participants with hepatic 
impairment. Therefore, individual plasma concentration and actual sample collection times of 
MK-8189 will be used to derive the PK parameter values such as AUC0-24, AUC0-inf,
Cmax, Tmax, C24hr, CL/F, Vd/F and apparent t1/2.  Protein binding for MK-8189 will also 
be analyzed. As MK-8189 is highly protein bound, the fraction unbound PK parameters (at a 
minimum CL/F, Vd/F) will be provided in healthy participants and participants with hepatic 
impairment.
4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, polymorphisms of CYP2C9 will 
specifically be investigated for association with the PK of MK-8189 since MK-8189 is 
partially metabolized by CYP2C9. Genetic variation in CYP2C9 may be analyzed for 
association with any laboratory or clinical data collected in this study
4.2.1.4
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
 
 
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.3
Justification for Dose
A single-dose of 4 mg will be administered in this trial.  The highest likely clinical dose of 
MK-8189 is expected to be 24 mg.  While multiple doses up to 48 mg of MK-8189 have 
been found to be generally well tolerated, a titration scheme has been used to step up to this 
supratherapeutic dose.  The titration approach has been used to mitigate dystonia which was 
observed in P001 with an immediate release formulation and the need to continue the 
titration approach with the CR formulation has not yet been evaluated.  To date, the highest 
generally well tolerated starting dose evaluated is 8 mg, providing a 2-fold clinical margin to 
the 4 mg dose to be administered in this trial.  While hepatic impairment may increase the 
exposure of MK-8189, this effect may be modest due to its low intrinsic clearance
[Heimbach, T., et al 2020]. MK-8189 is a BCS class 1 compound up to doses of 16 mg and 
BCS class 2 at 24 mg. In addition, PK of MK-8189 generally increases dose proportionally in 
subjects with schizophrenia over the dose range evaluated (2 mg to 48 mg). Thus, the effect 
of hepatic impairment at a low dose of 4 mg is expected to be extrapolatable, within 
reasonable variability, to the highest likely clinical dose of 24 mg.
4.3.1
Rationale for Dose Interval and Study Design
As MK-8189 PK is linear, single-dose PK will be predictive of multiple-dose PK and 
therefore, only a single-dose evaluation of MK-8189 in hepatic impairment is required.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
 
 
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4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
In Part 1 male and female participants with moderate hepatic impairment and  healthy 
participants between the ages of 18 and 75 years of age may be enrolled.  If Part 2 is 
conducted, male and female participants with mild hepatic impairment between the ages of 
18 and 75 will be enrolled.
The individual age and weight of the healthy participants is aimed to be within the range ± 15 
years and ± 20% of the mean age and weight of participants with moderate hepatic 
impairment. In addition, the numbers of males and females of the healthy participants will be 
generally matched to the numbers of hepatic insufficient participants within ± 1; i.e., if there 
are 4 males and 4 females in the hepatic insufficient group, every effort will be made to 
ensure a 4:4 ratio in the healthy participants, but 3:5 or 5:3 would be acceptable as well.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
5.1.1
Inclusion Criteria for Healthy Participants
1. Is in good health based on medical history, physical examination, VS measurements and 
ECGs performed prior to randomization.
Appendix 9 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 10
provides an algorithm for the assessment of out of range laboratory values.
3. Have a BMI≥18.5 and ≤40 kg/m2, inclusive. See Section 8.3.1 for criteria on rounding to 
the nearest whole number. BMI = weight (kg)/height (m)2.
4. Continuous non-smokers or moderate smokers (of fewer than 20 cigarettes/day or the 
equivalent). Subjects must agree to consume no more than 10 cigarettes or equivalent/day 
from the time of screening and throughout the period of sample collection.
 
 
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Demographics
5. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term 
and persistent basis), as described in Appendix 5 during the intervention period and for at 
least 14 days after the last dose of study intervention. The investigator should evaluate 
the potential for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. Note: participants intending to rely on 
abstinence as a birth control method should agree to use double-barrier birth control 
methods if they engage in intercourse.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 48 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
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.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
7. The participant has provided documented informed consent/assent for the study. The 
participant may also provide consent/assent for FBR. However, the participant may 
participate in the study without participating in FBR.
 
 
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5.1.2
Inclusion Criteria for Hepatically Impaired Participants
The following inclusion criteria apply to all hepatically impaired participants. A hepatically 
impaired participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the 
previous 2 months due to deterioration in hepatic function) hepatic impairment with 
features of cirrhosis due to any etiology.  
2. Part 1 only: Has a score on the Child-Pugh scale ranging from 7 to 9 (moderate hepatic 
impairment) at screening. At least 4 (or at least 3 in the situation where only 6 
participants are enrolled or complete the study) of the participants must have a score 
of 2 or higher on at least one of the laboratory parameters (i.e., albumin, INR, and 
bilirubin) at screening on the Child-Pugh scale.
3. Part 2 only: Patient’s score on the Child-Pugh scale must range from 5 to 6 (mild hepatic 
impairment).
4. With the exception of hepatic impairment, is in generally good health based on medical 
history, physical examination, VS measurements and ECGs performed prior to 
randomization.  Appendix 9 provides a table of the 12-Lead Electrocardiogram 
Abnormality Criteria. Participants with stable, chronic medical or psychiatric conditions 
may be included at the discretion of the investigator and the Sponsor.  
5. With the exception of hepatic impairment, is in good health based on laboratory safety 
tests obtained at the screening visit and prior to randomization. Appendix 2 provides a 
table of laboratory safety tests to be performed. Appendix 10 provides an algorithm for 
the assessment of out of range laboratory values.  
6. Has a BMI ≥ 18.5 and ≤ 40 kg/m2. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
Demographics
7. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
Female Participants
8. 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
 
