Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 499
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of MK-8189 at a range of doses (8 mg, 16 mg, and 24 mg once daily \[QD\]) in adult participants who have an acute episode of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria. The primary hypotheses were the following: (1) that MK-8189 24 mg is superior to placebo in reducing the Week 6 mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score, and (2) that MK-8189 16 mg is superior to placebo in reducing the Week 6 mean change from baseline in PANSS total score.

With Amendment 4, enrollment was changed to approximately 500 participants with removal of the MK-8189 8 mg treatment arm. Participants enrolled before Amendment 4 who were assigned to MK-8189 8 mg QD remained on that dose regimen per protocol.

Detailed description:

Arms:
arm 1: Participants received MK-8189 8 mg QD from Weeks 1 to 12, with 2 weeks of follow-up arm 2: Participants received MK-8189 16 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. arm 3: Participants received MK-8189 24 mg QD from Weeks 1 to 12, with 2 weeks of follow-up. arm 4: Participants will be treated for a total of 12 weeks. Participants will receive risperidone 6 mg QD in the acute treatment period from Week 1-6 followed by risperidone 6 mg QD in the extension treatment period from Week 7-12. arm 5: Participants received placebo QD from Weeks 1 to 6 and MK-8189 24 mg from Weeks 7 to 12, with 2 weeks of follow-up.

Interventions: intervention 1: MK-8189 intervention 2: Risperidone intervention 3: Placebo to MK-8189 intervention 4: Placebo to risperidone
Intervention descriptions: intervention 1: MK-8189 administered QD at a dose of 8 mg, 16 mg, or 24 mg via oral tablet. intervention 2: Risperidone administered QD at a dose of 6 mg via oral capsule. intervention 3: MK-8189-matching placebo administered QD via oral tablet. intervention 4: Risperidone-matching placebo administered QD via oral capsule.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:  
    NCT04624243
Document Date: 
     16-Mar-2023
A Phase 2B Randomized, Double-Blind, 
Placebo- and Active-Controlled Trial of the 
Efficacy and Safety of MK-8189 in Participants 
Experiencing an Acute Episode of 
Schizophrenia


PRODUCT: MK-8189
1
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2B Randomized, Double-Blind, Placebo- and Active-Controlled 
Trial of the Efficacy and Safety of MK-8189 in Participants Experiencing an Acute Episode 
of Schizophrenia
This protocol amendment is applicable only to Serbia
Protocol Number: 008-05
Compound Number: MK-8189
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not Applicable
EU CT
Not Applicable
EudraCT
2020-000094-24
JRCT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
118,986
Approval Date: 16 March 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 5
16-MAR-2023
Serbia-specific amendment to fulfill health authority 
request to correct minor discrepancies in 
Amendment 4.
Amendment 4
16-NOV-2022
Updates to remove MK-8189 8 mg treatment arm 
and Brief Assessment of Cognition (BAC) in 
response to enrollment and retention challenges.
Amendment 3
17-DEC-2021
Updates to increase flexibility in eligibility criteria 
in response to enrollment challenges.
Amendment 2
24-NOV-2020
Updated exclusion criterion and revised liver testing 
criteria to comply with FDA feedback.
Amendment 1
30-JUN-2020
Update number of capsules for risperidone due to 
change in dose strength and update with P007 data 
for Panel D.
Original Protocol
19-FEB-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 008-05
Overall Rationale for the Amendment:
Serbia-specific amendment to fulfill health authority request to correct minor discrepancies 
in Amendment 4.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
These changes were made to address agency 
request to amend protocol to correct minor 
discrepancies (in protocol clarification letter) in 
Amendment 4.
1.1 Synopsis
3. Hypotheses, 
Objectives, and 
Endpoints
The phrase “in men and women aged 18-50 
years who are experiencing an acute 
exacerbation of schizophrenia” was updated to 
refer to men and women aged 18-55 years
Typographical errors that do not align with the 
updated eligibility criteria in the protocol 
amendment.
1.1 Synopsis
Estimated Duration of Study that states, “The 
Sponsor estimates that the study will require 
approximately 2.5 years from the time the first 
participant (or their legally acceptable 
representative provides documented informed 
consent until the last participant’s last study-
related contact,” should instead be 
approximately 4 years.
Typographical error that does not align with the 
updated study timeline.
5.2 Exclusion 
Criteria
Exclusion criterion #21 
 
 
 
 
 
 
 
 
 
.
Typographical/grammatical clarification to 
ensure intended interpretation of the text for 
translations.
10.2 Appendix 2: 
Clinical 
Laboratory Tests
In Screening/Baseline laboratory notes, 
reference to exclusionary criterion for screening 
eGFR of <60 mL/min/1.73m2 should instead be 
<50 mL/min/1.73m2.
In Additional notes, references to 
discontinuation related to a persistent eGFR of 
<60 mL/min/1.73m2 should instead be <40 
mL/min/1.73m2.
Typographical errors that do not align with the 
updated discontinuation criteria in the protocol 
amendment.
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Section Number 
and Name
Description of Change
Brief Rationale
Other Changes in Amendment
The structure of the protocol has been updated.
To comply with current industry regulations and 
guidelines. This restructuring does not affect the 
clinical or regulatory integrity of the protocol. 
All other relevant changes and their primary 
reasons are included for completeness.
1.1 Synopsis
Type of control changed to “placebo” from 
“placebo, active control”
Simplification of choices in drop-down menu.
1.1 Synopsis
Intervention table updated to sync with Table 1 
in Section 6 
To match study intervention table in Section 6.
8.4.1 Time Period 
and Frequency 
for Collecting 
AE, SAE, and 
Other Reportable 
Safety Event 
Information
Added text noting that a positive pregnancy test 
at the time of initial screening is not a 
reportable event unless the participant has 
received study intervention
To provide clarity.
8.4.5 Pregnancy 
and Exposure 
During 
Breastfeeding
Added text regarding situations that qualify as 
an AE/SAE (eg, any pregnancy complication 
and medical reason for elective termination of a 
pregnancy)
To provide clarity and better align with 
regulations.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................21
2
INTRODUCTION..........................................................................................................31
2.1
Study Rationale....................................................................................................31
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................32
2.2.2
Ongoing Clinical Studies.............................................................................32
2.2.3
Information on Other Study-related Therapy ..............................................32
2.3
Benefit/Risk Assessment......................................................................................33
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................34
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.2
Safety Endpoints................................................................................39
4.2.1.3
Pharmacokinetic Endpoints ...............................................................39
4.2.1.4
Pharmacodynamic Endpoints.............................................................40
4.2.1.5
Planned Exploratory Biomarker Research.........................................40
4.2.1.5.1
Planned Genetic Analysis ........................................................40
4.2.1.6
Future Biomedical Research..............................................................40
4.2.2
Rationale for the Use of Comparator/Placebo .............................................41
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................41
4.3
Justification for Dose...........................................................................................41
4.3.1
Maximum Dose Exposure for This Study ...................................................42
4.3.2
Rationale for Dose Interval and Study Design ............................................42
4.4
Beginning and End-of-Study Definition ............................................................42
4.4.1
Clinical Criteria for Early Study Termination .............................................43
5
STUDY POPULATION ................................................................................................44
5.1
Inclusion Criteria.................................................................................................44
5.2
Exclusion Criteria................................................................................................47
5.3
Lifestyle Considerations......................................................................................50
5.3.1
Meals and Dietary Restrictions....................................................................50
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................51
5.4
Screen Failures.....................................................................................................51
5.5
Participant Replacement Strategy......................................................................51
6
STUDY INTERVENTION............................................................................................52
6.1
Study Intervention(s) Administered...................................................................52
6.1.1
Medical Devices...........................................................................................56
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................58
6.5.1
Rescue Medications and Supportive Care ...................................................58
6.6
Dose Modification (Titration).............................................................................58
6.7
Intervention After the End of the Study............................................................61
6.8
Clinical Supplies Disclosure................................................................................61
6.9
Standard Policies..................................................................................................61
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................62
7.1
Discontinuation of Study Intervention...............................................................62
7.2
Participant Withdrawal From the Study...........................................................64
7.3
Lost to Follow-up .................................................................................................64
8
STUDY ASSESSMENTS AND PROCEDURES........................................................65
8.1
Administrative and General Procedures ...........................................................65
8.1.1
Informed Consent.........................................................................................65
8.1.1.1
General Informed Consent.................................................................65
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................66
8.1.2
Inclusion/Exclusion Criteria ........................................................................66
8.1.3
Participant Identification Card.....................................................................66
8.1.4
Medical History ...........................................................................................67
8.1.5
Substance/Alcohol/Smoking History/Social History...................................67
8.1.6
Psychiatric History, Intake Evaluation, and MINI.......................................67
8.1.7
Identification of External Contact Person....................................................68
8.1.8
External SDE Review of Participant Eligibility Considerations .................69
8.1.9
Prior and Concomitant Medications Review...............................................69
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8.1.9.1
Prior Medications...............................................................................69
8.1.9.2
Concomitant Medications..................................................................69
8.1.10
Assignment of Screening Number...............................................................72
8.1.11
Assignment of Treatment/Randomization Number.....................................73
8.1.12
IRT ...............................................................................................................73
8.1.13
Study Intervention Administration ..............................................................73
8.1.13.1
Timing of Dose Administration.........................................................73
8.1.14
Discontinuation and Withdrawal .................................................................74
8.1.14.1
Withdrawal From Future Biomedical Research ................................74
8.1.15
Participant Blinding/Unblinding..................................................................74
8.1.16
Calibration of Equipment.............................................................................75
8.1.17
Hospitalization During the Study.................................................................75
8.1.18
Telephone or Virtual Contacts.....................................................................76
8.2
Efficacy Assessments ...........................................................................................77
8.2.1
PANSS.........................................................................................................78
8.2.2
PSP...............................................................................................................78
8.2.3
CGI-S...........................................................................................................78
8.3
Safety Assessments...............................................................................................78
8.3.1
Physical Examinations.................................................................................79
8.3.2
Height/Weight/Waist Circumference...........................................................79
8.3.3
Vital Signs....................................................................................................80
8.3.4
Electrocardiograms ......................................................................................80
8.3.5
Clinical Safety Laboratory Assessments .....................................................81
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................81
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................81
8.3.7
Monitoring of Extrapyramidal Symptoms...................................................82
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................82
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................83
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......85
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...85
8.4.4
Regulatory Reporting Requirements for SAE .............................................85
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................86
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................86
8.4.7
Events of Clinical Interest............................................................................86
8.5
Treatment of Overdose........................................................................................87
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8.6
Pharmacokinetics.................................................................................................88
8.6.1
Blood Collection for Plasma MK-8189 .......................................................89
8.7
Pharmacodynamics..............................................................................................89
8.8
Biomarkers ...........................................................................................................89
8.8.1
Planned Genetic Analysis Sample Collection..............................................89
8.9
Future Biomedical Research Sample Collection...............................................89
8.10
Visit Requirements...............................................................................................89
8.10.1
Screening......................................................................................................90
8.10.2
Treatment Period..........................................................................................91
8.10.3
Follow-up Period .........................................................................................92
8.10.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................92
8.10.5
Poststudy......................................................................................................92
9
KEY STATISTICAL CONSIDERATIONS ...............................................................93
9.1
Statistical Analysis Plan Summary.....................................................................93
9.2
Responsibility for Analyses/In-house Blinding .................................................95
9.3
Hypotheses/Estimation ........................................................................................95
9.4
Analysis Endpoints...............................................................................................95
9.4.1
Efficacy Endpoints.......................................................................................95
9.4.2
Safety Endpoints..........................................................................................97
9.4.3
Pharmacokinetic Endpoints .........................................................................98
9.4.4
...............................................................98
9.5
Analysis Populations............................................................................................99
9.5.1
Efficacy Analysis Populations.....................................................................99
9.5.2
Safety Analysis Populations ........................................................................99
9.5.3
Pharmacokinetic Analysis Populations......................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Efficacy Analyses.................................................100
9.6.2
Statistical Methods for Safety Analyses ....................................................103
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................107
9.7
Interim Analyses ................................................................................................107
9.8
Multiplicity .........................................................................................................108
9.9
Sample Size and Power Calculations ...............................................................110
9.9.1
Efficacy Parameter Estimates ....................................................................110
9.9.2
Efficacy Sample Size and Power Calculations ..........................................110
9.10
Subgroup Analyses.............................................................................................112
9.11
Compliance (Medication Adherence)...............................................................113
9.12
Extent of Exposure.............................................................................................113
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................114
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......114
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................114
10.1.2
Financial Disclosure...................................................................................116
10.1.3
Data Protection...........................................................................................117
10.1.3.1
Confidentiality of Data ....................................................................117
10.1.3.2
Confidentiality of Participant Records.............................................117
10.1.3.3
Confidentiality of IRB/IEC Information..........................................117
10.1.4
Committees Structure.................................................................................118
10.1.4.1
External Data Monitoring Committee .............................................118
10.1.4.2
Executive Oversight Committee......................................................118
10.1.4.3
Scientific Advisory Committee (SAC)............................................118
10.1.5
Publication Policy......................................................................................118
10.1.6
Compliance with Study Registration and Results Posting Requirements .119
10.1.7
Compliance with Law, Audit, and Debarment ..........................................119
10.1.8
Data Quality Assurance .............................................................................120
10.1.9
Source Documents .....................................................................................120
10.1.10
Study and Site Closure...............................................................................121
10.2
Appendix 2: Clinical Laboratory Tests............................................................122
10.2.1
Alcohol and Drug Screen...........................................................................125
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................126
10.3.1
Definition of AE ........................................................................................126
10.3.2
Definition of SAE ......................................................................................127
10.3.3
Additional Events Reported.......................................................................128
10.3.4
Recording AE and SAE .............................................................................128
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................131
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................133
10.5
Appendix 5: Contraceptive Guidance..............................................................134
10.5.1
Definitions..................................................................................................134
10.5.2
Contraceptive Requirements......................................................................136
10.5.3
Pregnancy Testing......................................................................................137
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................138
10.7
Appendix 7: Country-specific Requirements..................................................142
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10.8
Appendix 8: Abbreviations ...............................................................................143
11
REFERENCES.............................................................................................................147
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LIST OF TABLES
Table 1
Study Interventions......................................................................................53
Table 2
Down-titration and Rechallenge Scenario Chart .........................................60
Table 3
Prohibited Medications During the Treatment Period.................................71
Table 4
Medications and Procedures Permitted During the Treatment Period.........72
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................84
Table 6
PK Sampling Schedule ................................................................................88
Table 7
Directionality of Improvement in Efficacy Measures .................................96
Table 8
Analysis Strategy for Key Efficacy Variables...........................................102
Table 9
Analysis Strategy for Safety Parameters....................................................106
Table 10
Summary of Interim Analysis Strategy......................................................107
Table 11
Primary Assumptions for Primary and Key Secondary Endpoints............110
Table 12
Power Calculations for PANSS Total Score (128 Randomized 
Participants Per/Arm).................................................................................................111
Table 13
Marginal Power Calculations for PANSS-PSS and CGI-S .......................111
Table 14
Marginal Power Calculations for Weight ..................................................112
Table 15
Protocol-required Safety Laboratory Assessments....................................124
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LIST OF FIGURES
Figure 1
Study Design................................................................................................20
Figure 2
Testing Strategy to Address Multiplicity...................................................109
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2B Randomized, Double-Blind, Placebo- and Active-Controlled 
Trial of the Efficacy and Safety of MK-8189 in Participants Experiencing an Acute Episode 
of Schizophrenia
Short Title: Phase 2B Study of MK-8189 in Participants with an Acute Episode of 
Schizophrenia
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In men and women aged 18-55 years who are experiencing an acute exacerbation of 
schizophrenia:
Primary Objective
Primary Endpoint
To compare the efficacy of MK-8189 at 16 
and 24 mg to placebo in reducing the 
PANSS total score at Week 6
•
Hypothesis (H1): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS total score
•
Hypothesis (H2): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS total score
PANSS total score
To evaluate the safety and tolerability of 
MK-8189
Adverse events
Study intervention discontinuations due to 
adverse events
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Secondary Objectives
Secondary Endpoints
To compare the efficacy of MK-8189 at 16 
and 24 mg to placebo in reducing the 
PANSS positive subscale at Week 6