 
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•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term 
and persistent basis), as described in Appendix 5 during the intervention period and for at 
least 14 days after the last dose of study intervention. The investigator should evaluate 
the potential for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. Note: participants intending to rely on 
abstinence as a birth control method should agree to use double-barrier control methods if 
they engage in intercourse.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 48 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
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.
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
9. The participant has provided documented informed consent/assent for the study. The 
participant may also provide consent/assent for FBR. However, the participant may 
participate in the study without participating in FBR.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
5.2.1
Exclusion Criteria for Healthy Participants
The following exclusion criteria apply to all healthy participants. The participant must be 
excluded from the study if the participant:
Medical Conditions
1. 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 (eg, uncomplicated 
 
 
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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.
Subjects with stable chronic conditions that are adequately controlled by medication may 
be enrolled upon discussion with the Sponsor.
2. 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.
3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated non-melanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
4. Has known hypersensitivity to the active substance of any of the excipients of the study 
drug.
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
6. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
8.
Participant has an estimated CrCl ≤70 mL/min based on the CG Equation at Screening.
Cockcroft-Gault Equation: 
CrCl = (140-age[yr])(body wt [kg])
(72)(serum creatinine [mg/dL])
[When creatinine is measured in µmol/L, use this formula]
CrCl = (140-age[yr])(body wt[kg])
(72)(serum creatinine [µmol/L] x 0.0113)
For females, multiply the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
 
 
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Participants who have a measured CrCl of up to 10% below 70 mL/min may be enrolled in 
the study at the discretion of the investigator.
Prior/Concomitant Therapy
9. Has taken any drugs known to be moderate or strong inhibitors of CYP3A, CYP2C9 or 
P-gp for 14 days (or 5 half-lives, whichever is greater) or CYP3A or CYP 2C9 inducers,
including St. John’s Wort, for 28 days (or 5 half-lives, whichever is greater) prior to 
dosing of study drug and throughout the study. Use of weak CYP3A/2C9
inhibitors/inducers or P-gp inhibitors may be deemed acceptable following consultation 
with the Sponsor Clinical Monitor and the Investigator. Acetaminophen (up to 2 g per 24-
hour period) may be permitted during the study. In addition, participants who are taking 
medications (excluding inhibitors or inducers  discussed above) for stable diseases for ~1 
month prior to dosing may be allowed to participate in the study at the discretion of the 
Investigator and following consultation with the Sponsor.
Prior/Concurrent Clinical Study Experience
10. Has participated in another investigational study within 4 weeks (or 5 half-lives of the 
investigational drug, 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
11. Has a mean QTc interval >450 msec, has a history of risk factors for Torsades de Pointes 
(eg, heart failure/cardiomyopathy or family history of long QT syndrome), has 
uncorrected hypokalemia or hypomagnesemia, is taking concomitant medications that 
prolong the QT/QTc interval.
Other Exclusions
12. Is under the age of legal consent.
13. Does not agree to follow the smoking restrictions as defined by the CRU. 
14. 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.
15. 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.
16. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 2 years. With the exception of cannabis, participants must 
have a negative UDS prior to randomization.
 
 
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17. 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.
18. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
19. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.2.2
Exclusion Criteria for Hepatically Impaired Participants
The following exclusion criteria apply to all hepatically impaired participants.  
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of any illness that, in the opinion of the Investigator, might confound the 
results of the study or poses an additional risk to the participant by their participation in 
the study.
2. Is institutionalized or mentally or legally incapacitated at the time of prestudy (screening) 
visit or expected during the conduct of the study.
3. Has a history of cancer (malignancy).
4. Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
6. Has known hypersensitivity to the active substance or any of the excipients of the study 
drug.
7. Is positive for HIV. 
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
 
 
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9. Participant has an estimated CrCl ≤60 mL/min based on the CG Equation at Screening.
Cockcroft-Gault Equation: 
CrCl = (140-age[yr])(body wt [kg])
(72)(serum creatinine [mg/dL])
[When creatinine is measured in µmol/L, use this formula]
CrCl = (140-age[yr])(body wt[kg])
(72)(serum creatinine [µmol/L] x 0.0113)
For females, multiply the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
Participants who have a measured CrCl of up to 10% below 60 mL/min may be enrolled in 
the study at the discretion of the investigator.
Prior/Concomitant Therapy
10. Has taken any drugs known to be moderate or strong inhibitors of CYP3A, CYP2C9 or 
P-gp  for 14 days (or 5 half-lives, whichever is greater) or CYP3A or CYP 2C9  inducers, 
including St. John’s Wort, for 28 days (or 5 half-lives, whichever is greater) prior to 
dosing of study drug and throughout the study. Use of weak CYP3A/2C9 inducers or P-
gp inhibitors may be deemed acceptable following consultation with the Sponsor Clinical 
Monitor and the Investigator. Acetaminophen (up to 2 g per 24 hour period) may be 
permitted during the study. In addition, participants who are taking medications 
(excluding inhibitors or inducers  discussed above) for stable diseases for ~1 month prior 
to dosing may be allowed to participate in the study at the discretion of the Investigator 
and following consultation with the Sponsor.
11. Is taking medications to treat chronic medical conditions and has not been on a stable 
regimen for at least 1 month and/or is unable to withhold the use of the medication(s) as 
specified in Section 6.5. Exceptions may be granted for participants in whom a 
medication regimen has been adjusted within the one-month window, at the discretion of 
the Investigator and following consultation with the Sponsor. See Section 5.1.2 for 
allowed medical conditions, and Section 6.5 for allowed medications.
Prior/Concurrent Clinical Study Experience
12. Has participated in another investigational study within 4 weeks (or 5 half-lives of the 
investigational drug, whichever is greater) prior to the prestudy (screening) visit. The 
window will be derived from the date of the last visit in the previous study.
 
 
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Diagnostic Assessments
13. Has a mean QTc interval >450 msec, has a history of risk factors for Torsades de Pointes 
(eg, heart failure/cardiomyopathy or family history of long QT syndrome), has 
uncorrected hypokalemia or hypomagnesemia, is taking concomitant medications that 
prolong the QT/QTc interval.
Other Exclusions
14. Is under the age of legal consent.
15. Does not agree to follow the smoking restrictions as defined by the CRU.
16. 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.
17. Is a regular user of cannabis, any illicit drugs or has a history of drug abuse within 
approximately 3 months. Participants must have a negative alcohol test and with the 
exception of cannabis, participants must have a negative UDS prior to randomization.  
Participants with hepatic impairment may be allowed for inclusion with a positive UDS 
for opiates or benzodiazepines if they have an active prescription from a licensed health 
care provider.
18. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions. 
19. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
20. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
In each treatment period, participants will fast from all food and drinks, except water, for at 
least 8 hours before study drug administration. 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 study flowchart. 
Participants will fast from all food and drinks except water between meals and snacks. After 
the 24-hour postdose procedures have been completed, subsequent meals and snacks will be 
unrestricted in caloric content, composition, and timing.
 
 
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Water will be provided during study drug administration. Water will be restricted 1 hour 
before and 1 hour after study drug administration.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study until the last PK sample is collected. 
Participants also will refrain from the consumption of all fruit juices 24 hours prior to and 
after study drug administration. On all other days during the study, consumption of fruits and 
fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits and from 12 hours prior to 
and after study drug administration in each treatment period. At all other times, caffeinated 
beverages or xanthine-containing products will be limited to no more than 6 units per day (1 
unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits and from 24 hours prior to drug administration until participants are 
discharged in each treatment period. At all other times, alcohol consumption is limited to no 
more than approximately 3 alcoholic beverages or equivalent (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight- lifting, running, 
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information may be 
 
 
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included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant withdraws from the study a replacement participant may be enrolled if 
deemed appropriate by the investigator and Sponsor. The replacement participant will 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/randomization number. The study site should contact the Sponsor for the 
replacement participant’s treatment/randomization number.
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 will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement participant. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in [Table 1].
 
 
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Table 1
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Healthy 
Control
Experi
mental
MK-8189
Drug
Tablet
4 mg
4 mg
Oral
Single Dose on Day 
1
Experi
mental
IMP
Provided 
by the 
sponsor
Moderate 
Hepatic 
Impairment 
Group
Experi
mental
MK-8189
Drug
Tablet
4 mg
4 mg
Oral
Single Dose on Day 
1
Experi
mental
IMP
Provided 
by the 
sponsor
Mild 
Hepatic 
Impairment 
Group
Experi
mental
MK-8189
Drug
Tablet
4 mg
4 mg
Oral
Single Dose on Day 
1
Experi
mental
IMP
Provided 
by the 
sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
 
 
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All supplies indicated in [Table 1] will be provided per the "Sourcing" column depending 
upon local country operational requirements. If local sourcing, every attempt should be made 
to source these supplies from a single lot/batch number where possible (eg, not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned an AN for a single open-label treatment using the allocation 
schedule shown in [Table 2].
Table 2
Allocation of Participants to Treatment
Part 1a
Hepatic Impairment 
Stage 
N
Treatment
Moderate
6≤n≤8
MK-8189 4 mg
Healthy b
6≤n≤8
MK-8189 4 mg
Part 2a
Mild
6≤n≤8
MK-8189 4 mg
a The participants in the groups defined by hepatic function should be reasonably similar to one another with 
respect to age, gender, and weight. However, participants with normal hepatic function should be matched at 
the group level. In order to make this matching  possible, participants with normal hepatic function need to 
be enrolled after the participants with moderate hepatic impairment subjects have been recruited in Part 1.  
The participants with normal hepatic function in Part 1 also serve as control for mild hepatic category in Part 
2.
b Participants with normal hepatic function are within ±15 years of the mean age and within ± 20%  of the 
mean weight for the moderate hepatic function group. In addition, the numbers of males and females of the 
healthy participants will be generally matched to the numbers of hepatic insufficient participants within ± 1; 
i.e., if there are 4 males and 4 females in the hepatic insufficient group, every effort will be made to ensure a 
4:4 ratio in the healthy participants, but 3:5 or 5:3 would be acceptable as well
6.3.2
Stratification
Not applicable
6.3.3
Blinding
This is an open-label study.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the CRF. The dose of study intervention 
and study participant ID will be confirmed at the time of dosing by a member of the study-
 