Hypothesis (H3): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS positive subscale

Hypothesis (H4): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS positive subscale
PANSS positive subscale score
To evaluate the efficacy of MK-8189 at 16 
and 24 mg in reducing the CGI-S score at 
Week 6, as compared to placebo

Hypothesis (H5): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
CGI-S

Hypothesis (H6): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
CGI-S
CGI-S score
To evaluate the impact of MK-8189 on 
weight at Week 12, as compared to 
risperidone

Hypothesis (H7): MK-8189 24 mg is 
superior to risperidone in reducing the 
Week 12 mean change from baseline in 
weight

Hypothesis (H8): MK-8189 16 mg is 
superior to risperidone in reducing the 
Week 12 mean change from baseline in 
weight
Weight (kg)
To evaluate the impact of MK-8189 on 
weight at Week 6, as compared to placebo
Weight (kg)
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Schizophrenia
Population
Adult participants experiencing an acute 
episode of schizophrenia, according to the 
criteria specified in the Diagnostic and 
Statistical Manual of Mental Disorders Fifth 
Edition (DSM-5™)
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Investigator
Sponsor
Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 4 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 500 participants will be randomized such that sufficient evaluable 
participants complete the study as described in Section 9.
Before Amendment 4, the total sample size was to be approximately N=576; on 
implementation of Amendment 4 the total sample size is predicted to be approximately 
N=500, noting that the exact number of participants to be ultimately enrolled is, in part, a 
function of the (unknown) number of participants randomized to the MK-8189 8 mg 
treatment arm before the implementation of Amendment 4. On implementation of 
Amendment 4, eligible participants will be randomized in a 2:2:1:2 ratio to 1 of the 4 
following treatment sequences: MK-8189 16 mg/MK-8189 16 mg, MK-8189 24 mg/MK-
8189 24 mg, risperidone 6 mg/risperidone 6 mg, or placebo/MK-8189 24 mg.
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PRODUCT: MK-8189
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16-MAR-2023
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
MK-8189 
8 mg/ MK-
8189 8 mg
MK-8189
4 mg + 
0 mg
4 mg qd
Oral
Days 1-3
Day 8 to Week 
12
Test Product
MK-8189 
8 mg/ MK-
8189 8 mg
MK-8189
4 mg +
4 mg
8 mg qd
Oral
Day 4 to Week 
12
Test Product
MK-8189 
8 mg/ MK-
8189 8 mg
Placebo to 
risperidone
0 mg
0 mg qd
Oral
Day 1 to Week 
12
Placebo
MK-8189 
16 mg/ MK-
8189 16 mg
MK-8189
4 mg +
0 mg
4 mg qd
Oral
Days 1-3
Test Product
MK-8189 
16 mg/ MK-
8189 16 mg
MK-8189
4 mg +
4 mg
8 mg qd
Oral
Days 4-6
Test Product
MK-8189 
16 mg/ MK-
8189 16 mg
MK-8189
12 mg + 
0 mg
12 mg qd
Oral
Day 8 to Week 
12
Test Product
MK-8189 
16 mg/ MK-
8189 16 mg
MK-8189
4 mg + 
12 mg
16 mg qd
Oral
Day 7 to Week 
12
Test Product
MK-8189 
16 mg/ MK-
8189 16 mg
Placebo to 
risperidone
0 mg
0 mg qd
Oral
Day 1 to Week 
12
Placebo
MK-8189 
24 mg/ MK-
8189 24 mg
MK-8189
4 mg +
4 mg
8 mg qd
Oral
Days 1-3
Test Product
MK-8189 
24 mg/ MK-
8189 24 mg
MK-8189
4 mg +
12 mg
16 mg qd
Oral
Days 4-6
Day 8 to Week 
12
Test Product
MK-8189 
24 mg/ MK-
8189 24 mg
MK-8189
12 mg +
12 mg
24 mg qd
Oral
Day 7 to Week 
12
Test Product
MK-8189 
24 mg/ MK-
8189 24 mg
Placebo to 
risperidone
0 mg
0 mg qd
Oral
Day 1 to Week 
12
Placebo
Risperidone 6 
mg/
Risperidone 6 
mg
Placebo to MK-
8189
0 mg + 
0 mg
0 mg qd
Oral
Day 1 to Week 
12
Placebo
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Risperidone 6 
mg/
Risperidone 6 
mg
risperidone
2 mg
2 mg qd
Oral
Days 1-3
Test Product
Risperidone 6 
mg/
Risperidone 6 
mg
risperidone
2 mg
4 mg qd
Oral
Days 4-6
Day 8 to Week 
12
Test Product
Risperidone 6 
mg/
Risperidone 6 
mg
risperidone
2 mg
6 mg qd
Oral
Day 7 to Week 
12
Test Product
Placebo/MK-
8189 24 mg
Placebo to MK-
8189
0 mg + 
0 mg
0 mg qd
Oral
Days 1-42
Placebo
Placebo/MK-
8189 24 mg
MK-8189
4 mg + 
4 mg
8 mg qd
Oral
Days 43-45
Test Product
Placebo/MK-
8189 24 mg
MK-8189
4 mg + 
12 mg
16 mg qd
Oral
Days 46-48
Day 50 to 
Week 12ᵃ
Test Product
Placebo/MK-
8189 24 mg
MK-8189
12 mg + 
12 mg
24 mg qd
Oral
Day 49 to 
Week 12
Test Product
Placebo/MK-
8189 24 mg
Placebo to 
risperidone
0 mg
0 mg qd
Oral
Day 1 to Week 
12
Placebo
Total Number of Intervention Groups/Arms
5
Duration of Participation
Each participant will participate in the study 
for approximately 15 weeks from the time 
the participant provides documented 
informed consent through the final contact. 
After a screening period of 2 to 7 days
(including, if needed, a tapering of 
prohibited medications), participants will be
randomized to receive assigned intervention 
for approximately 12 weeks (6 weeks acute 
treatment, then 6 weeks extension 
treatment). After end of study intervention,
each participant will be followed for 14
days.
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PRODUCT: MK-8189
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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16-MAR-2023
1.3
Schedule of Activities (SoA)
Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Administrative and 
General Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Not required for 
participation in 
main study
Inclusion/Exclusion 
Criteria
X
X
Participant Identification 
Card
X
X
X
ID card to be 
updated at V2 to 
include 
randomization 
information. At 
Visit 6 (or 
discharge day, if 
later), confirm 
card is in 
participant’s 
possession.
Psychiatric History
X
Psychiatric Intake 
Evaluation 
X
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Clinical Validation 
Inventory for Study 
Admission (C-VISA™)
X
Must be reviewed 
and approved by 
the external SDE 
before 
randomization. 
See Section 8.1.8.
MINI International 
Neuropsychiatric Interview 
X
Must be recorded 
using Sponsor-
provided recording 
technology. See 
Section 8.1.6.
Medical History
X
Substance, Alcohol and 
Smoking History
X
Social History
X
Identification of External 
Contact Person
X
Participants must 
have an identified 
external contact 
person meeting all 
criteria as 
specified in 
Section 8.1.7
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
No prohibited 
psychotropic 
medications to be 
taken before V12 
or EOT visit
IRT Visit Registration
X
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
IRT Randomization
X
Study Intervention 
Dispensing
X
X
X
X
X
X
X
X
X
X
First dose to be 
taken PM on V2 
and last dose to be 
taken PM before 
V12 or EOT visit
Study Intervention 
Compliance
X
X
X
X
X
X
X
X
X
X
X
Down-titration for 
tolerability not 
allowed during 
Weeks 1 or 7.  
After down-
titration, 1 
rechallenge 
attempt may be 
made during the 
study (see Section 
6.6).
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PRODUCT: MK-8189
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Telephone or Virtual 
Contacts between visits (if 
Outpatient)
X 
X
X
X
X
X
X
First TC within 3 
days post 
discharge. 
Other TCs to 
occur 
approximately 
midway between 
visits. 
If participant is an 
outpatient for first 
dose in extension, 
then a TC is to 
occur on the day 
after first 
extension dose. 
Additional TCs 
may be conducted 
at investigator 
discretion (see 
Section 8.1.18).
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Efficacy Assessments
Positive and Negative 
Syndrome Scale (PANSS)
X
X
X
X
X
X
X
X
X
X
X
X
As best practice 
PANSS interviews 
to be conducted 
early in visit and 
must be recorded 
using Sponsor-
provided recording 
technology. 
Screening PANSS 
must be reviewed 
and approved by 
external SDE 
before 
randomization.
Personal and Social 
Performance Scale (PSP)
X
X
X
Clinical Global 
Impression-Severity of 
Illness (CGI-S)
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Physical Examination
X
X
X
Height
X
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PRODUCT: MK-8189
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Weight, Waist 
Circumference
X
Xa
X
X
X
X
X
aWaist 
circumference is 
not collected at 
baseline (see 
Section 8.3.2)
Vital Signs (pulse, blood 
pressure)
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
At SCR, perform 
triplicate ECG. 
Otherwise, 
perform triplicate 
ONLY if QTc 
prolongation is 
suspected (see 
Section 8.3.4).
Columbia Suicide Severity 
Rating Scale (C-SSRS) 
Baseline/Screening 
Version
X
C-SSRS Since Last Visit 
Version
X
X
X
X
X
X
X
X
X
X
X
Abnormal Involuntary 
Movement Scale (AIMS)
X
X
X
X
X
X
X
Barnes Akathisia Rating 
Scale (BARS)
X
X
X
X
X
X
X
X
X
Simpson Angus 
Extrapyramidal Side 
Effects Scale (SAS)
X
X
X
X
X
X
X
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
AE/SAE review
     X===========================================================X
Chemistry/Hematology/Li
pid Panel
X
X
X
X
X
X
Specific tests in 
Appendix 2. 
laboratory samples 
are collected in 
fasting state while 
inpatient.
Outpatients will be 
instructed and 
encouraged to fast 
overnight, before 
sample collection.
Insulin
X
X
X
Prolactin
X
X
X
X
TSH
X
With free 
thyroxine (T4) if 
TSH is abnormal.
HbA1c
X
X
X
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PRODUCT: MK-8189
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Serum β-Human Chorionic 
Gonadotropin(hCG)
X
WOCBP only
Also required to 
confirm a positive 
urine pregnancy 
test; or may 
replace a urine test 
per local 
guidelines. May 
also be done at 
investigator 
discretion 
throughout study.
Serum Follicle-Stimulating 
Hormone (FSH) -
X
Only required if 
needed to evaluate 
for WOCBP status
HIV Screen 
X
Per site SOP and 
at discretion of the 
investigator
Hepatitis Screen
X
Per site SOP and 
at the discretion of 
the investigator
Blood for Genetic Analysis
X
Refer to 
Biomarkers and 
FBR sections 
(Sections 8.8 and 
8.9)
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PRODUCT: MK-8189
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
Urine Alcohol/Drug 
Screen 
X
X
X
X
May also be done
at investigator 
discretion 
throughout study
Urinalysis
X
X
X
X
X
X
Specific tests 
noted in Appendix 
2
Urine Pregnancy Test 
X
X
X
X
X
X
WOCBP only. If 
urine test is 
positive, it must be 
confirmed with a 
serum pregnancy 
test. May also be 
done at 
investigator 
discretion 
throughout study.
Pharmacokinetics
Pharmacokinetics Blood 
Sample
X
X
Xb
X
X
Xc
bRobust PK 
sampling scheme 
on, and 1 day 
before V6 PANSS.
cPK samples not 
collected after 
EOT. See Section 
8.6 (Table 6).
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Study Period
Screening
Acute Treatment Period
Extension Treatment 
Period
Postdosing
Follow-up
Period
Notes
Visit Number/Title
1 
SCR
2
Base-
line
3
4
5
6
7
8
9
10
11
12/
DC/
EOT
Follow-up 
TC 7 &14 
days post 
dose
Inpatient stay is 
required to V6 if 
on treatment, but 
may be longer if 
needed. 
Scheduled Visit Day and 
Window:
-7 to -
2
1
8±1
15±1
22±1
29±1
36±1
43±1
50±1
57±3
71±3
85±3
LD+7±3
LD+14+3
AE=adverse event(s); BL=baseline; DC=discontinuation; ECG=electrocardiogram; EOT=end of treatment; FBR=future biomedical research; HIV= human 
immunodeficiency virus; IRT=interactive response technology; LD=last dose; PANSS=positive and negative syndrome scale; PK=pharmacokinetic; 
SCR=screening; SDE=Sponsor-designated expert; SOP=standard operating procedure; TC=telephone or virtual contact; TSH= thyroid-stimulating hormone; 
V=visit; WOCBP=women of childbearing potential.  Notes: See Section 8.10.4 for information for participants who discontinue study intervention before 
V12.
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2
INTRODUCTION
Schizophrenia is a chronic debilitating disorder consisting of 3 symptom domains: positive 
symptoms (eg, psychosis, hallucinations, and delusions); negative symptoms (eg, apathy, 
amotivation); and cognitive impairment (eg, impaired memory, planning). Schizophrenia 
affects about 1% of the population globally. It is believed that disruption of corticostriatal 
signaling, stemming from increased dopamine and decreased glutamate neurotransmission, 
results in the positive symptoms of schizophrenia, and may also contribute to cognitive 
impairment. Atypical antipsychotics are the current standard of care medications used for the 
treatment of schizophrenia and are frequently used in bipolar disorder. However, a 
substantial portion of patients with schizophrenia and bipolar disorder are not adequately 
treated by these medications. Approximately 65% of patients with schizophrenia switch 
medications within a year, either due to dissatisfaction with efficacy or due to intolerability 
arising from various AEs. The major AEs associated with these medications include weight 
gain/metabolic effects, extrapyramidal side effects, increased prolactin secretion and sedation 
[Conley, R. R. 2005].
MK-8189 is a potent and selective inhibitor of PDE10A that is being developed as a novel 
therapeutic for the treatment of schizophrenia. PDE10A is highly expressed in the striatum 
and functions to metabolically inactivate the second messengers cAMP and cGMP. 
Preclinical experiments show that PDE10A inhibition increases cAMP/cGMP signaling in 
pathways in the striatum that have been associated with underlying pathology (glutamate) 
and clinically validated therapeutics (D2 receptor antagonists) for schizophrenia. MK-8189 
was shown to be fully efficacious in 3 well defined preclinical assays predictive of 
antipsychotic activity. Other preclinical findings suggest that PDE10A inhibitors may 
attenuate cognitive impairment, while preclinical and preliminary clinical data suggest that 
PDE10A inhibition may be associated with weight loss and without negative impacts on 
metabolic parameters or prolactin secretion. PDE10A inhibitors may therefore potentially be 
an alternative treatment as monotherapy or as adjunct treatment in patients with 
schizophrenia who have inadequate response to first-line AAP treatment.
2.1
Study Rationale
The purpose of this Phase 2b study is to evaluate the efficacy and safety of MK-8189 at a 
range of doses in adult participants who have an acute episode of schizophrenia according to 
DSM-5™ criteria. 
This study will provide important dose-ranging information to appropriately evaluate the 
dose-response relationship for the compound and improve the understanding of the 
compound’s benefit/risk profile. The 12-week treatment period also permits an evaluation of 
the time course for weight changes, effects on metabolic parameters, and exploratory 
investigations into negative symptom effects.
2.2
Background
Refer to the IB for detailed background information on MK-8189.
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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 striatum, an integral part of the corticostriatal 
pathway that regulates and modulates motivation, cognition, and goal-directed motor 
function [Seeger, T. F., et al 2003]. Preclinical pharmacology studies show that PDE10A 
inhibition increases cAMP/cGMP signaling in pathways associated with underlying 
schizophrenia pathology (glutamate) as well as clinically validated therapeutics (dopamine 
D2 receptor antagonists). Enhanced signaling in these pathways is hypothesized to restore the 
behavioral inhibition that is disrupted in schizophrenia [Grauer, S. M., et al 2009] [Schmidt, 
C. J., et al 2008]. PDE10A inhibitors may potentially be an alternative treatment as 
monotherapy or as adjunct treatment in patients with schizophrenia who have inadequate 
response to first-line AAP treatment. Preclinical findings also suggest that PDE10A 
inhibitors such as MK-8189 may be efficacious in improving motivation and cognitive 
dysfunction in schizophrenia. 
MK-8189 has been tested in a variety of preclinical and Phase 1 clinical 
 