 
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site staff other than the person administering the study intervention. Study-site personnel will 
examine each participant’s mouth to ensure that the study intervention was ingested.
6.5
Concomitant Therapy
Hepatic impairment and healthy participants: All prescription or non-prescription 
medications known to be moderate or strong inhibitors of CYP3A, CYP2C9 or P-gp  or 
inducers of CYP3A or CYP2C9, will be prohibited throughout the study.  Medications of 
particular concern include, but are not limited to azole antifungals (ketoconazole, 
itraconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, HIV protease 
inhibitors, nefazodone, rifampin, rifabutin, bosentan, modenafil, phenytoin, dexamethasone, 
troglitazone, barbiturates, and any drug or supplement (e.g., St. John’s Wort).  Weak CYP3A 
and/or CYP2C9 inhibitors or inducers or weak P-gp inhibitors may be deemed acceptable 
following consultation with the Sponsor Clinical Monitor and the Investigator.
Participants who are taking medications for stable diseases that are on a steady dose and 
regimen for ~1 month prior to dosing on Day 1 may be allowed to participate in the study at 
the discretion of the Investigator, and following consultation with the Sponsor Clinical 
Monitor.
Hepatically impaired participants only: Certain prescription medications used to treat 
manifestations of hepatic disease or medications needed to treat stable diseases (e.g., 
diuretics, lactulose, neomycin, etc.) will be allowed during the study, but the patient must be 
on a steady dose, drug, and regimen  for ~1 month prior to dosing on Day 1. Lactulose 
should be restricted at least 24 hours prior to and 18 hours after dosing on Day 1 since it may 
potentially affect absorption of MK-8189. Neomycin, diuretics, beta-blockers and other 
approved concomitant medications should be restricted at least 4 hours prior to and 24 hours 
after dosing on Day 1. Any diuretics or beta-blockers that are significant CYP3A or CYP2C9 
inhibitors or inducers (e.g., conivaptan) are not permitted.
Concurrent therapy with any medication during the course of the protocol including both 
prescription and non-prescription drugs must first be discussed with the Sponsor Medical 
Monitor prior to administration, unless appropriate medical care necessitates that therapy 
should begin before the Sponsor Medical Monitor can be consulted. Any medication used 
during the study conduct must be recorded on the appropriate case report form and include 
the name of the drug, dosage, date/time of and reason for administration.
6.5.1
Rescue Medications and Supportive Care
For the treatment of EPS, such as acute dystonia, all participants may be treated with an 
anticholinergic. If the symptoms are unresponsive to anticholinergic treatment, a 
benzodiazepine can be used.
In case the participant presents with signs of akathisia without signs of dystonia, the 
participant can be treated with a β-adrenergic blocker. If symptoms do not disappear with the 
β-adrenergic blocker, treatment with an anticholinergic may be used. An anticholinergic may 
 
 
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be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred 
treatment based on a participant’s medical history and/or concomitant medication.
Anticholinergics, benzodiazepines and β-adrenergic blockers are often used in the treatment 
of EPS and are considered standard practice. Oral anticholinergic treatment is also used as 
concomitant medication to prevent EPS symptoms with antipsychotic medication.
6.6
Dose Modification
Dose modifications are not applicable to this study
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
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (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
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
 
 
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
 
 
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The maximum amount of blood collected from each participant over the duration of the study
is outlined in Appendix 8.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or his/her legally acceptable representative will be asked to sign 
consent.
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.
 
 
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention allocation, site 
personnel will add the treatment/randomization number to the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
 
 
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participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention(s) will be monitored by the investigator and/or study 
staff.
Participants will fast from all food and drinks, except water, for at least 8 hours prior to study 
drug administration. Participants will remain fasted for 4 hours post dose. Approximately 240 
mL of water will be provided during study drug administration, but will be restricted 1 hour 
prior to and 1 hour post dose.
8.1.8.1
Timing of Dose Administration
Participants will be dosed according to the SoA (Section 1.3).
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study . If a participant discontinues for any reason at any 
time during the course of the study, the participant may be asked to return to the clinic (or be 
contacted) for a poststudy visit as per the number of days described in Section 1.3 to have the 
applicable procedures conducted. However, the investigator may decide to perform the 
poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs prior to the safety follow-up time frame as 
specified in Section 8.4.1, the investigator should perform a follow-up telephone call at the 
end of the follow-up period ( Section 8.4.1) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
 
 
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from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Domiciling
Hepatic Impairment participants will report to the CRU on Day -1 before the scheduled day 
of study intervention administration on Day 1 and remain in the unit until 120 hours 
postdose. At the discretion of the investigator, participants may be requested to remain in the 
CRU longer. 
Healthy matched participants will report to the CRU on Day-1 before the scheduled day of 
study intervention administration on Day 1 and remain in the unit until 48 hours postdose. At 
the discretion of the investigator, participants may be requested to remain in the CRU longer.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
 
 
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, via contactless forehead thermometer, heart rate, respiratory rate, and 
blood pressure will be assessed.
•
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
•
Vital signs will be measured in a semirecumbant position after 10 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse 
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 10 minutes before having VS measurements obtained. Semirecumbent 
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements.
The predose (baseline) HR and BP will be triplicate measurements obtained at least 1-2 
minutes apart within 3 hours of dosing MK-8189/placebo. 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.
 