. It has also been tested at the 12-mg dose level in 1 Phase 2a study of adult 
participants experiencing an acute exacerbation of schizophrenia. The Phase 2a study (P005) 
was a randomized, double-blind study with placebo and active control (risperidone). Study 
medication was titrated over a 1-week period to the target dose (12 mg for MK-8189 and 6 
mg for risperidone). The primary endpoint was the change from baseline in PANSS total 
score at 4 weeks. While MK-8189 showed improvement in the PANSS total score of -14.6 
points, improvement was not significant (placebo-subtracted difference -4.7, 95% CI (-9.8, 
0.5), p=0.074). However, the observed effects of MK-8189 and risperidone overlapped 
(p=0.440), suggesting evidence of MK-8189 effect. Also, MK-8189 was superior to placebo 
on the PANSS positive subscale, as was risperidone. Overall, the results suggested evidence 
of activity for MK-8189’s novel mechanism of action and supported further development.
Overall, the preclinical and clinical pharmacology findings suggest that MK-8189 may 
potentially have a therapeutic effect in the treatment of schizophrenia. Further details may be 
found in the IB.
2.2.2
Ongoing Clinical Studies
P014 is a Phase 1 study to evaluate the safety, tolerability, PK and the effect of MK-8189 on 
QTc in participants with schizophrenia.
P017 is a Phase 1 study to evaluate the safety and tolerability of MK-8189 in participants 
with Alzheimer’s Disease with and without neuropsychiatric symptoms.
2.2.3
Information on Other Study-related Therapy
Risperidone is indicated for the treatment of schizophrenia. Efficacy was established in 4 
short-term studies in adults, 2 short-term studies in adolescents (ages 13 to 17 years), and 1
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long-term maintenance study in adults. Risperidone will act as the active control in this study 
to aid interpretation of the study results.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
MK-8189, as a PDE10A inhibitor, represents a novel mechanism of action that may 
potentially address psychotic symptoms. Data from P005 suggest possible efficacy in 
improving psychosis at a tolerated dose and associated with modest decrease in weight. 
However, further investigation into safety and effectiveness are required.
Based on the mechanism of action of PDE10A inhibition, which modulates dopaminergic 
pathways, EPS may be expected after treatment with MK-8189. In this study, participants
will be assessed for signs of EPS (dystonia, dyskinesia, akathisia and parkinsonism) using 
specific rating scales. Close medical supervision and monitoring should be provided if EPS 
occurs. Details on supportive medication for the treatment of EPS are provided in Section 
8.3.7.
The safety monitoring practices used by this protocol (ie, physical examination, vital signs, 
12-lead ECG, laboratory tests, C-SSRS assessments, EPS assessments, and adverse events 
monitoring) are considered to be adequate to protect the participants’ safety and to detect 
adverse events. This study requires frequent observations including initial treatment in an 
inpatient setting, flexible discharge requirements based on clinical readiness, discontinuation 
criteria, and follow-up after treatment period. An external contact person, who has regular 
contact with the participant, is required as part of inclusion criteria for this study.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In men and women aged 18-55 years who are experiencing an acute exacerbation of 
schizophrenia:
Primary Objective
Primary Endpoint
To compare the efficacy of MK-8189 at 16 
and 24 mg to placebo in reducing the 
PANSS total score at Week 6
•
Hypothesis (H1): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS total score
•
Hypothesis (H2): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS total score
PANSS total score
To evaluate the safety and tolerability of 
MK-8189
Adverse events
Study intervention discontinuations due to 
adverse events
Secondary Objectives
Secondary Endpoints
To compare the efficacy of MK-8189 at 16 
and 24 mg to placebo in reducing the 
PANSS positive subscale at Week 6

Hypothesis (H3): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS positive subscale

Hypothesis (H4): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
PANSS positive subscale
PANSS positive subscale score
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To evaluate the efficacy of MK-8189 at 16 
and 24 mg in reducing the CGI-S score at 
Week 6, as compared to placebo

Hypothesis (H5): MK-8189 24 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
CGI-S

Hypothesis (H6): MK-8189 16 mg is 
superior to placebo in reducing the 
Week 6 mean change from baseline in 
CGI-S
CGI-S score
To evaluate the impact of MK-8189 on 
weight at Week 12, as compared to 
risperidone

 

Hypothesis (H8): MK-8189 16 mg is 
 
Weight (kg)
To evaluate the impact of MK-8189 on 
weight at Week 6, as compared to placebo
Weight (kg)
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind study to 
evaluate the efficacy and safety of MK-8189 at 16 and 24 mg qd dosing using risperidone as 
an active control in adult participants who have a current acute episode of schizophrenia 
according to DSM-5™ criteria.
For each participant, this study will last approximately 15 weeks, with an initial screening 
period from 2 to 7 days, followed by a treatment period of 12 weeks. The 12-week treatment 
period consists of a 6-week acute treatment period inclusive of an initial 1-week titration 
period to reach target dose, followed by a 6-week extension treatment period. A follow-up 
period consists of 14 days after the last dose of study intervention. 
The screening period will include a screening visit and a taper period. All participants must 
be safely tapered off psychotropic medications in a manner consistent with local medical 
practice with the last dose of all prohibited medications to be taken no later than the evening 
before the baseline visit.
Participants could be admitted to the hospital/inpatient unit as early as the day of signing 
consent, but no later than the evening of the screening (V1) visit after assessment completion. 
It is anticipated that participants will continue as inpatients in this study until at least Week 4 
(V6) assessments are completed. Participants are not to be discharged from an inpatient 
setting unless they are clinically ready to be discharged: that is, deemed clinically stable, 
capable of self-administration of study intervention, and able to comply with the visit 
schedule as an outpatient, according to the investigator. Hospitalization beyond what is 
required for the protocol may apply if consistent with standard of care. Refer to Section 
8.1.17 for details on hospitalization under this protocol.
At the baseline (V2) visit, participant eligibility will be reassessed for final eligibility per 
inclusion/exclusion criteria as described in Section 5. The participant must not be 
randomized into the study until after ensuring that they meet all criteria, including approval 
by the external SDEs where noted. Note: randomization and first dose must occur on the 
same day.
Before Amendment 4, eligible participants were randomly assigned to 1 of 5 treatment 
sequences, with each sequence detailing the treatments that the participants were to receive in 
the acute and extension treatment periods (acute treatment/extension treatment). Participants 
were randomized in a 2:2:2:1:2 ratio to one of the following treatment sequences: MK-8189 
8 mg/MK-8189 8 mg, MK-8189 16 mg/MK-8189 16 mg, MK-8189 24 mg/MK-8189 24 mg, 
risperidone 6 mg/risperidone 6 mg, or placebo/MK-8189 24 mg.  
On implementation of Amendment 4, eligible participants will be randomized in a 2:2:1:2 
ratio to 1 of the 4 following treatment sequences: MK-8189 16 mg/MK-8189 16 mg, MK-
8189 24 mg/MK-8189 24 mg, risperidone 6 mg/risperidone 6 mg, or placebo/MK-8189 
24 mg.  
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Before Amendment 4 the total sample size was to be approximately N=576; on 
implementation of Amendment 4 the total sample size is predicted to be approximately 
N=500, noting that the exact number of participants to be ultimately enrolled is, in part, a 
function of the (unknown) number of participants randomized to the MK-8189 8 mg 
treatment arm before the implementation of Amendment 4.
Participants randomized to receive placebo in the acute treatment period will receive 
MK-8189 24 mg qd in the extension period. During the first week of the extension treatment 
period, participants in this treatment group sequence will be up-titrated to MK-8189 24 mg 
qd. Note that initial dosing and titration of study intervention to target dose is described in 
Section 6.6. 
For participants who complete 12 weeks of study intervention treatment, the Week 12 visit is 
intended to take place the day after the participant’s last dose of study intervention. 
Medication prohibitions in Table 3 and restrictions as listed in Table 4 do not end until after 
all assessments have been completed for the Week 12 visit. 
If the participant discontinues study intervention treatment before the intended last visit at 
Week 12, then an EOT visit should be completed as soon as possible after the last dose. 
Medication prohibitions in Table 3 and restrictions as listed in Table 4 do not end until after 
all assessments have been completed for the EOT visit.
For participants who continue study visits after the EOT visit, refer to Section 8.10.4.
Participants will have follow-up TC (post treatment Days 7 and 14) after their last dose of 
study intervention, regardless of whether they complete the full treatment period or 
discontinue study intervention early.
An eDMC will evaluate the unblinded safety data on a regular basis. In addition, the eDMC 
will review unblinded efficacy data if the futility IA is conducted (Section 9.7), noting that 
the eDMC may also request unblinded efficacy data at any time to assess the benefit/risk 
profile.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
The primary endpoint and secondary endpoints are described in Section 3.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of 
schizophrenia and will be used as the primary efficacy endpoint measure [Kay, S. R., et al 
1987]. The PANSS has been used extensively as a primary endpoint in multiple global 
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pivotal studies of therapies for schizophrenia, is capable of detecting treatment effects, and 
captures clinically relevant aspects of the condition. 
The CGI-S is a single-item, 7-point clinician-rated scale for assessing the global severity of 
the illness, taking all relevant clinical information into account [Haro, J. M., et al 2003]. 
Similar to the PANSS, the CGI-S has been extensively used in schizophrenia studies to 
detect treatment effects and has been well characterized in multiple populations.  
The PSP scale is a clinician-rated scale that measures personal and social functioning in the 
domains of Socially useful activities, Personal and social relationships, Self-care, and 
Disturbing and aggressive behaviors. [Morosini, P. L., et al 2000]. The PSP scale is 
considered to be a reliable and valid instrument for assessing social functioning of patients 
with schizophrenia and is therefore a useful and patient-relevant measure of activities of 
daily living.
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical adverse experiences. Physical examinations, vital signs, 12-lead ECGs and laboratory 
safety tests will be performed routinely to detect any clinically meaningful effects.
The AIMS, BARS, and SAS are clinician-rated scales that will be used to standardize the 
evaluation of EPS observed in the study. 
The AIMS is a 12-item scale to assess severity of dyskinesias (specifically, orofacial 
movements and extremity and truncal movements), global severity, and participant’s 
awareness and distress related to said movement disorders. [Department of Health, 
Education, and Welfare Public Health Servi 1976].
The BARS is a combined clinical observation and interview that evaluates for akathisia and 
consists of the following items: objective items for clinician rating of observable restless 
movements that are associated with akathisia, subjective items related to awareness of the 
restlessness and distress associated with akathisia, and a global severity item [Barnes, T. R. 
E. 1989].
The SAS is a structured clinical examination that measures drug-induced parkinsonism. The 
rater asks the participant to perform tasks and rates responses from normal to severe. Specific 
symptoms include muscle rigidity, tremor, akinesia, and salivation [Simpson, G. M. and 
Angus, J. W. S. 1970].
The C-SSRS will be administered to screen for the presence, and assess the severity, of 
possible suicidal ideation and behavior in all study participants (refer to Section 4.2.3).
4.2.1.3
Pharmacokinetic Endpoints
Blood will be drawn at time points specified in the SoA for MK-8189 PK measurements. The 
plasma samples will be used to evaluate the PK of MK-8189 in a patient population, and to 
enable the characterization of the PK/pharmacodynamics and PK/AE relationships. 
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Additional metabolites based on ongoing metabolites in safety testing analysis may also be 
evaluated. These data will be used in PK model development and analysis with results 
reported separately.
The final decision as to which plasma samples will be assayed will be made by the Sponsor’s 
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism and the Clinical 
Director. Information regarding the collection and shipping of plasma samples will be 
provided in the administrative binder.
4.2.1.4
Pharmacodynamic Endpoints
Pharmacodynamic endpoints are not applicable.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
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4.2.2
Rationale for the Use of Comparator/Placebo
Despite the seriousness of the condition, a placebo treatment arm is necessary to evaluate 
both efficacy and safety. Without the use of placebo, false assumptions regarding the true 
efficacy of new drugs may be made. In the absence of a placebo control, it is nearly 
impossible to distinguish true drug effects from nonspecific effects in this study population.
Risperidone is an antipsychotic drug mainly used to treat schizophrenia (including adolescent 
schizophrenia), schizoaffective disorder, and the mixed and manic states of bipolar disorder. 
Risperidone is a second-generation atypical antipsychotic. It is a dopamine antagonist 
possessing antiserotonergic, antiadrenergic and antihistaminergic properties. The 
recommended starting dose of risperidone approved by the FDA for schizophrenia in adults 
is 2 mg (qd). Further dosage adjustments in 1 to 2 mg qd increments are recommended if 
necessary, to the recommended target dose of 4 to 8 mg qd. Efficacy with risperidone in 
schizophrenia was shown in a dose range of 4 to 16 mg qd in clinical trials according to the 
US approved label. However, doses above 6 mg per day were not shown to be more 
efficacious than lower doses, were associated with more extrapyramidal symptoms and other 
adverse effects, and are generally not recommended. The current study will use a target dose 
of risperidone 6 mg qd as the active control to aid interpretation of the study results.
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or biologics license application, as well as assessment in 
studies that fall within the guidance for other reasons (eg, CNS active/penetrant compounds, 
and known mechanisms or indications for which suicidal ideation/behavior has been 
previously identified as a potential concern).
4.3
Justification for Dose
The first-in-human SAD study (P001) identified that the immediate-release formulation 
would not be desirable for further development given the relatively high peak:trough ratio 
and the presence of mild dystonia in 3 participants receiving 3 mg and moderate dystonia in 1 
participant at 6 mg. The controlled-release formulation was subsequently developed with 
improved peak:trough ratios and improved tolerability (see IB for details). The prior POC 
study (P005) tested a dose of 12mg as this was a well-tolerated dose in the MAD study 
(P004) and, based on PET EO, was predicted to achieve exposures that would reach or 
exceed the minimal efficacy threshold of 30% PDE10A inhibition at trough for >90% of the 
estimated population. The POC study supported the tolerability and efficacy of 12mg, and no 
dose-limiting adverse effects were identified.
In the current study (before Amendment 4), 8 mg, 16 mg, and 24 mg doses were selected. 
These 3 doses provide maximal spread across the dose-response range still predicted to be 
efficacious based on enzyme occupancy from the PET EO study (P002). Across these doses, 
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the range of median EO is approximately 52% to 77%, with the estimated fifth percentile 
exposures ranging from approximately 30% at 8 mg to 50% at 24 mg.
4.3.1
Maximum Dose Exposure for This Study
The maximum dose of MK-8189 in this study is 24 mg qd. 
In the clinical pharmacology program to date, MK-8189 has been generally well tolerated at 
doses of up to 24 mg. Three single-dose and 1 multiple-dose clinical studies have been 
conducted in healthy subjects and subjects with schizophrenia (as both monotherapy and 
adjunctive) to evaluate safety, tolerability, and PK from 2 mg to 16 mg, with a total of 6
patients exposed to 16 mg. Dose-limiting toxicities have not been identified, and a maximum 
tolerated dose has not been established. Adverse events have been generally mild to 
moderate. There have generally been no clinically significant changes or group trends in 
laboratory, vital sign or ECG assessments. 
The PK data from P005 were also included to update the population PK model of MK-8189 
and an updated PK-EO relationship was produced.
 
 
4.3.2
Rationale for Dose Interval and Study Design
Based on the controlled-release formulation and estimated half-life of the compound, once 
daily dosing is predicted to be an appropriate dosing interval for the treatment of 
schizophrenia.
MK-8189 doses will be up-titrated (refer to Section 6.6) to the target dose per treatment 
sequence to improve tolerability and minimize EPS, and a matched placebo control will be 
included to reduce bias with regards to patient reporting and investigator assessment of AEs.
The 12-week treatment duration was selected to cover both the acute episode and the early 
residual period to evaluate early durability of efficacy. The selected treatment duration also 
permits exploratory evaluation of negative symptoms and cognitive performance, as well as 
an improved understanding of the trajectory for weight changes and effects on metabolic 
parameters.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3).
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
The diagnosis will be confirmed using the MINI, Version 7.0.2. All psychiatric diagnoses 
specified in the inclusion and exclusion criteria will be made according to the DSM-5™ 
criteria by a qualified psychiatrist (MD) or psychologist (PhD) (or equivalent qualification). 
The investigator responsible for psychiatric diagnoses must also have at least 3 years of 
psychiatric clinical experience and be approved by the Sponsor.
All assessments of psychiatric symptoms that require an interview with the participant (ie, 
MINI, PANSS, PSP, C-SSRS and CGI-S) must be performed in a language in which both the 
assessor and the participant are fluent, ie, no interpreter is needed.
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 is eligible for inclusion in the study if the participant meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Meet the diagnostic criteria for schizophrenia according to the DSM-5™ (for further 
details, refer to Section 8.1.6).
2. Be currently experiencing active phase symptoms of schizophrenia (DSM-5™Criterion 
A, for further details, refer to Section 8.1.6).
3. Have an illness duration for schizophrenia of at least 1 year (for further details, refer to 
Section 8.1.6). 
4. Be confirmed to be experiencing an acute episode of schizophrenia, as evidenced by ALL 
of the following:
a.
Onset of the current acute episode 
 before screening
b. Current symptoms represent a marked and substantial worsening compared with the 
participant’s usual symptomatic state prior to the current acute episode, and are 
associated with diminished functional ability
c.
In need of increased psychiatric attention to treat worsening acute episode symptoms
For further details, refer to Section 8.1.6. Note: this criterion will be reviewed and 
approved by the external SDE prior to randomization.
5. Have a minimum PANSS total score of ≥80 at screening.
Note: the screening minimum PANSS total score will be independently verified by a 
SDE prior to randomization.
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6. Have a score of ≥4 (moderate) in 2 or more of the following items in the positive 
subscale of the PANSS at screening:
 
Note: these scores will be independently verified by the SDE prior to randomization.
7. Have a CGI-S score of ≥4 (moderately ill) at screening and baseline.
8. Be able to taper off psychotropic medications (including antipsychotics, antidepressants 
and mood stabilizers) without significant destabilization or increased suicidality in the 
opinion of the investigator (see Table 3)
 
 with the exception that the last dose of past MAO 
inhibitors cannot be within 30 days of the screening visit.  
9. Have had a positive response to antipsychotic medication (other than clozapine) during at 
least 1 period of treatment for a prior psychotic episode (for further details, refer to 
Section 8.1.6). 
Demographics
10. Be male or female, from 18 years to <56 years of age inclusive, at the time of signing the 
informed consent.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 

Not a WOCBP
OR

A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), as described in Appendix 5 during the intervention period and for at least 14 
days after the last dose of study intervention. The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. Contraceptive use by women 
should be consistent with local regulations regarding the methods of contraception for 
those participating in clinical studies.
-
Has a negative highly sensitive pregnancy test ([urine or serum] as required by local 
regulations) 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 
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pregnancy result is positive. Additional requirements for pregnancy testing during 
and after study intervention are in Section 10.5.3.
-
Abstains from breastfeeding during the study intervention period and for at least 7 
days after study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
12. Provide documented informed consent for the study. The participant may also provide 
consent for future biomedical research. However, the participant may participate in the 
main study without participating in future biomedical research.
13. Have a level of decision-making capacity needed to make a meaningful choice about 
whether to participate in the study.
Additional Categories
14. Be willing and considered able by the investigator to participate in protocol assessments, 
including recordings of interviews, adhere to dose and visit schedules, study procedures 
and restrictions; this includes the ability to participate in all study procedures without the 
use of a language interpreter. 
15. Have an identified responsible person (eg, family member, social worker, case worker, 
case manager, or nurse), referred to as the “external contact person” in the protocol, who 
has agreed to provide information about the participant’s location if needed during 
outpatient portion of the study. The site personnel must consider this identified 
responsible person a reliable contact person, and the contact person must have regular 
contact with the participant (defined at screening as direct contact no fewer than 3 times 
per week with the participant), and with the expectation that this frequency of contact 
would continue (either in person or via other contact method) throughout duration of 
study, including the follow-up period). 
Note: if the participant does not have a reliable external contact person, then the site may 
designate a site staff member who will take on the role of external contact person, with 
the same responsibilities as described above.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a primary current diagnosis other than schizophrenia or a comorbid diagnosis (for 
example, major depression) that is primarily responsible for the current symptoms and 
functional impairment.
2. Meets criteria for moderate to severe substance use disorder currently or within past 6 
months prior to screening (excluding those related to caffeine or tobacco/nicotine).
3. Has a known history of the following:
a.
Borderline personality disorder, antisocial personality disorder, or bipolar disorder 
b. Traumatic brain injury causing ongoing cognitive difficulties, Alzheimer’s Disease or 
another form of dementia, or any chronic organic disease of the central nervous 
system
c.
Intellectual disability of a severity that would impact the ability of the participant to 
participate in the study
4. Has a current diagnosis of a psychotic disorder (other than schizophrenia), or a behavioral 
disturbance thought to be substance-induced or due to substance abuse.
5. Has moderate or severe tardive dyskinesia according to the investigator.
6. Is or was under involuntary commitment for the current acute episode, because the 
participant is considered a danger to themselves or others.
7. Has committed an act of violence (assaultive behavior) ≤2 years prior to the screening 
visit. 
 
 
 
 
8. Has a BMI <18.5 kg/m2.
9. Has a risk factor for QTc prolongation as defined by:
a.
A known history or current evidence of QTc interval >450 msec for both men and 
women
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b. A known history of risk factors for Torsades de Pointes (eg, heart failure, 
cardiomyopathy or family history of long QT syndrome)
Note: determination of QTc interval at screening as a pretreatment reference will be 
based on the average of 3 measurements, using the Fridericia formula (QTcF) for 
correction. The average will be calculated by the site based on the central read.
10. Has known renal disease or is experiencing renal insufficiency as defined by: 
eGFR of <50 mL/min/1.73m2 (as measured by CKD-EPI formula) 
11. Has known history of chronic convulsive disorder (eg, epilepsy or seizure disorder)
except febrile seizures of childhood.
12. Has a history of neuroleptic malignant syndrome.
13. Has a history of malignancy ≤3 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
14. Is at imminent risk of self-harm or harm to others as assessed by the investigator, based 
on clinical interview, MINI, or responses provided on the C-SSRS.  
Note: participants must be excluded if they report suicidal ideation meeting the 
description of C-SSRS Type 4 or 5 (ie, suicidal ideation with intent, with or without a 
plan) within the past 2 months or suicidal behavior (as described by the C-SSRS) within 
the past 6 months at screening. Participants must be excluded at baseline if they report 
suicidal ideation of Type 4 or 5 or suicidal behavior between screening and baseline.
15. Has a history of 3 or more significant allergies (including latex allergy) to prescription or 
nonprescription drugs or food, according to the investigator. 
16. Has a known allergy or intolerance to risperidone or any of its active or inert ingredients.
17. Has hypothyroidism, diabetes, high blood pressure, cardiovascular condition, respiratory 
condition or other chronic medical conditions unless the condition is stable according to 
the investigator; the prescribed dose and regimen of medication are stable for ≥ 3 months 
prior to screening; and there are no expected changes in comedication during the study.
Note: the prescribed dose and regimen of medication are considered stable if dose 
adjustments reflect optimizing treatment rather than reacting to significant changes in the
treated conditions.
Prior/Concomitant Therapy
18. Has a history of treatment resistance exhibited by any of the following:
a.
No or minimal response to at least 2 periods of treatment lasting 6 weeks or longer,
with antipsychotic agents (from at least 2 different chemical classes) at the maximally 
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tolerated dose. Participants who have responded to antipsychotics only when paired 
with clozapine are considered treatment-resistant (for further details, refer to Section 
8.1.6).
b. History of ECT treatment for treatment-resistant schizophrenia within the past 6 
months.
c.
Past or current use of clozapine as single or adjunctive therapy for schizophrenia 
within the past 3 months.
19. Is currently taking and benefiting from a moderate or strong CYP3A and/or CYP2C9 
inhibitors and inducers and/or CYP2B6 sensitive substrates (see Section 8.1.9 and 
Table 3).
20. Is currently taking and benefiting from strong CYP2D6 inhibitors (see Section 8.1.9 and 
Table 3). 
Prior/Concurrent Clinical Study Experience
21.
 
 
22. Has been previously participated in the MK-8189 program according to the following: 
previous screen failure in this study; was previously randomized (regardless of treatment) 
in any MK-8189 study.
Diagnostic Assessments
23. Is unwilling to allow the recording of the MINI and PANSS interview at screening and 
baseline. 
24. Has laboratory or clinical evidence of clinically significant hepatic conditions such as one 
or more of the following:
a.
ALT or AST ˃2X ULN and total bilirubin ˃1.5X ULN
b. ALT or AST ˃3X ULN 
c.
A history of hepatitis or liver disease that, in the opinion of the investigator, has been 
active within the 6 months prior to screening
25. Has a prolactin laboratory value of ≥ 5X ULN at screening.
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26. Has a positive urine alcohol/drug screen at the screening visit with the following 
exceptions: 
a.
Participants with positive psychotropic medication results for drugs permitted at time 
of screening may be included, provided the finding(s) can be accounted for by 
documented prescription use, the participant is able and willing to comply with 
protocol requirements regarding excluded medications, and eligibility criteria 
pertaining to the use of concomitant medications and substance use disorder are met 
b. Participants with positive alcohol or cannabis results on the urine alcohol/drug screen 
may be included at the investigator’s discretion, provided the investigator does not 
feel the participant is a compliance risk and the participant does not fulfill the criteria 
for moderate or severe substance use disorder
Other Exclusions
27. Is unwilling or unable to remain hospitalized for the duration of screening and at least the 
first 28 days of treatment period.
28. Has a severe, acute or chronic medical condition or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator or Sponsor, would make the participant inappropriate for 
entry into this study.
29. Has adverse events or clinically significant abnormal laboratory, vital sign, or physical 
examination, or ECG finding during screening period indicative of emerging or unstable 
medical conditions that potentially interfere with the ability to evaluate the safety, 
tolerability and the efficacy of the study intervention, according to the judgment of the 
investigator.
30. Is known to be repeatedly medically noncompliant in the management of their 
schizophrenia as assessed by the investigator.
31. Is known to be noncompliant or who is assessed by the investigator to be potentially 
noncompliant with the management of a current severe, acute or chronic medical 
condition which requires strict adherence to treatment (eg, tuberculosis, HIV).
32. 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
Participants should refrain from the consumption of more than 1 grapefruit or 1 glass (8 
ounces) of grapefruit juice a day, throughout the entire study period. Otherwise, participants
are allowed to consume their usual diet throughout the study period.
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no caffeine and tobacco/nicotine restrictions.  
See Table 3 and Appendix 2 regarding illicit drug use prohibitions.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Note that participants who are screen failures cannot repeat screening.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of MK-8189 and risperidone will be packaged to support enrollment.
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
Titration schedules to reach target dose strengths specified in Table 1, as well as rules 
pertaining to subsequent dose down-titration and rechallenge, are specified in Section 6.6.
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Table 1
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
IMP or 
NIMP/AxMP
Sourcing
MK-8189 
8 mg/ MK-
8189 8 mg
Experimental MK-8189
Drug
Tablet
4 mg + 
0 mg
4 mg qd
Oral
Days 1-3
Day 8 to 
Week 12
Test 
Product
IMP
Central
MK-8189 
8 mg/ MK-
8189 8 mg
Experimental MK-8189
Drug
Tablet
4 mg +
4 mg
8 mg qd
Oral
Day 4 to 
Week 12
Test 
Product
IMP
Central
MK-8189 
8 mg/ MK-
8189 8 mg
Experimental Placebo to 
risperidone
Drug
Capsule
0 mg
0 mg qd
Oral
Day 1 to 
Week 12
Placebo IMP
Central
MK-8189 
16 mg/ MK-
8189 16 mg
Experimental MK-8189
Drug
Tablet
4 mg +
0 mg
4 mg qd
Oral
Days 1-3
Test 
Product
IMP
Central
MK-8189 
16 mg/ MK-
8189 16 mg
Experimental MK-8189
Drug
Tablet
4 mg +
4 mg
8 mg qd
Oral
Days 4-6
Test 
Product
IMP
Central
MK-8189 
16 mg/ MK-
8189 16 mg
Experimental MK-8189
Drug
Tablet
12 mg + 
0 mg
12 mg 
qd
Oral
Day 8 to 
Week 12
Test 
Product
IMP
Central
MK-8189 
16 mg/ MK-
8189 16 mg
Experimental MK-8189
Drug
Tablet
4 mg + 
12 mg
16 mg 
qd
Oral
Day 7 to 
Week 12
Test 
Product
IMP
Central
MK-8189 
16 mg/ MK-
8189 16 mg
Experimental Placebo to 
risperidone
Drug
Capsule
0 mg
0 mg qd
Oral
Day 1 to 
Week 12
Placebo IMP
Central
MK-8189 
24 mg/ MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
4 mg +
4 mg
8 mg qd
Oral
Days 1-3
Test 
Product
IMP
Central
MK-8189 
24 mg/ MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
4 mg +
12 mg
16 mg 
qd
Oral
Days 4-6
Day 8 to 
Week 12
Test 
Product
IMP
Central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
IMP or 
NIMP/AxMP
Sourcing
MK-8189 
24 mg/ MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
12 mg +
12 mg
24 mg 
qd
Oral
Day 7 to 
Week 12
Test 
Product
IMP
Central
MK-8189 
24 mg/ MK-
8189 24 mg
Experimental Placebo to 
risperidone
Drug
Capsule
0 mg
0 mg qd
Oral
Day 1 to 
Week 12
Placebo IMP
Central
Risperidone 
6 mg/
Risperidone 
6 mg
Active 
Comparator
Placebo to 
MK-8189
Drug
Tablet
0 mg + 
0 mg
0 mg qd
Oral
Day 1 to 
Week 12
Placebo IMP
Central
Risperidone 
6 mg/
Risperidone 
6 mg
Active 
Comparator
risperidone
Drug
Capsule
2 mg
2 mg qd
Oral
Days 1-3
Test 
Product
IMP
Central
Risperidone 
6 mg/
Risperidone 
6 mg
Active 
Comparator
risperidone
Drug
Capsule
2 mg
4 mg qd
Oral
Days 4-6
Day 8 to 
Week 12
Test 
Product
IMP
Central
Risperidone 
6 mg/
Risperidone 
6 mg
Active 
Comparator
risperidone
Drug
Capsule
2 mg
6 mg qd
Oral
Day 7 to 
Week 12
Test 
Product
IMP
Central
Placebo/MK-
8189 24 mg
Experimental Placebo to 
MK-8189
Drug
Tablet
0 mg + 
0 mg
0 mg qd
Oral
Days 1-42
Placebo IMP
Central
Placebo/MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
4 mg + 
4 mg
8 mg qd
Oral
Days 43-45
Test 
Product
IMP
Central
Placebo/MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
4 mg + 
12 mg
16 mg 
qd
Oral
Days 46-48
Day 50 to 
Week 12ᵃ
Test 
Product
IMP
Central
Placebo/MK-
8189 24 mg
Experimental MK-8189
Drug
Tablet
12 mg + 
12 mg
24 mg 
qd
Oral
Day 49 to 
Week 12
Test 
Product
IMP
Central
Placebo/MK-
8189 24 mg
Experimental Placebo to 
risperidone
Drug
Capsule
0 mg
0 mg qd
Oral
Day 1 to 
Week 12
Placebo IMP
Central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
IMP or 
NIMP/AxMP
Sourcing
EEA=European Economic Area; IMP=investigational medicinal product; mg= milligram; NIMP/AxMP=noninvestigational/auxiliary medicinal product, qd=once daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: MK-8189 8 mg/MK-8189 8-mg treatment arm will be removed as of Amendment 4; however there are participants enrolled before Amendment 4 who will remain on 
8 mg MK-8189 and continue to receive study drug per protocol.
Arm names are treatment sequences.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.13 for details regarding administration of the study intervention.
All placebos will be created by the Sponsor to match active product.
6.1.1
Medical Devices
Medical devices are not used in this study.
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.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. Prior to Amendment 4, there were 5 study intervention arms. 
Participants were assigned randomly in a 2:2:2:1:2 ratio to one of the following treatment 
sequences (acute treatment/extension treatment): MK-8189 8 mg /MK-8189 8 mg MK-8189,
16 mg /MK-8189 16 mg, MK-8189 24 mg/MK-8189 24 mg, risperidone 6 mg/risperidone 6
mg, and placebo/MK-8189 24 mg.
On implementation of Amendment 4, eligible participants will be randomized in a 2:2:1:2 
ratio to 1 of the 4 following treatment sequences: MK-8189 16 mg/MK-8189 16 mg, MK-
8189 24 mg/MK-8189 24 mg, risperidone 6 mg/risperidone 6 mg, or placebo/MK-8189 
24 mg.  
6.3.2
Stratification
Intervention allocation will be stratified according to the following factors:
1.
Region/race (US–Black, US–Non-Black, Japan, Rest of World)
This stratification was selected as recent US schizophrenia studies have shown changing 
demographics and conflicting evidence for possible subgroup effects on efficacy 
[Mahableshwarkar, A. R., et al 2017]. While there are no known intrinsic factors that could 
explain these potential differences, it is difficult to exclude extrinsic factors, including 
recruitment practices, ascertainment biases, variable socioeconomic factors, or variable 
access to mental health care.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-8189 and risperidone
will be packaged identically relative to their matching placebos so that blind is maintained.
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment longer than
 