 
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Participants will continue to rest semirecumbent from dosing until 4 hours postdose except to 
stand for other study-related procedure.
Body Temperature
Body temperature will be measured via contactless forehead thermometer. The same method 
must be used for all measurements for each individual participant and should be the same for 
all participants.
8.3.3
Electrocardiograms
•
Triplicate and single 12-lead ECG will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
(Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals. Refer to Appendix 9 for evaluation and 
withdrawal criteria and additional QTc readings that may be necessary.
•
At each time point when triplicate ECG are required, 3 individual ECG tracings should 
be obtained at least 1 to 2 minutes apart, but no more than 2 minutes apart. The full set of 
triplicates should be completed in no more than 6 minutes.
•
Special care must be taken for proper lead placement by qualified personnel. Skin should 
be clean and dry before lead placement. Participants may need to be shaved to ensure 
proper lead placement. Female participants may need to remove interfering garments.
•
Participants should be resting in the semirecumbent for at least 10 minutes before each 
ECG measurement. 
•
The correction formula to be used for QTc is Fridericia.
•
Screening and Predose ECGs will be obtained in triplicate at least 1 to 2 minutes apart 
within 3 hours before dosing MK-8189. The mean of the predose (Day 1) measurements 
will be used as the baseline to calculate change from baseline for safety evaluations (and 
for rechecks, if needed).
•
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with  predose baseline measurement, the ECG will be repeated twice 
within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent the 
value at that time point. If the QTc interval increase from baseline for any postdose time 
point is ≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs 
every 15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
•
If the QTc interval is ≥500 msec on any postdose ECG, the Sponsor should be notified 
and the ECGs should be reviewed by a cardiologist. The participant should be telemetry-
 
 
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monitored (until the QTc is <500 msec) or should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
•
If the participant has unstable hemodynamics, or has any clinically significant 
dysrhythmias noted on telemetry, the participant should be immediately transferred to an 
acute care setting for definitive therapy.
•
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
•
A cardiologist will be consulted by the investigator as needed to review ECG tracings 
with significant abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
 
 
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation, must be reported by the 
investigator for randomized participants only if the event is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo, or a procedure.
From the time of intervention allocation through 14 days following cessation of intervention, 
all AEs, SAEs and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in [Table 3].
 
 
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously reported 
– Follow to 
completion/terminati
on; report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days of 
learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
(unless serious)
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 24 hours 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
 
 
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Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Dystonia
3. 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.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
 
 
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8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for CYP2C9 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CYP2C9. Leftover extracted DNA will be stored for FBR if the participant 
provides documented informed consent for FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the FBR consent, the following specimens will be obtained as part of 
FBR:
•
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
 
 
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8.10.1
Screening
Approximately 4 weeks prior to intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in Section 
5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol.
8.10.2
Treatment Period
Refer to the Schedule of Activities (Section 1.3).
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all of study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. 
8.10.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sampling for MK-8189 is the critical procedure.
At any postdose time point, the blood sample for MK-8189 needs to be collected as close to 
the exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed prior or after the 
prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director. Blood samples should be taken after vital sign and ECG 
assessments or there should be a 10-minute window between a blood draw and the start of a
vital sign or ECG assessment.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
 
 
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•
PK Collection as outlined in [Table 4].
Table 4
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
0 - <1 hr
5 min
1 - <24 hr
15 min
24 - 48 hr
30 min
>48 - 120 hr
30 min domiciled, 2 hrs outpatient visits
•
Predose standard safety evaluations: vital signs and ECG (up to 3 hrs prior to dose)
laboratory safety tests and physical exam (up to 24 hrs prior to dose)
•
Postdose standard safety evaluations: vital signs, ECG, laboratory safety tests, and
physical exam
-
<24 hr postdose may be obtained within 15 min of the theoretical sampling time
-
24 hr - <48 hr postdose may be obtained within 1 hr of the theoretical sampling time
-
48 hr – 120 hr postdose may be obtained within 2 hr of the theoretical sampling time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study intervention to any participant may not be modified. 
If necessary, a participant must be discontinued for the reasons described in Section 7.
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 75 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
 
 
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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
Separately for each PK parameter, individual values of AUC0-24, Cmax, C24, AUC0-last, 
and AUC0-inf will be natural log-transformed and evaluated with a linear fixed effects model 
containing a fixed effect for population (each hepatic impairment group, and normal hepatic 
function). For each population, least-squares geometric means and their corresponding 95% 
CIs will be provided. Additionally, to compare participants with hepatic impairment to 
participants with normal hepatic function, a 2 sided 90% confidence interval for the true 
GMR (hepatic impairment/normal hepatic function) will be calculated for AUC0-24, Cmax, 
AUC0-last, and AUC0-inf.
The safety and tolerability of MK-8189 will be monitored by clinical assessment of adverse 
experiences and other safety measurements (e.g., labs, vital signs, ECGs).
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
Part 1 Estimation: The AUC0-inf and Cmax in participants with moderate hepatic 
impairment will be estimated and compared to those obtained from healthy control 
participants. 
Part 2 Estimation: The AUC0-inf and Cmax in participants with mild hepatic 
impairment will be estimated and compared to those obtained from healthy control 
participants in Part 1.
9.4
Analysis Endpoints
Primary Endpoints: MK-8189 PK variables (AUC0-inf and Cmax)
Secondary Endpoints:  All types of adverse experiences, in addition to laboratory safety tests, 
12-lead ECGs, and VS. 
Exploratory Endpoints: AUC0-last, AUC0-24, C24hr, Tmax, CL/F, Vd/F and t1/2.
 