 will require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
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A missed dose is defined as taking less study intervention than specified (ie, fewer tablets or 
capsules than required) per day.  
Tablets and capsules are packaged in blister packs designed to electronically capture the time 
and date of blister openings.
Medication compliance during the study will be monitored and determined by study 
intervention counts for both tablets and capsules. The dispensed blister pack(s), including any 
remaining study intervention will be returned. The site will perform a tablet and capsule 
count and also review associated electronically captured dispensing data. The site will use 
both participant report and electronic dispensing data to help assess compliance.  
The circumstances under which electronically captured dispensing data must be edited are 
captured in the AARDEX manual. When editing is necessary, the site will need to determine 
the most accurate representation of actual study intervention administration.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol for that medication. Specific prohibitions for concomitant 
therapy during the treatment period are listed in Table 3 and restricted permitted concomitant 
therapies during the treatment period are listed in Table 4.
If there is a clinical indication for any medications specifically prohibited, discontinuation 
from study intervention may be required. The investigator should discuss any questions 
regarding this with the Sponsor Clinical Director. The final decision on any supportive 
therapy rests with the investigator and the participant’s primary physician, if applicable. 
However, the decision to continue the participant on study intervention requires the mutual 
agreement of the investigator, the Sponsor, and the participant.
6.5.1
Rescue Medications and Supportive Care
Refer to Section 8.1.9 regarding the use of EPS medications and permitted medications for 
treating insomnia, agitation, and anxiety as supportive care during the study (Table 4).   
Medication prohibitions in Table 3 and restrictions as listed in Table 4 do not end until after 
all assessments have been completed for the applicable study visit (either EOT or Week 12 
visit as described in Section 4.1), which takes place after the last dose of study intervention 
treatment. 
6.6
Dose Modification (Titration)
Eligible participants will receive treatment in a double-dummy fashion of 2 tablets (either 
which may contain MK-8189 or placebo matching MK-8189) and 3 capsules (risperidone or 
placebo matching risperidone) taken qd.
Participants randomized to the MK-8189 and the risperidone treatment sequence groups will 
be titrated to their target doses during the first week of the acute treatment period in a blinded 
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fashion. Participants randomized to the MK-8189 and the risperidone treatment sequence 
groups will start the extension period on the same treatment dose as received on the last day 
of the acute treatment period. Participants randomized to the placebo/MK-8189 24 mg 
treatment sequence group will start the extension period after the same titration schedule as 
that prescribed for the MK-8189 24-mg dose group in the acute period. 
If a participant cannot tolerate being up-titrated to the target dose during the first 7 days of 
treatment in the acute or extension treatment periods, the participant will be discontinued 
from treatment. 
Titration requests can be made on Days 8 to 42 of the acute treatment period or Days 50 to 
84 of the extension treatment period. Titration requests to the IRT are blinded and limited 
with a maximum of 3 dose changes allowed during the entire 12-week period in this fixed 
order: down-titration, rechallenge, down-titration. Participants may be down-titrated based on 
lack of tolerability after at least 1 target dose is taken, as an alternative to discontinuing the 
participant from treatment. A subsequent rechallenge may occur. In the event of intolerability 
after the rechallenge, down-titration may occur after which no further titration steps are 
allowed. 
Permitted dose adjustment scenarios for all the treatment sequence groups in the 2 treatment 
periods is shown in Table 2 below. 
MK-8189 16 mg and 24 mg treatment sequence groups may down-titrate to 12 mg and 16 
mg, respectively. Risperidone 6 mg treatment sequence group may down-titrate to 4 mg. 
Titration requests may also be made for participants in the Placebo/MK-8189 24 mg 
treatment sequence group during the acute treatment period to maintain the blind; however, 
these requests will not result in a dose change (ie, participant remains on placebo). 
Placebo/MK-8189 24 mg treatment sequence group may down-titrate to MK-8189 16 mg 
after extension target dose is reached if, during the acute treatment period, there was no
initial down-titration request made or if a rechallenge request was made.
Decisions to change the dose are to be made at scheduled visits whenever possible. If 
intolerable adverse events prohibit a delay in dose reduction, then an unscheduled visit for 
drug dispensing may be conducted. 
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Table 2
Down-titration and Rechallenge Scenario Chart 
Treatment Sequence
Intolerability 
During Days 
1-7 and Day 
43-49
Down-titration #1: 
First Instance of 
Intolerability Day 8-Day 
42 or Day 50 to Day 84 
Rechallenge Dose 
Day 8-Day 42 or 
Day 50 to Day 84  
Down-Titration 
#2: Day 8-Day 42 
or Day 50 to 
Day 84  
MK-8189 8 mg/ 
MK-8189 8 mga
Discontinue 
study 
intervention
Down-titrate to 4 mg MK-
8189
8 mg MK-8189
Down-titrate to 4 
mg MK-8189 for 
remainder of 
treatment periodb
MK-8189 16 mg/ 
MK-8189 16 mg
Discontinue 
study 
intervention
Down-titrate to 12 mg MK-
8189
16 mg MK-8189
Down-titrate to 12 
mg MK-8189 for 
remainder of 
treatment periodb
MK-8189 24 mg/ 
MK-8189 24 mg
Discontinue 
study 
intervention
Down-titrate to 16 mg MK-
8189
24 mg MK-8189
Down-titrate to 16 
mg MK-8189 for 
remainder of 
treatment period
Risperidone 6 mg/
Risperidone 6 mg
Discontinue 
study 
intervention
Down-titrate to 4 mg 
risperidone
6 mg risperidone
Down-titrate to 4 
mg risperidone for 
remainder of 
treatment periodb
Placebo/
MK-8189 24 mg acute 
treatment only
Discontinue 
study 
intervention 
Down-titration leads to no 
dose change (ie, participant 
remains on placebo Day 8-
Day 42)
Rechallenge leads to 
no dose change 
(Day 8-Day 42)
Down-titration 
leads to no dose 
change 
(Day 8-Day 42)
Placebo/
MK-8189 24 mg 
extension treatment only 
if participant not down-
titrated in acute treatment
Discontinue 
study 
intervention
Down-titrate to 16 mg MK-
8189 
(Day 50-Day 84)
24 mg MK-8189 
(Day 50-Day 84)
Down-titrate to 16 
mg MK-8189 (Day 
50-Day 84)
Placebo/
MK-8189 24 mg 
extension treatment only 
if participant was down-
titrated in acute treatment 
with no subsequent 
Discontinue 
study 
intervention 
Down-titration not allowed
Participant already down-
titrated (Day 8-42) 
No change in dose 
(Day 50-Day 84) ie, 
participant remains 
at 24 mg
Down-titrate to 16 
mg MK-8189 
(Day 50-Day 84)
Placebo/
MK-8189 24 mg 
extension treatment only 
if participant was down-
titrated in acute treatment 
with subsequent 
Discontinue 
study 
intervention 
Down-titrate to 16 mg MK-
8189 
(Day 50-Day 84)
Rechallenge not 
allowed
Down-titration not 
allowed
a. MK-8189 8 mg/MK-8189 8 mg treatment arm will be removed as of Amendment 4, however there are participants enrolled before
Amendment 4 who will remain on 8 mg MK-8189 and continue to receive study drug per protocol
b If a participant is unable to tolerate the reduced dose, study intervention should be discontinued. For participants that wish to remain in 
the study after discontinuation of study intervention, refer to Section 8.10.4 for details.  
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6.7
Intervention After the End of the Study
After the last dose of study intervention, assessments for the EOT visit (for participants who 
discontinue study intervention treatment early) or for the Week 12 visit (for participants who 
complete 12 weeks of study intervention treatment) should be completed as soon as possible 
after the last dose, preferably on the day after the participant’s last dose of study intervention. 
After the assessments have been completed, the participant may begin standard of care 
treatment for schizophrenia.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.15). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention allocation/randomization system (IRT) should be used to unblind 
participants and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment
regimen will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.10.4 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has been confirmed pregnant by a positive serum pregnancy test.
o
A positive or ambiguous urine pregnancy test requires immediate interruption of 
study intervention until serum hCG can be performed. Participant must be 
permanently discontinued from study intervention and reported and followed per 
Section 8.4.5, if pregnancy is confirmed by a positive serum pregnancy test. If the 
serum pregnancy test is negative, blinded study intervention can be resumed and the 
participant should be counseled about appropriate contraceptive measures. Refer to
Appendix 2 and Section 10.5 for pregnancy testing.

The participant experiences a further increase of psychotic symptoms during the study 
intervention which, in the opinion of the investigator or Sponsor, places the participant at 
unnecessary risk or does not allow the participant to adhere to the requirements of the 
protocol.
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
The participant experiences one of the following elevated liver enzyme conditions, which 
is confirmed by repeat testing. Repeat testing is to be conducted within 48-72 hours for 
the following:
o 
ALT or AST ≥3X ULN 
Note: the appearance of jaundice, worsening of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia need not be accompanied by an 
elevated liver enzyme condition of ALT or AST ≥3X ULN to consider the participant, in 
their medical judgment, as being in need of study intervention discontinuation to avoid 
unnecessary risk to the participant.

The participant experiences an ECI consistent with meeting DILI criteria: ALT or AST 
≥3X ULN with TBL ≥2X ULN and ALP <2X ULN. See Section 8.4.7. The study site 
guidance for assessment and follow-up of these criteria can be found in the Investigator 
Study File Binder (or equivalent).

The participant has an absolute neutrophil count of <1000 per mm3, and after repeat 
testing within 48-72 hours, the values are not normalized or increased.

The participant reports suicidal ideation with intent, with or without a plan or method 
through an AE or C-SSRS (ie, a positive response to Items 4 or 5 in the assessment of 
suicidal ideation on the C-SSRS) or suicidal behavior. If the reported suicidal ideation is 
passive, and participant expressly denies any intent to act, and who, after evaluation, are 
not judged to be at serious risk for self-harm during the study, the participant may
continue on study intervention. Refer to Section 8.3.6.1 for requirements pertaining to the 
evaluation of such events and Section 8.4.7. 

The participant has a persistent eGFR of <40 mL/min/1.73m2 as measured by CKD-EPI 
formula (refer to Appendix 2 for definition and determination of persistent eGFR).

The participant has a QTcF interval of ≥500 msec (the average of the 3 QTcFs will be 
used and the average will be calculated by the site based on the central read).

The participant cannot tolerate being up-titrated before receiving 7 days of treatment in 
the acute period or before receiving 7 days of treatment in the extension period.

The participant is determined to have previously participated in a MK-8189 study.
In the event of any reason for discontinuation from treatment, all procedures for the EOT
visit should be performed.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed. Refer to 
Section 8.10.4 for details.
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Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.14. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
Refer to Section 8.1.7 and Section 8.1.18 for protocol-specific procedures in place to avoid 
lost to follow-up.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet 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.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
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A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
For assessments that require review by a central reader or external SDE for eligibility 
qualification, the review must be completed before randomization. Refer to the rater manual 
for details.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant ID 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.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
Clinically significant findings in physical examination, laboratory tests, ECGs, and other 
physical evaluations during screening are to be noted in the medical history. Clinically 
significant changes from the screening evaluation during the study should be captured as 
adverse events.
Psychiatric conditions and symptoms that are not core symptoms of schizophrenia (eg,
agitation, anxiety, insomnia, depression), including those captured in the MINI evaluation,
are to be recorded in the medical history.
8.1.5
Substance/Alcohol/Smoking History/Social History
Personal and social history such as living/employment/arrest and substance/alcohol/smoking 
will be reviewed.
 