 
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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: 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: 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 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 procedures as
aforementioned and have available data from at least one treatment will be included in the
per-protocol dataset.  This population will be used for the PK analysis.
9.6
Statistical Methods
Pharmacokinetics: 
At the end of the study, the final analysis will be run on pooled data from both study parts (if 
both parts are conducted).
Separately for each PK parameter, individual values of AUC0-24, Cmax, C24, AUC0-last, 
and AUC0-inf will be natural log-transformed and evaluated with a linear fixed effects model
containing a fixed effect for population (each hepatic impairment group, and normal hepatic 
function).  An unstructured covariance matrix will be used to allow for unequal population 
variances via the REPEATED and GROUP statement in SAS PROC MIXED.  Kenward and 
Roger's method will be used to calculate the denominator degrees of freedom for the fixed 
effect (DDFM=KR).  Ninety-five percent (95%) CIs for the least squares means for each 
population will be constructed on the natural log scale and will reference the t-distribution. 
Exponentiating the least-squares means and their corresponding 95% CIs will yield estimates 
for the population geometric means and confidence intervals about the geometric means on 
the original scale.  Sample SAS code is given below:
proc mixed data=data; 
   class population; 
   model lnpk = population /ddfm=kr; 
   repeated/ group= population;  
   lsmeans population /cl alpha=0.05; 
run;   
 
 
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To compare participants in each hepatic impairment population to participants with normal 
hepatic function, a two sided 90% confidence interval for the true difference in means 
(hepatic impairment – normal hepatic function) will be calculated for AUC0-24, Cmax, 
AUC0-last, and AUC0-inf using the mean square error from the model and referencing a t-
distribution.  These confidence limits will be exponentiated to obtain the 90% confidence 
interval for the true ratio of geometric means (hepatic impairment/normal hepatic function) 
for each PK parameter and each hepatic population.
Figures showing individual PK values with GMs (95% CIs) by population, plotted on the 
natural log scale, will be provided for PK parameters AUC0-24, Cmax, AUC0-last, and 
AUC0-inf. A figure showing the GMR (hepatic impairment/normal hepatic function) and 
corresponding 90% CI will be provided for PK parameters AUC0-24, Cmax, AUC0-last, and 
AUC0-inf.
The above analyses will be carried out for PK calculated from both total and unbound 
concentrations.
Individual values will be listed for each PK parameter (CL/F, Vd/F, AUC0-24, AUC0-last, 
AUC0-inf, C24, Cmax, Tmax, fraction unbound for PK parameters (at a minimum of CL/F, 
Vd/F), and terminal half-life (t1/2)) by population, 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, geometric mean, and geometric 
percent CV (calculated as  100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the 
natural log-scale). 
The relationship between MK-8189 PK and hepatic impairment will be examined in an 
exploratory manner via a scatter plot of PK values (AUC0-24, Cmax, AUC0-last, and AUC0-
inf) versus the Child-Pugh score. Plots of PK values (AUC0-24, Cmax, AUC0-last, and 
AUC0-inf) and the baseline laboratory components of the Child-Pugh score (i.e., bilirubin, 
albumin levels, and INR time) may be provided.  Plots of PK parameter values (AUC0-24, 
Cmax, AUC0-last, and AUC0-inf) vs age and body weight may also be provided. 
Additionally, individual participant PK parameter values (AUC0-24, Cmax, AUC0-last, and 
AUC0-inf) may also be plotted against CrCL (estimated from Cockcroft-Gault Equation), 
using different symbols to identify participants from each population.   Note: CrCL will be 
calculated as the mean of the two values determined at screening.  
Safety: The safety and tolerability of MK-8189 will be monitored by clinical assessment of 
adverse experiences and other safety measurements (e.g., labs, vital signs, ECGs).
9.7
Interim Analyses
A preliminary analysis of Part 1 data may be conducted to inform on whether the study will 
proceed to Part 2.
 
 
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9.8
Multiplicity
No multiplicity adjustment is needed as the study has no hypothesis testing.
9.9
Sample Size and Power Calculations
The sample size selected for each population to evaluate the effect of hepatic impairment on 
the PK of MK-8189 was not chosen to satisfy any a priori statistical requirement.  This 
sample size (N=6-8 per group) has historically been shown to be sufficient for studies of this 
type and should provide adequate data to support the planned analyses.  Nevertheless, 
estimates of the expected precision of the estimates, based on these sample sizes and the 
known variability obtained from hepatic PK studies are presented below.
The precision of the estimated ratios of geometric means (hepatic impairment / normal 
hepatic function) of PK parameters obtained from this study can be assessed by calculating 
the half-width of the 90% CIs expected for the given sample size and assumed variability. 
The pooled between-subject standard deviation (on the natural log scale) for AUC0-24 in
participants with normal hepatic function and participants with schizophrenia on 4 mg MK-
8189 was 0.29 ln(nM*hr) from P003. The pooled between-subject standard deviation for 
AUC0-24 was obtained using the between subject standard deviation of 0.16 ln(nM*hr) in 
healthy and between subject deviation of 0.39 ln(nM*hr) in participants with schizophrenia 
on 4 mg MK-8189 in P003.  The variability for AUC0-inf in participants with moderate 
hepatic impairment is assumed to be similar to the variability in AUC0-24 in participants 
with schizophrenia for 4 mg dose from P003. The variability for AUC0-inf in participants 
with normal hepatic function is assumed to be similar to the variability in AUC0-24 in 
healthy participants for 4 mg dose from P003. Assuming a minimum sample size of 6
participants per population and observed between-subject standard deviation as given above, 
then the half width of the 90% CIs of GMRs for MK-8189 AUC0-inf on the log scale will be 
0.30. The lower and upper 90% confidence limits for the true GMRs will be given by 
OBS/1.35 and OBS*1.35 for AUC0-inf, where OBS is the observed GMR.   Thus, for 
example, if the observed GMR for AUC0-inf was 1.50, then the 90% CI for the GMR would 
be 1.11 to 2.03.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
 
 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
 
 
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
 
 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
 
 
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
 
 
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the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in [Table 5] will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 5
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal)
Albumin
Bicarbonate or 
Total CO2
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Coagulation
•
INR (International normalized ratio, for hepatic impaired participants only)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
Serum or urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines). Alcohol breath test 
for alcohol screen is permitted.
•
Highly sensitive serum or urine human chorionic gonadotropin (β-hCG) pregnancy test 
(as needed for WOCBP)
•
Serology (HIV-1 and HIV-2 antibodies in all participants, HBsAg, and hepatitis C 
virus antibody in healthy participants only
NOTES: The investigator (or medically qualified designee) must document their review of each laboratory 
safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
    An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
    NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
    NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
    Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
    Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
    Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
    Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
    For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
    Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
    Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
    Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
    Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
    Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
    When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
    The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
·    It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
    There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
 
 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
    The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
    An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
- Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
- Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
- Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
 
 
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count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
 
 
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
    The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
    New or updated information will be recorded in the CRF.
    The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
    In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c   Male condoms must be used in addition to female participant hormonal contraception.
d   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation. 
e   IUS is a progestin releasing IUD.
f   A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
 
 
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.  Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.7
Appendix 7: Country/Site-specific Requirements
10.7.1
Site 0001-specific Requirements
Section 1.3.1 Schedule of Activities - Hepatic Impairment Participants
C-SSRS Baseline Version at screening is mandatory. Refer to Appendix 7 Section 8.3.5 for 
further information.
C-SSRS Since Last Assessment Version at the Day -1 predose, 48 hours postdose, and post-
study visits are mandatory. Refer to Appendix 7 Section 8.3.5 for further information.
Section 1.3.2 Schedule of Activities - Healthy Matched Participants
C-SSRS Baseline Version at screening is mandatory. Refer to Appendix 7 Section 8.3.5 for 
further information.
C-SSRS Since Last Assessment Version at the Day -1 predose, 48 hours postdose, and post-
study visits are mandatory. Refer to Appendix 7 Section 8.3.5 for further information.
Section 5.2.1 Exclusion Criteria for Healthy Participants
Exclusion Criteria: Is at imminent risk of self-harm, based on clinical interview and 
responses on the CSSRS, or of harm to others in the opinion of the investigator. Participants 
must be excluded if they report suicidal ideation with intent, with or without a plan or 
method (eg, positive response to item 4 or 5 in assessment of suicidal ideation on the 
CSSRS) in the past 5 years or suicidal behavior in their lifetime.
Section 5.2.2 Exclusion Criteria for Hepatically Impaired Participants
Exclusion Criteria: Is at imminent risk of self-harm, based on clinical interview and 
responses on the CSSRS, or of harm to others in the opinion of the investigator. Participants 
must be excluded if they report suicidal ideation with intent, with or without a plan or 
method (eg, positive response to item 4 or 5 in assessment of suicidal ideation on the 
CSSRS) in the past 5 years or suicidal behavior in their lifetime.
Section 8.3.5 Suicidal Ideation and Behavior Monitoring
Section 8.3.5.1 Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness. If the C-SSRS is administered 
by someone other than the investigator, consider providing the completed C-SSRS to the 
investigator for review, before their assessment of the participant and to further inform their 
 
 
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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 AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). After that evaluation, only those participants whose suicidal ideation is considered by 
the evaluator to be passive, and who expressly deny any intent to act, and who, after 
evaluation, are not judged to be at serious risk for self-harm during the course of the study 
may continue in the study; other participants must be discontinued from study participation 
and receive appropriate clinical follow-up care to ensure their safety.
Section 9.6 Statistical Methods
If the C-SSRS data are collected then the responses on the C-SSRS will be classified 
according to 11 prespecified categories as described in protocol Appendix 7.  The most 
severe treatment-emergent event within each of three broad categories (suicidal ideation, 
suicidal behavior, and non-suicidal self-injurious behavior) reported at a visit will be used for 
reporting. An event is considered treatment-emergent during the assessment phase if it is 
either newly emerged or is more severe than the most severe event reported to have occurred 
in the trial-defined pre-treatment reference period.
 