 
8.1.6
Psychiatric History, Intake Evaluation, and MINI
All psychiatric diagnoses specified in the inclusion/exclusion criteria will be made according 
to the relevant DSM-5™ criteria. 
A psychiatric history and intake evaluation will be conducted by the investigator or qualified 
designee. The investigator may review and use multiple information sources 
 
 to obtain relevant 
historical information.
The psychiatric intake evaluation of the participant will include:
•
Participant’s psychiatric and treatment history (including response to previous 
antipsychotics as described in the inclusion criteria), medical history, mental status and 
treatment plan, approximate number of psychiatric hospital admissions (lifetime), and 
illness duration. To determine illness duration, the PI will use their best estimate based on 
available resources (including medical charts, participant self-report, family member, 
health or paraprofessional report).
•
A detailed description of the current acute episode (onset, duration, precipitants, evidence 
that symptoms and function have worsened vs. usual baseline).
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•
The aforementioned detailed description will be used to complete the C-VISA™, which is 
an instrument detailing the required elements for participant eligibility. As stated in 
Section 8.1.8 External SDE Review of Participant Eligibility Considerations, the C-
VISA™ once completed is submitted for review by the SDE to ensure that protocol 
eligibility criteria pertaining to psychiatric history, diagnostic eligibility, and psychiatric 
assessments are met and that corroborative sources as specified in this section are 
adequate. 
•
The C-VISA™ notes must include a description of the nature and duration of the 
relationship between the participant and corroborative sources, for corroboration both of 
schizophrenia diagnosis and illness duration and of the current acute episode onset, as 
described here:
 
•
Sites are expected to perform due diligence to confirm, at a minimum, that the diagnosis 
and the duration of schizophrenia is based on site-independent, professional sources. 
Professional sources could include medical records, psychiatric records, discussion with 
the potential participant’s treating psychiatrist, or information from other health care 
professionals/paraprofessionals. 
•
If the site is unable to acquire site-independent, professional corroboration during the 
screening window, please see SDE guidance document. 
Corroborative sources of the current acute episode onset: 
•
Only if no professional sources are available, nonprofessional sources may be considered
to corroborate the duration of the current acute episode, if those sources meet the criteria 
specified in the SDE guidance document. Participant self-report cannot be used as the 
sole corroborator of the duration of the current acute episode. Nonprofessional sources
could include: family member, friend, roommate, etc. 
•
 
8.1.7
Identification of External Contact Person
To be considered eligible for enrollment, the participant must have an identified responsible 
external contact person who agrees to aid the site in locating the participant if the participant 
cannot be reached during the outpatient phase. The external contact person may be a family 
member, social worker, case worker, case manager, nurse or other individual who has a 
significant relationship with the participant as evidenced by a broad range of assistance 
typically provided to the participant by the external contact person. The participant must 
provide the name and contact information of this person. Site personnel must confirm that 
this person has agreed to be available to locate the participant if the participant cannot be 
contacted. The site must interview the potential external contact person and consider this 
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person reliable and that this person confirmed that they anticipate having contact no less than 
3 times per week with the participant as an outpatient during the study; either in person or via 
other contact method. The source documents must record the external contact person’s 
agreement to act as the participant’s contact person. If the participant does not have an 
external contact person that is considered reliable by the site, the site may designate a site 
representative to act as the participant’s external contact person, with the same 
responsibilities as described above. The investigator may not act as the external contact 
person. In the event the external contact person cannot participate for the entire study 
duration, a new external contact will need to be identified with the same requirements as 
above.
The investigator is responsible for documenting in the source that the external contact person 
will have sufficient time to meet their responsibilities as defined by the protocol 
requirements.
8.1.8
External SDE Review of Participant Eligibility Considerations 
Participants cannot be randomized without the approval of the external SDE, which will be 
based on the review of screening PANSS and MINI interview, the scores of PANSS, CGI-S 
and C-SSRS, and the completed C-VISA™. The C-VISA™will be used to provide the 
relevant elements of the psychiatric history, diagnostic eligibility, and psychiatric 
assessments to the SDE for independent review. Refer to the rater manual for details. To 
ensure a timely review, the above-mentioned screening assessments, which include the 
completed C-VISA™, should be transmitted immediately (within 2 calendar days of the 
screening visit).
In the event of unforeseen circumstances that may delay the submission of the C-VISA™
and screening rating scales data, the investigator or pertinent site staff must contact the 
external SDE immediately to ensure speedy remediation.
In those circumstances where C-VISA™and screening rating scales data cannot be 
transmitted on time to ensure V2 can be completed within 7 days of V1, the external SDE 
and PI will agree on an acceptable alternative, which may include telephone review of 
critical elements.
8.1.9
Prior and Concomitant Medications Review
8.1.9.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 3 months before V2. One-year history of antipsychotics will also be recorded.
8.1.9.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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The following therapies are prohibited or restricted during the course of the study:
1. Medications specifically prohibited in the exclusion criteria are also prohibited during the 
treatment period.
2. Medications with a moderate or strong inhibiting or inducing effect on cytochrome P450 
CYP3A or CYP2C9, or the use of medications that are sensitive substrates of CYP2B6, 
are prohibited during the treatment period. 
3. All psychotropic medications (including antipsychotics, antidepressants, mood 
stabilizers, other psychotropics) are prohibited during the treatment period, except as 
described in Table 4.
4. Medications that are strong CYP2D6 inhibitors are prohibited during the treatment 
period. 
5. Medications for the treatment of agitation, anxiety, and insomnia are prohibited during 
the screening and treatment periods, except for those stated in Table 4. 
The participant must be able to discontinue or, in the opinion of the investigator, safely taper 
off, of any prohibited treatment listed under “Medications Supplements, Other Substances 
and Procedures” in Table 3 during the taper period 
 
 without significant destabilization or increased 
suicidality. See footnotes in Table 3 for exceptions. 
The following list of prohibited medications in Table 3 is not comprehensive. The 
investigator should use their medical judgment when a participant presents with a medication 
that meets a prohibited category, but is not on the list or call the Sponsor for clarification.
Prohibitions and restrictions are not lifted until after the completion of V12/EOT visit (see 
Section 8.10).
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Table 3
Prohibited Medications During the Treatment Period
CYP Inducers, Inhibitors And Sensitive Substratesa
CYP3A strong or moderate
inhibitors:
amprenavir, aprepitant, atazanavir, boceprevir, casopitant, ceritinib, 
cimetidine, ciprofloxacin, clarithromycin, cobicistat, conivaptan,
crizotinib, cyclosporine, danoprevir, darunavir, diltiazem, 
dronedarone, duvelisib, elvitegravir, erythromycin, faldaprevir, 
fedratinib, fluconazole, idelalisib, imatinib, indinavir, isavuconazole, 
istradefylline, itraconazole, ketoconazole, letermovir, lopinavir, 
mibefradil, mifepristone, nefazodone, nelfinavir, netupitant, nilotinib, 
posaconazole, ravuconazole, ribociclib, ritonavir, saquinavir, 
telaprevir, telithromycin, tipranavir, tofisopam, troleandomycin, 
verapamil, voriconazole  
CYP3A strong or moderate inducers
apalutamide, asunaprevir, avasimibe, beclabuvir, bosentan, 
carbamazepine, dabrafenib, daclatasvir, efavirenz, enzalutamide, 
etravirine, ivosidenib, lersivirine, lesinurad, lopinavir, lorlatinib, 
lumacaftor, mitotane, modafinil, nafcillin, phenobarbital, phenytoin,
rifabutin, rifampin, rifapentine, St. John’s Wort extract, talviraline,
telotristat ethyl, thioridazine
CYP2C9 strong or moderate
inhibitors
amiodarone, ataciguat, azapropazone, benzbromarone, bucolome, 
fluconazole, miconazole, oxandrolone, piperine, phenylbutazone,
sulfaphenazole, tasisulam, tienilic acid, voriconazole
CYP2C9 strong or moderate
inducers
carbamazepine, enzalutamide, rifampin, ritonavir
CYP2B6 known substrates with 
sensitive therapeutic range
bupropion, efavirenz
CYP2D6 strong inhibitors
bupropion, dacomitinib, fluoxetine, paroxetine, pridopidine, 
quinidine
Medications Supplements, Other Substances and Procedures
Antipsychotics (other than study intervention)
Antidepressants
Mood stabilizers
Stimulants such as methylphenidate and amphetamines
MAO inhibitorsb
Herbal drugs/dietary supplements, including and not limited to St John’s Wort, ginkgo, goldensealc
Antiemetics with dopamine antagonist activity
Illicit drugsd
Benzodiazepines are prohibited during the screening and treatment period for any indication, except as stated 
in Table 4
ECT
CYP=Cytochrome P450; ECT=electroconvulsive therapy; MAO=monoamine oxidase; UDS=urine drug screen
a
Sources include the FDA website 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.ht
m#potency. Note the prohibitive list is not exhaustive. Applies to agents with significant systemic absorption (eg, oral, 
subcutaneous).
b
The last dose of a MAO inhibitor must be ≥30 days before screening.
c
Dietary supplements that are specifically marketed for psychiatric symptoms (eg, valerian, Bach’s flower remedies) are 
prohibited. Supplements with broader applications for general health (such as omega-3-fatty acids, magnesium) are not 
prohibited.
d
In the event of positive UDS, the investigator should interview the participant and ensure that the participant understands to 
refrain from using cannabinoid drugs and prohibited psychotropic medications throughout their participation in the study. 
Alcohol use during the study should also be discouraged. This discussion must be noted in the source documents or on the 
laboratory report.  
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Table 4
Medications and Procedures Permitted During the Treatment Period
Permitted medications post baselinea
As needed use nonpsychotropic medications
Aspirin, NSAIDs, acetaminophens  
Chronic use medication
Chronic use of certain medications are allowed if the 
history of its use and participant’s condition meets 
specifications of the eligibility criteria.
Approved extrapyramidal symptoms medications
Anticholinergic or any other medications to treat 
EPS ongoing at the time of screening can be 
maintained as needed through the treatment period, 
and doses adjusted as needed. If EPS begins at any 
time during the study, then the use of anticholinergic 
or any other medications to treat EPS may be 
considered for use by the investigator. 
Lorazepam up to 6 mg/day during the taper period 
and the first 14 days of active treatment or the 
equivalent dose of approved benzodiazepines for the 
treatment of agitation, anxiety.   
Remainder of days on active treatment: lorazepam up 
to 4 mg/day or an equivalent dose of approved
benzodiazepine on a daily basis.b,c
To be used only on as needed basis. For recording in 
the CRF, enter total daily dose for each day when 
recording benzodiazepine use. If a daily dose is the 
same over consecutive days, recording of the 
consecutive date range for the same daily dose is 
acceptable.
Partial benzodiazepine agonists for the treatment of 
insomnia at recommended dose rangesc,d
Suvorexante
Zolpidem (2.5 to 10 mg/day), zaleplon (5 to 
20 mg/day), zopiclone (7.5 to 15 mg/day), or any 
equivalent short half-life nonbenzodiazepine 
hypnotic may also be used for insomnia/sleep 
disturbance if zolpidem, zaleplon, or zopiclone are 
not available in specific countries. To be used only 
on an as needed basis: suvorexant (10 mg to 20 mg).
CRF=case report form; EPS=extrapyramidal symptoms; NSAIDs=nonsteroidal anti-inflammatory drugs
a
Chronic use of certain medications are allowed if the participant’s condition is stable, and the dose was stabilized 
before the first dose on Day 1 and they are not strong or moderate CYP3A known inhibitors and inducers, strong or 
moderate CYP2C9 known inhibitors and inducers, and CYP2B6 known substrates with sensitive therapeutic range.
b
To be used on as needed basis.
 
c
The use of drugs to treat agitation, anxiety, or insomnia or with known sedative effects have the potential to impact 
efficacy assessments. The sites should consider avoiding their use within the 4 to 8 hours before efficacy assessments.
d
Any equivalent short half-life nonbenzodiazepine hypnotic may also be used for insomnia/sleep disturbance if 
zolpidem, zaleplon, or zopiclone are not available in specific countries.
e
In countries where approved (USA, Japan).
8.1.10
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
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8.1.11
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.12
IRT
The investigator or designee will call/log into IRT as specified in the SoA. On confirmation 
of a participant’s eligibility at V2, the investigator or designee will call/log into IRT to 
randomize the participant. Participants who do not meet eligibility criteria will be screen-
failed in IRT. IRT will also be used for drug dispensing in the event of a down-titration or 
rechallenge. For completed participants or participants who discontinue study intervention,
the investigator or designee will make the call/log into IRT at their last treatment visit (EOT
or Week 12 visit). Refer to IRT user manual for actions performed through IRT.
8.1.13
Study Intervention Administration
Study intervention is administered by the study or inpatient staff during the inpatient phase. 
All personnel responsible for overseeing/managing study intervention administration must 
receive training 1) at the investigator meeting, or 2) on site from a Sponsor representative.
All individuals who dispense study intervention to the participant should monitor the 
participant to ensure doses are ingested as directed and record relevant dosing information 
which includes number of tablets and capsules and time taken in source documents.
Study intervention will be self-administered after hospital discharge.
Before discharge, participant will be educated by a trained member of the study staff on 
dosing requirements, package opening, the requirement to return all drug package(s) at each 
outpatient visit, and compliance. Documentation of participant training must be filed with the 
participant’s source documents.
8.1.13.1
Timing of Dose Administration
The first dose will be administered after all baseline visit safety assessments and efficacy 
assessments are completed (including the collection of blood samples and predose PK 
sample) and after subsequent randomization. The first dose will be taken in the evening on 
the day of the baseline visit only after all baseline assessments have been completed. 
Thereafter, participants should be administered their study intervention at approximately the 
same time each evening. If a dose is delayed into the next calendar day (eg, 1:00 am), then 
the dose may be taken provided it is at least 12 hours before the next scheduled dose. 
Participants should not take double or extra doses to attempt to make up for a missed dose.
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Before being discharged to an outpatient setting, participants will be instructed to endeavor to 
take their doses in the evening, at the same time each evening, and review what steps to take 
if a dose is late or missed. 
Study intervention can be taken without regard to food intake.
8.1.14
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.10.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT/DC visit at the time of withdrawal. Any AEs that are present 
at the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.14.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.15
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
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unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician may be allowed to continue study 
intervention with Sponsor consultation and should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.16
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.
8.1.17
Hospitalization During the Study
For those participants who were already hospitalized when approached for recruitment into 
this study, the start of hospitalization for the study must be no earlier than the day of the 
signing of the consent form.
For participants who are outpatients when approached for recruitment into this study, 
participants could be admitted to the hospital as early as the day of start of consenting, but no 
later than the evening of the screening visit.
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Participants will continue as inpatients in this study throughout at least the first 29 ±1 days of 
the active treatment period. Participants may be considered for discharge after completing V6
(Week 4) assessments if the following minimum conditions are met: 

According to investigator’s judgment, the participant’s clinical symptoms and 
functioning are sufficiently improved that continued treatment can occur safely in a 
less restrictive environment (eg, participant is not at risk to self or others); 

The participant can self-administer the study intervention correctly;

The participant can abide by all study procedures as an outpatient as described in this
protocol.
On the day of discharge, the participant will be given the visit schedule, dosing instructions, 
and a dosing notebook. The site will ensure that the participant has their participant ID card. 
 
 
 
 
Standard local practice that includes exceptions to the typical inpatient/outpatient model (eg,
intensive observaton period as an outpatient before confirming they meet criteria for formal 
discharge) may apply after V6 (Week 4) and should be documented for review and approval 
by Sponsor before the execution of that practice for this study.  
 
 
 
The Sponsor is to be contacted if it is anticipated that the participant will not be ready to be 
discharged from the hospital after screen fail, treatment discontinuation, or after V6 
assessments are completed on Day 28.
8.1.18
Telephone or Virtual Contacts
TCs will be performed as specified in the SoA in between outpatient visits by a trained site 
representative to check compliance and ability to manage self-administration of study
intervention, review adverse events, and remind participants of the visit schedule. TCs during 
the follow-up period will be used to review adverse events and concomitant medications. 
Where applicable, TCs will also be used to instruct and encourage participants to fast 
overnight before scheduled outpatient clinical laboratory sample collection (refer to
Appendix 2 for definition of fasting). Additional TCs/visits may be scheduled at the 
investigator’s discretion.
The principal investigator is responsible for ensuring that all TCs are performed by a site 
staff member who is a health care professional qualified to elicit a discussion with the 
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participant that will lead to a clinically meaningful disclosure on the participant’s well -
being. TCs are to be documented in a contact log, and the investigator must review the 
updated log within 2 days of the new log entry. In the event of worsening symptoms reported 
by either the participant or the external contact person, the ensuing action steps taken by the 
site must be recorded. The site must follow-up on any report of worsening symptoms by 
contacting the participant to schedule an immediate visit.
If the participant cannot be reached by TC at the regularly scheduled time or misses a visit, 
the site should make at least 3 attempts (in addition to the initial TC) to contact the 
participant within 48 hours of the missed scheduled time. The last contact attempt should 
represent stronger action by the site to contact the participant (ie, a visit to the participant’s 
residence, an attempt to reach the external contact person identified at the time of screening) 
if the participant cannot be reached on the third attempt. All TCs, attempted contacts, and 
home visits should be recorded in source documents.
8.2
Efficacy Assessments
Efficacy assessments are performed at each site by raters who meet the qualification and 
training requirements per scale. Rater qualifications, training and applicable certification 
process are established in a separate document. Each efficacy assessment may require 
different raters, but it is strongly encouraged that the same rater evaluates the same 
participant for the duration of the study. 
As a best practice, a back-up PANSS rater should be prospectively identified for each 
participant at screening to improve continuity and reliability of the ratings. 
Recommendations for preparing the prospective back-up rater to rate the participant’s 
behavior is provided in the rater manual.
To avoid the influence of participant fatigue on the diagnostic and primary outcome data, the 
recommended order of assessments is to perform the PANSS interview as the first clinical 
assessment conducted at each applicable visit. The CGI-S is recommended as the last clinical 
efficacy assessment so that all relevant information can be reviewed when completing the 
CGI-S.
All PANSS interviews are to be recorded and submitted for review to the SDE. Some or all 
of the PANSS recorded interviews will be reviewed and scored by an SDE. All screening 
PANSS interviews will be reviewed and must be approved by the external SDE before 
randomization. The external SDE will provide feedback to the site raters on the quality of the 
site rater interviews and ratings to help develop and maintain good interrater reliability. 
Additionally, the external SDE feedback may be used to refine the PANSS scores entered by 
the site for an individual rating, at the discretion of the site rater.
The PANSS rating includes collection of information from an informant. Ideally, all PANSS 
informant interviews will be recorded when performed in person. Informants must provide 
consent before any audio recordings of their interview. It is acknowledged that PANSS 
informants may change over time.
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While concerns have been raised that recording assessments via audiotaping or videotaping 
could theoretically compromise participant privacy, this issue must be balanced with the need 
to conduct methodologically adequate and scientifically rigorous trials that are capable of 
testing key hypotheses. Given that the key endpoints in this study involve subjective clinical 
judgments, monitoring the adequacy of participant interviews and ratings is essential and part 
of strong research methodology. Prior studies suggest that the failure to adequately monitor 
such ratings can substantially increase the risk of failed trials [Khan, A., et al 2013]. 
Recorded interviews will be encrypted using state-of-the-art methods to ensure privacy. 
Additional steps will be taken to ensure anonymity of specific private health information. 
Recordings will be reviewed only by approved study personnel for quality control purposes 
and will be destroyed in accordance with current retention requirements.   
8.2.1
PANSS
The PANSS is a 30-item clinician-rated instrument for assessing the symptoms of 
schizophrenia and will be used as the primary efficacy endpoint measure. The PANSS is 
comprised of 3 subscales that measure positive symptoms, negative symptoms, and general 
psychopathology [Kay, S. R., et al 1987]. The PANSS Positive subscale consists of 7 items 
that measure delusions, conceptual disorganization, hallucinations, excitement, grandiosity, 
hostility, and suspiciousness/persecution. The PANSS Negative subscale consists of 7 items 
that measure blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and 
stereotyped thinking. The General Psychopathology subscale consists of 16 items that
measure somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, 
depression, motor retardation, unusual thought content, uncooperativeness, disorientation, 
poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, 
preoccupation, and active social avoidance.
8.2.2
PSP
The PSP scale is a clinician-rated 100-point (1-100) scale that measures personal and social 
functioning in 4 domains: Socially Useful Activities, Personal and Social Relationships, Self 
Care, and Disturbing and Aggressive Behaviors [Morosini, P. L., et al 2000]. The rater 
evaluates the participant’s level of impairment in each domain, ranging from absent, mild, 
manifest, or marked to severe or very severe; however, different descriptive anchors are used 
for disturbing and aggressive behaviors.    
8.2.3
CGI-S
The CGI-S is a single-item, 7-point clinician-rated scale for assessing the global severity of 
the illness [Haro, J. M., et al 2003]. It is recommended that the CGI-S be performed as the 
last efficacy assessment. 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
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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, per institutional standard. The 
investigator or medically qualified designee (consistent with local requirements) will perform 
a physical examination that includes the following organ systems:
•
Head, eyes, ears, nose, and throat
•
Neck
•
Respiratory system
•
Cardiovascular system
•
Abdomen
•
Skin and extremities
•
General appearance
•
Neurological system, including mental status, motor strength, muscle tone, and reflexes
Height, weight, and waist circumference will also be measured and recorded (Section 8.3.2).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any medical conditions found during the full physical examination will be 
recorded in the Sponsor database.
8.3.2
Height/Weight/Waist Circumference
Height (inches/centimeter) and waist circumference (inches/centimeter) will be collected and 
recorded at time points specified in the SoA. Measurements should be recorded to the nearest 
inch/centimeter. 
Abdominal waist circumference should be measured by encircling the participant’s body at 
the navel with a cloth measuring tape or similar pliable measuring device. It is important that 
the position of the participant while measuring circumference, be consistent throughout the 
study. If circumference is measured with the participant lying down, it is important to be 
performed on a firm surface (eg, an examination table or bed with minimal padding).  
Body weight will be measured using a standardized scale provided by Sponsor and should be 
reported to 1 decimal place (eg, 0.1 kg). The procedure will be conducted as follows:
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•
Weight will be taken in duplicate throughout the study at approximately the same time of 
day, after voiding and while wearing only light clothing (no coats, shoes or socks)
•
The 2 measurements should be recorded in the source documents. If the 2 measurements 
differ by more than 0.2 kg or by 0.4 lb then:
◦
Check the participant to ensure proper positioning
◦
Collect a new set of duplicate measurements that should be recorded in the source 
documents
8.3.3
Vital Signs
Pulse and BP will be assessed.
Vital signs will be measured in a semisupine position after 5 minutes rest and will include 
systolic and diastolic blood pressure and pulse.
For blood pressure readings, the correct size of the blood pressure cuff and the correct 
positioning on the participant’s arm is essential to increase the accuracy of blood pressure 
measurements. The same method for measuring pulse and blood pressure (eg, manual or 
automated) is recommended for all measurements for each individual participant and should 
be the same for all participants throughout the study.
8.3.4
Electrocardiograms
12-lead ECG will be obtained using central ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTcF intervals according to the instructions in a 
separate ECG Instruction Manual. Cardiologist overread will be provided by central ECG 
vendor. 
For the purposes of determining baseline QTcF, the central read will be used.
Triplicate measurements of ECG will be required at the screening visit. 
When triplicate ECG measurements are required, the 3 individual ECG tracings should be 
obtained as close in succession as possible, but no more than 2 minutes apart, with the full set 
of triplicates to be completed in less than 4 minutes.
A single ECG is required at postscreening visits unless there is an observation of a QTc 
prolongation (QTcF interval of ≥500 msec) according to the ECG printout. An additional 2 
ECGs will be required, and an average taken to determine the QTc interval for that visit 
based on central over read QTc interval values. 
If a postbaseline single ECG has a printout of QTcF interval<500 msec (ie, there is no 
requirement to do a triplicate ECG), but subsequent central over read finds a QTcF interval 
of ≥500 msec, then an additional 3 ECGs will be required soon as practical, but no later than 
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next scheduled visit, and average taken to determine the QTc interval will be based on central 
over read QTc interval values.
See exclusion criterion 9 regarding exclusions for QTc prolongation as measured by ECG.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
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, the assessor should 
also inquire and document if this is also present at the time of the screening visit.
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 specified time points, as 
indicated in the SoA, as well as at unscheduled visits as clinically indicated. Site staff should 
review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consideration should 
be given to providing the completed C-SSRS to the investigator for review before their 
assessment of the participant and to further inform their evaluation.
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 
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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.
 
Sites are to 
designate which health care professionals are to be responsible for acute care on-site and to 
specify referral center(s) to be used for further evaluation.
8.3.7
Monitoring of Extrapyramidal Symptoms
Extrapyramidal symptoms (including dystonia, dyskinesia, akathisia, and parkinsonism) will 
be evaluated via routine AE evaluation and reporting. Also, dyskinesia, akathisia, and 
parkinsonism will be assessed using the AIMS, BARS and SAS, which are described in 
Section 4.2.1.2. 
It is strongly encouraged that the same rater evaluates the same participant throughout their 
participation in the study.
EPS present at screening must be recorded in the medical history.
During the study, EPS must be recorded as an AE when:

Clinically significant movement disorder side effects are observed by study staff or 
volunteered by the participant

A clinically significant movement disorder already present at screening increases in 
severity

Concomitant therapy for increasing or emerging EPS symptoms is initiated, 
increased, or reinstated while the participant is in the study
 
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators 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
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment; if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
From the time of intervention allocation/randomization through 14 days after cessation of 
treatment, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 5
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Events resulting in or prolonging an existing inpatient hospitalization will not be considered 
an SAE if:

The admission or prolongation is solely for social reasons

Extended hospitalization for subjects not clinically ready to be discharged is not in 
itself an SAE. The PI instead should consider whether the events associated with 
extended hospitalization meet the definition of an SAE. Extended hospitalization 
beyond standard of care must be discussed with the Sponsor and the reasons for 
extended hospitalizations must be documented in the medical record daily until 
discharge.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
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Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
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).
2.
3. EPS resulting in study intervention discontinuation  
4. Treatment-emergent adverse event of new or worsening tardive dyskinesia 
5.
Note that the above AEs are classified as ECIs only after treatment allocation.
8.5
Treatment of Overdose
In this study, an overdose is a dose that is >2X higher than the intended number of either 
tablets or capsules in 1 dosing interval (refer to Section 8.1.13.1 for definition of dosing 
interval and Appendix 3 for reporting of overdose). 
No guidance can be given at this stage on recognition of potential signs and symptoms of 
overdose. There is no specific antidote for overdose with MK-8189. If overdose is suspected, 
treatment should consist of general supportive measures.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
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8.6
Pharmacokinetics
Table 6
PK Sampling Schedule
Acute Treatment Period
PK 
Sample
PK Collection Day 
PK Collection
Time Window
Notes
1
Baseline (Day 1)
Any time before first dose
Blood for PK sampling is collected at 
the baseline visit laboratory blood draw 
2
V4 
Within 24 hours before dose 
on day of visit
Collect date/time of dose on day before 
V4 
3
Day before V6 
-3 to 0 hr Predose
Suggested dose window (6-10pm) 
Sample 0-3 hr before dose on day before 
V6
4
Day before V6
2 to 4 hr Postdose
Suggested dose window (6-10pm) 
Sample 2-4 hr after dose on day before 
V6
5
V6
10 to 12 hr Postdose
Relative to dose taken on day before V6
6
V6
16 to 18 hr Postdose
Relative to dose taken on day before V6
7
V8
Anytime during visit
Collect date/time of dose on day before 
V8
Extension Treatment Period
8
V10
Anytime during visit
Collect date/time of dose on day before 
V10
9
V12
Anytime during visit
Collect date/time of dose on day before 
V12
hr=hour; PK=pharmacokinetic; V=visit.
Note that PK collection is not required once the participant discontinues study intervention 
treatment. If a participant discontinues before V12, then the last PK sample is collected at 
any time during the EOT visit. 
An exposure-response analysis of PANSS total score data will be explored to determine the 
efficacious dose range of MK-8189 for the treatment of schizophrenia and to assess the 
impact of factors such as exposure, patient population characteristics and drop-out on 
outcomes with MK-8189.
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8.6.1
Blood Collection for Plasma MK-8189
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Laboratory 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 will be collected from all participants as specified in the 
SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the 
Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA from the planned genetic analysis sample
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. It is important that the site carefully schedule visit assessments to avoid 
unnecessary burden to the participant: assessments should be scheduled at the participant’s 
convenience so that participant is not forced to wait between assessments. Refer to Section 
8.1 for recommended order of assessments.
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8.10.1
Screening
The screening period will include a screening (V1) visit and a taper period. All participants 
must be safely tapered off psychotropic medications with the
 
Informed consent is provided before the start of any study-specific procedures. The first day 
of the screening/tapering period starts on the day the consent form is signed. Note that the
intended screening period is a maximum of 7 days, and that the baseline visit (V2) is the day 
after the last day of the screening period (maximum of 8 days from screening visit).
Screening periods beyond this interval require Sponsor consultation before randomization.
During the screening visit, potential participants will be evaluated to determine if they fulfill 
the entry requirements as described in Section 5.1 and Section 5.2. A psychiatric diagnostic 
assessment will be performed and recorded using the MINI, Version 7.0.2. The participant’s 
medical history, prior and current medications, and demographic information will be 
obtained. Additional assessments of psychiatric symptoms and safety evaluations will be 
performed (see SoA). If the participant meets the screening eligibility criteria for which 
results are available, the participant will begin the tapering period. Participants could be 
admitted to the hospital/inpatient unit as early as the day of signing consent, but no later than 
the evening of the screening (V1) visit after assessment completion. 
Note that central laboratory results, final central ECG interpretation and external review and 
subsequent documented approval of MINI, PANSS scores and corroboration of acuity by the 
SDE may be pending at the start of the tapering period. If the participant is deemed ineligible 
based on review and corroboration of the screening eligibility criteria, the participant will be 
considered a screen failure before the baseline visit (V2).
The tapering period will begin after the screening visit is completed. All participants must be 
safely tapered off prohibited medications (antipsychotics, antidepressants and mood
stabilizers, see Table 3) and abide by medication allowances (see Table 4) in a manner 
consistent with local practices. The duration of the taper period should balance the need to 
taper medication safely with the need to limit the duration of time the acutely ill participant 
remains in screening. 
 
 
Note that if exclusion criteria are met pertaining to laboratory values (ie, prolactin, eGFR and 
LFT values), those results are final, ie, assessments are not to be repeated to challenge those 
results. Other screening laboratory and ECG procedures may be repeated only after Sponsor 
consultation and subsequent approval.
 