 
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Mapping Between the 11 Categories of Suicidal Ideation and Behavior and the C-SSRS
Category
C-SSRS Question (from eCRF)†
Suicidal ideation
1. Passive
1. Wish to be dead
2. Active: Nonspecific (no method, intent, or 
plan)
2. Non-specific active suicidal thoughts
3. Active: Method, but no intent or plan
3. Active suicidal ideation with any methods (not 
plan) without intent to act
4. Active: Method and intent, but no plan
4. Active suicidal ideation with some intent to 
act, without specific plan
5. Active: Method, intent and plan
5. Active suicidal ideation with specific plan and 
intent
Suicidal behavior
6. Preparatory actions toward imminent 
suicidal behaviors
Preparatory acts or behavior
7. Aborted attempt
Aborted attempt
8. Interrupted attempt
Interrupted attempt
9. Suicide attempt
Actual attempt
10. Completed suicide
Completed suicide
Self-injurious behavior, no suicidal intent
Has subject engaged in non-suicidal self-injurious 
behavior?
†Data are "yes" or "no" 
 
 
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10.8
Appendix 8: Blood Volume Table
Pre-
study
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Participants with hepatic impairment
Laboratory Safety Tests 
(all participants; includes 
FSH if applicable, β-
hCG if applicable, and 
HIV/Hepatitis screen)
2
2
1
5
17
85
Blood for Planned 
Genetic Analysis 
1
0
0
1
8.5
8.5
Blood for MK-8189
1
15
0
16
4
64
Blood for Protein 
Binding Plasma
1
0
0
1
10
10
Total Blood Volume per Participants with hepatic impairment for Part 1 and Part 2 a
167.5 mL
Healthy Matched Participants
Laboratory Safety Tests 
(all participants; includes 
FSH if applicable, β-
hCG if applicable, and 
HIV/Hepatitis screen)
2
1
1
4
17
68
Blood for Planned 
Genetic Analysis 
1
0
0
1
8.5
8.5
Blood for MK-8189
1
11
0
12
4
48
Blood for Protein 
Binding Plasma
1
0
0
1
10
10
Total Blood Volume per Healthy matched participants for Part 1 a
134.5 mL
a
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up 
to 75 mL) may be obtained.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR <40 
bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB (ICRBBB) 
(QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTc 
Male
QTcF 450 ms
QTc (B or F) 500 ms or Increase of 
60 ms From Baseline
Female
QTcF >450 ms
QTc (B or F) 500 ms or Increase of 
60 ms From Baseline
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale 
or P Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
 
 
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The participant may be excluded from the study;
2.
The participant may be included in the study if the abnormal value(s) is NCS 
(the investigator must annotate the laboratory value “NCS” on the laboratory 
safety test source document).
3.
The participant may be included in the study if the abnormality is consistent 
with a pre-existing medical condition which is not excluded per protocol (eg, 
elevated eosinophil count in a participant with asthma or seasonal allergies),
the medical condition should be annotated on the laboratory report.
OR
4.
The abnormal test may be repeated (refer items a. and b. below for 
continuation of algorithm for repeated values).
a.   If the repeat test value is within the normal range, the participant may 
enter the study.
b.   If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.11 Appendix 11: Child-Pugh classification of the severity of liver disease  
Finding
Points Scored for Each Observed Finding
1
2
3
Encephalopathy a
None
1 or 2 (or suppressed 
with medication)
3 or 4 (or refractory)
Ascites b
Absent
Slight or Subject on 1 
or 2c medication to 
control ascites
Moderate or Severe or 
Subject on 2c or more 
medications to control 
ascites or requires 
paracentesis
Bilirubin (mg/dL)
<2
2 to 3
>3
Albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INR
<1.7
1.7 to 2.3
>2.3
a. Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity
b. Ascites is graded according to the following criteria:
Absent: No ascites detectable by manual investigation.
Slight: Ascites palpation doubtful
Moderate: Ascites detectable by palpation
Severe: Necessity of paracentesis, does not respond to medication treatment.
c. If a combination of 2 medications are used primarily to minimize adverse effects (e.g. potassium imbalance), ascites
may be scored as 2 per the investigator’s clinical judgement.
 
 
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
AAP
Atypical Antipsychotic
ADME
Absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
Alanine transaminase
AN
Allocation number
AST
Aspartate transaminase
AUC
Area under the curve
β-hCG
β-human chorionic gonadotropin
BCS
Biopharmaceutics Classification System
BMI
body mass index
BP
blood pressure
cAMP/cGMP
Adenosine 3',5'-cyclic monophosphate/Guanosine 3',5'-cyclic monophosphate
CCU
Critical Care Unit
CG
Cockcroft-Gault
CGI-S
Clinical Global Impression, Severity of Illness
CI
Confidence Interval
CL
Clearance
Cmax
Maximum plasma concentration
CrCl
creatinine clearance
CR
Controlled Release
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTFG
Clinical Trial Facilitation Group 
CYP
Cytochrome P450
DDI
Drug-Drug Interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EPS
Extrapyramidal symptoms
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GCV
Generalized cross validation
GMR
Geometric Mean Ratio
HBsAg
Hepatitis B surface antigen
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICU
Intensive Care Unit
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
 
 
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Abbreviation
Expanded Term
INR
International Normalized Ratio
IR
Immediate Release
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LS
Least Squares
NCS
not clinically significant
OR
Odds Ratio
PDE10A
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
P-gp
P-glycoprotein 1
PANSS
Positive and Negative Syndrome Scale
PK
pharmacokinetic
POC
Proof of Concept
QD
Once daily
RNA
ribonucleic acid
SAE
serious adverse event 
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
t1/2
Half-life
Tmax
Time to maximum plasma concentration
UDS
urine drug screen
Vd
volume of distribution
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of nonchildbearing potential
 
 
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11
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[Schmidt, C. J., et al 
2008]
Schmidt CJ, Chapin DS, Cianfrogna J, Corman 
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