Note that participants who are screen failures cannot repeat screening.
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8.10.2
Treatment Period
Each visit should be performed as noted in the SoA. For visits that require additional 
explanations, please see those specific visits below.
A visit must occur within the scheduling window around the actual scheduled day (relative to 
Day 1, the day on which study intervention is first taken), regardless of the actual day the 
previous visit occurred. For example, V8 must occur on Day 43 1 day, regardless of how 
many days early or late any of the previous visits actually occurred. If visits deviate from the 
schedule, an attempt should be made to follow the original visit schedule for subsequent 
visits.
It is anticipated that participants will continue as inpatients in this study until at least Week 4 
(V6) assessments are completed. Refer to Section 8.1.17 for details on hospitalization under 
this protocol.
Visit 2
Participants will be assessed for final eligibility per inclusion/exclusion criteria as described 
in Section 5.1 and Section 5.2. The participant may be randomized into the study and will be 
assigned a randomization number (via IRT) only after ensuring that the participant meets all 
criteria. For study intervention titration and timing of first dose, refer to Section 6.6 and 
Section 8.1.13.1.
Visit 12
Prohibited medications (Table 3) must not be initiated until after all visit assessments are 
completed. Restrictions on medications (see Table 4) are lifted the same day as the Week 12
(V12) visit, but only after all visit assessments are completed.  
Study Intervention Discontinuation (End of Treatment)
EOT visit procedures as outlined in the SoA will be performed for participants who 
discontinue study intervention. The visit should occur as soon as possible after the decision is 
made, and must be before the initiation of prohibited medication and lifting of medication 
restrictions (see Table 3 and Table 4). All participants who discontinue study intervention
before completion of the protocol-specified treatment period will be encouraged to continue 
their participation in the study off study intervention and be followed for all remaining study 
visits as outlined in the SoA (Section 8.10.4). For participants who discontinue study 
participation on the same date as they discontinue study intervention, their last visit will be 
the EOT visit. If the participant discontinues treatment during the first 28 days of study, and 
after completion of the EOT visit, the protocol-specified inpatient period is no longer 
required for those who wish to continue participating in study visits. On the day of discharge, 
the participant will be given the visit schedule, and the site will ensure that the participant has 
their ID card. Approximately midweek after discharge, the participant should be telephoned 
by study staff to assess AEs, and to remind the participant of the visit schedule.
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Study Discontinuation Visit (DC)
DC visit procedures as outlined in the SoA will be performed for participants who 
discontinue the study after the EOT visit (see Section 8.10.4). The DC visit should occur as 
soon as possible once the decision is made. 
8.10.3
Follow-up Period
Participants will be followed after the last dose of study intervention according to the SoA. 
Note that more frequent contact may be performed if necessary. The 14-day follow-up period 
consists of a schedule of TCs. Safety follow-up occurs unless participant explicitly 
withdraws consent from being followed up for safety.    
Refer to Section 8.1.18 regarding telephone or virtual contact procedures. 
If the follow-up period occurs before the participant being discharged, it is anticipated that 
these specified contacts will still take place, but may be conducted between the site personnel 
and participant in person. 
Scheduling of follow-up TCs are based on day of last dose, not last visit in the treatment 
period. Requirements for follow-up visits may then run concurrently with routine scheduled 
visits if participants continue to participate in study visits of the treatment period after last 
dose. A routine scheduled visit will replace a follow-up TC if both are scheduled on same 
day or within the same window.
Once participants have discontinued study medication (whether at DC visit or end of 
treatment), they will typically require a transition to treatment with approved medications. 
Investigators should manage this transition for participants based on local norms and 
standard of care.
8.10.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
If the participant chooses to continue in the study after discontinuation of treatment (after 
completion of EOT visit), they will be encouraged to continue their participation in the study 
off study intervention and be followed for all remaining study visits as outlined in the SoA. 
Exception: PK samples will not be collected after the EOT visit. 
If the participant continues with study visits off study intervention, but discontinues before
the Week 12 (V12) visit, a DC visit will be conducted with the same procedures as the EOT 
visit.
8.10.5
Poststudy
Participants will not be followed after their completion of the study.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before any unblinding/final database lock, changes are made to primary 
or key secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before
unblinding/final database lock, will be documented in a sSAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned 
analyses (eg, those specific to the analysis of PK data, participant-reported outcomes, and 
FBR) will be documented in separate analysis plans.
Treatment sequences (MK-8189 8 mg/MK-8189 8 mg, MK-8189 16 mg/MK-8189 16 mg, 
MK-8189 24 mg/MK-8189 24 mg, placebo/MK-8189 24 mg and risperidone/risperidone) 
will be used for analyses of extension period data as well as for analyses of data that span the 
acute treatment and extension periods. Treatment groups (MK-8189 8 mg, MK-8189 16 mg, 
MK-8189 24 mg, placebo, and risperidone) will be used for analyses of data solely collected 
in the acute treatment period. Within this section, the terms “treatment” or “treatment arm” 
will be used generally to refer to either “treatment group” or “treatment sequence” depending 
on the period(s) to which the analyses refer. 
9.1
Statistical Analysis Plan Summary
Study Design Overview
A Phase 2B Randomized, Double-Blind Trial of the Efficacy and Safety 
of MK-8189 Compared with Placebo Using Risperidone as an Active 
Comparator in Participants Experiencing an Acute Episode of 
Schizophrenia
Treatment Assignment
Before Amendment 4, eligible participants were randomly assigned to 1 
of 5 treatment sequences in a 2:2:2:1:2 ratio in a double-blind fashion via 
IRT, with each sequence detailing the treatments that the participants are 
to receive in the acute and extension treatment periods. The treatment 
sequences were MK-8189 8 mg/MK-8189 8 mg, MK-8189 16 mg/MK-
8189 16 mg, MK-8189 24 mg/MK-8189 24 mg, risperidone 6 
mg/risperidone 6 mg, and placebo/MK-8189 24 mg. Specifically, 
participants randomized to receive either MK-8189 or risperidone in the 
acute treatment period continued to receive that same treatment in the 
extension period. Participants randomized to receive placebo in the acute 
treatment period received MK-8189 24 mg in the extension period. A mix 
of region and race (US-Black, US–Non-Black, Japan, Rest of World) will 
be the lone stratification factor.
On implementation of Amendment 4, eligible participants will be 
randomized in a 2:2:1:2 ratio to 1 of the 4 following treatment sequences: 
MK-8189 16 mg/MK-8189 16 mg, MK-8189 24 mg/MK-8189 24 mg, 
risperidone 6 mg/risperidone 6 mg, or placebo/MK-8189 24 mg.  
Analysis Populations
Efficacy: FAS
Safety: APaT
PK: PP
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Primary Efficacy Estimand
The primary efficacy estimand follows the guidance in ICH E9 (R1) and 
has the following 4 attributes:
1. The population targeted by the scientific question: individuals 
diagnosed with schizophrenia experiencing an acute episode of 
schizophrenia.
2. The endpoint: Week 6 CFB score in PANSS Total Score.
3. The specification of how to account for intercurrent events to reflect 
the scientific question of interest: any assessments either obtained after 
initiation of prohibited psychotropic medication or obtained more than 
5 days after study intervention discontinuation will be excluded.
4. The population-level summary for the endpoint which provides the 
basis for a comparison between-treatment conditions: difference 
(MK-8189 - placebo) in mean CFB at 6 weeks, as computed using the 
primary longitudinal ANCOVA model.
Primary Endpoint
CFB in PANSS Total Score at Week 6 (MK-8189 16 and 24 mg 
compared to placebo)
Key Secondary Endpoints
CFB in PANSS-PSS at Week 6 (MK-8189 16 and 24 mg compared to 
placebo)
CFB in CGI-S at Week 6 (MK-8189 16 and 24 mg compared to placebo)
 
Statistical Methods for Key 
Efficacy Analyses
The primary efficacy hypotheses will be evaluated by comparing MK-
8189 to placebo with respect to the mean change from baseline in PANSS 
total score at Week 6 using a longitudinal ANCOVA model. Both primary 
hypotheses (1 each for 16 mg and 24 mg) will be assessed using the p-
values corresponding to the mean CFB treatment comparisons, in 
conjunction with a Bonferroni approach.
The overall study will be considered as successful if at least 1 of the 2 
primary hypotheses is supported.
Statistical Methods for Key 
Safety Analyses
95% CIs (Tier 2 endpoints) will be provided for between-treatment 
differences in the percentage of participants with events; these analyses 
will be performed using the Miettinen and Nurminen method.
Interim Analyses
Two types of interim analyses may be performed in this study. Results will 
be reviewed by an eDMC. These interim analyses are summarized below. 
Additional details are provided in Section 9.7. 
The first type of interim analysis will be for safety only and will be 
conducted approximately every 4 to 6 months, with the frequency subject 
to change per eDMC recommendation.
The second type of interim analysis pertains to futility. This futility IA may 
be conducted at the behest of the Sponsor, and if conducted will occur only 
once (though it is noted that the eDMC may request efficacy analyses at 
any time to assess the benefit-risk profile). If conducted, the futility IA will 
be conducted when ~50% of the randomized participants in the MK-8189 
16 mg, MK-8189 24 mg, and placebo treatment arms (N=~64/arm) are 
estimated to have had the opportunity to treat for 6 weeks. Futility may be 
declared if the conditional power for both primary hypotheses is less than 
10%.
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Multiplicity
The Type-I error rate over the multiple treatment comparisons will be 
controlled using a Bonferroni procedure (across doses), in conjunction with 
sequential testing over the multiple endpoints (see Section 9.8).  
Sample Size and Power 
The planned sample size is ~500 participants (128/arm for MK-8189 16 
mg, MK-8189 24 mg, and placebo; 64 for risperidone 6 mg, and ~52 for 
MK-8189 8 mg). It is noted that the number of participants that will 
ultimately be randomized to the MK-8189 8 mg treatment arm is 
unknown before final database lock and unblinding.
There is 
 probability that at least 1 of MK-8189 16 mg or MK-8189 
24 mg will be superior to placebo as measured by the change in PANSS 
total score at Week 6 under the primary assumptions as provided in 
Table 11 with 128 participants randomized per arm.
9.2
Responsibility for Analyses/In-house Blinding
The final statistical analysis of the data obtained from this study will be the responsibility of 
the Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. The official, final database will not be unblinded until after the final Week 12 visit 
has occurred. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.  
Blinding issues related to the planned interim analyses are described in Section 9.7.  
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
9.4.1
Efficacy Endpoints
Primary Endpoint
The PANSS is a 30-item clinical-rated instrument for assessing the symptoms of 
schizophrenia. The CFB in the PANSS total score at Week 6 is the primary efficacy 
endpoint. 
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Key Secondary Endpoints
The 30-items within the PANSS may be categorized into 3 domains. One of these domains is 
the Positive Symptom Domain, with the sum of these items defined as the PANSS-PSS. The 
CFB in the PANSS-PSS score at Week 6 is a key secondary efficacy endpoint. 
The CGI-S is a 7-point clinician-rated scale for assessing the global illness severity. The CFB 
in the CGI-S at Week 6 is a key secondary efficacy endpoint. 
CFB for weight at Week 12 is considered as a key secondary endpoint.
Other Secondary Endpoints
CFB for weight at Week 6 is considered as a secondary endpoint.
Exploratory Endpoints
Analyses of the PANSS total score, PANSS-PSS, and CGI-S will also be conducted in an 
exploratory fashion at all other scheduled time points (with Week 6 already denoted as 
primary/ key secondary). Model-based analyses of weight will also be conducted in an 
exploratory fashion at all other scheduled time points (with Weeks 6 and 12 already denoted 
as secondary). 
Unless otherwise noted, all other exploratory measures will be analyzed at all scheduled time 
points, including:

The other domains from the PANSS, namely the PANSS-NSS and the PANSS-GSS 
and the PANSS Marder factor scores (positive symptom score, negative symptom 
score, disorganized thought symptom score, hostility/excitement symptom score, and 
anxiety/depression symptom score).

The PSP is a clinician-rated scale that measures personal and social functioning in the 
domains of Socially useful activities, Personal and social relationships, Self-care, and 
Disturbing and aggressive behaviors. The change from baseline in PSP at Week 6 
compared to placebo and at Weeks 6 and 12 compared to risperidone are tertiary 
efficacy endpoints.
Table 7 describes the directionality of improvement in efficacy measures.
Table 7
Directionality of Improvement in Efficacy Measures
Measurement
Direction of Improvement
Direction of Treatment Difference 
(vs. pbo) Indicating Favorable Efficacy
PANSS (and all subscales)
Decrease
Negative
CGI-S
Decrease
Negative
PSP
Increase
Positive
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Measurement
Direction of Improvement
Direction of Treatment Difference 
(vs. pbo) Indicating Favorable Efficacy
CGI-S=Clinical Global Impression-Severity; PANSS=Positive and Negative Syndrome Scale; pbo=placebo; 
PSP=Personal and Social Performance Scale; vs=versus 
Most efficacy endpoints are derived as a function of subquestions/items (eg, the PANSS total 
score is calculated as the sum of 30 items). Details pertaining to the imputation and 
calculation of these total scores when one or more of the subquestions/items is missing are 
discussed in the sSAP. 
The number and percent of participants showing a 30% response in PANSS total score %-
response = ([postdose – baseline]/baseline) will be summarized by treatment group and time 
point. 
It is noted that participants enrolled before Amendment 4 were administered the BAC, and 
that the BAC was defined as an exploratory endpoint. However, given the limited amount of 
data collected on the BAC before its removal at Amendment 4, no analyses will be presented 
for the BAC in the CSR. 
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values and vital signs.
Responses on the C-SSRS are classified according to 11 prespecified categories (Ideation: 
Passive, Active-nonspecific, Active-method, Active-method and intent, and Active-method, 
intent and plan; Behavior: Preparatory actions or behaviors, Aborted attempt, Interrupted 
attempt, Suicide attempt, and Completed suicide; Nonsuicidal Self-Injurious Behavior). The 
most severe treatment-emergent event within each of 3 broad categories (suicidal ideation, 
suicidal behavior, and nonsuicidal self-injurious behavior) reported at a visit will be used for 
analysis and reporting. An event is considered treatment-emergent during the assessment 
phase if it is either newly emerged or is more severe than the most severe event reported to 
have occurred in the study-defined pretreatment reference period.
The AIMS is a 12-item clinician-rated scale to assess severity of dyskinesias (specifically, 
orofacial movements and extremity and truncal movements), global severity, and 
participant’s awareness and distress related to said movements. Most items are scored on a 0 
(none) to 4 (severe) basis. 
The BARS rates objective and subjective components of akathisia (restlessness) using 3 
items scored on 4-point scale (0 to 3): objective akathisia, subjective awareness of 
restlessness, and subjective distress related to restlessness. These 3 items may be summed to 
obtain a total score (ranging from 0-9). In addition, a global clinical assessment of akathisia 
assessment item is also present and is rated on a 0 to 5 scale. For all components, higher 
scores represent higher degrees of impairment.
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The SAS evaluates symptoms of parkinsonism or parkinsonian side effects (including 
rigidity, tremor, akinesia, and salivation) using 10 items each on a 5-point scale (0 [normal]
to 4 [most severe, according to description]). A total score will then be computed as the 
average of these 10 items.
In addition, composite AEs for dystonia, dyskinesia, akathisia, parkinsonism, and EPS will 
be analyzed.
9.4.3
Pharmacokinetic Endpoints
Descriptive statistics of PK parameters including AUC0-24, Cmax, and C24 will be derived. 
Plasma concentration values from P008 will also be added to historical MK-8189 data in 
ongoing efforts to build the population PK modeling for MK-8189 and may also be used in 
describing exposure-response relationships for efficacy and safety. The modeling results of 
MK-8189 will be reported separately from the clinical study report. 
9.4.4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population will be defined separately for each efficacy measure and 
consists of all randomized participants who:

Receive at least 1 dose of study intervention

Have a baseline measurement and at least 1 valid postrandomization observation for 
the analysis measurement after at least 1 dose of study intervention
o
for analyses-by-time point, a valid postrandomization observation is an 
observation which: 1) is within an analysis window 2) is in the treatment period 
corresponding to the analysis window (eg, observations in the Week 6 analysis 
window occurring after the first dose of extension study intervention will be 
excluded and thus do not grant inclusion into the analyses population) and 3) does 
not occur after the relevant window pertaining to either cessation of study 
intervention or initiation of prohibited medication (for those analyses in which 
such observations are to be excluded).
Participants will be included in the treatment arm to which they were randomized for the 
analysis of efficacy data using the FAS population.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention.

For analyses conducted by time point, participants must have a baseline measurement 
and at least 1 valid posttreatment observation for the analysis measurement.
o
For analyses-by-time point, a valid posttreatment observation is an observation 
which is: 1) within the analysis window 2) in the treatment period corresponding 
to the analysis window, 3) does not occur after the relevant window pertaining to 
either cessation of study intervention or initiation of prohibited medication (for 
those analyses in which such observations are to be excluded).
Participants will be included in the treatment arm corresponding to the study intervention
they actually received for the analysis of safety data using the APaT population. This will be 
the treatment arm to which they are randomized except for participants who take incorrect 
study intervention for the entire treatment period; such participants will be included in the 
treatment arm corresponding to the study intervention actually received.    
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9.5.3
Pharmacokinetic Analysis Populations
The PP Population will be used for the PK analyses. The PP 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 show 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 before unblinding by 
individuals responsible for data collection/compliance, and its analysis and interpretation. 
Any participants or data values excluded from analysis will be identified, along with their 
reason for exclusion, in the CSR. At the end of the study, all participants who are compliant 
with the study procedure as aforementioned and have available data from at least 1 treatment 
(dose level) will be included in the PP dataset. 
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type-I error control strategy are described in Section 9.8. Nominal p-values and 95% CIs 
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity, sample size, etc. This section describes the statistical methods 
that address the primary and secondary objectives. Methods related to exploratory objectives 
will be described in the sSAP.
The primary analysis for all efficacy endpoints will exclude any assessments obtained

After initiation of prohibited psychotropic medication (eg, selected antipsychotics; 
see sSAP for complete handling) 

More than 5 days after study intervention discontinuation

After premature unblinding of either the investigator or participant
Unless otherwise noted:

The term “MK-8189” refers to the treatment arms “MK-8189 8 mg”, “MK-8189 
16 mg”, and “MK-8189 24 mg” in the acute period and to the treatment sequences 
“MK-8189 8 mg/MK-8189 8 mg”, “MK-8189 16 mg/MK-8189 16 mg”, and 
“MK-8189 24 mg/MK-8189 24mg” in the extension period. It does not include the 
“Placebo/MK-8189 24 mg” arm.

Tables in which only summary statistics are presented will include analyses for all 3 
“MK-8189” doses (8 mg, 16 mg, and 24 mg), in addition to the risperidone and 
placebo treatment arms. 

Tables which include model-based analyses will exclude the MK-8189 8 mg 
treatment arm. 
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
Analyses involving baseline are with respect to the baseline assessment collected 
before the first dose of study intervention for the acute period. This is the case even 
when the analysis being conducted pertains to the extension period.
Basic summary statistics will be computed for all efficacy endpoints over time. This 
minimally includes means and standard deviations for continuous-type endpoints and counts 
and percents for categorical endpoints.
For the analysis of all continuous measures (including PANSS total score), a longitudinal 
ANCOVA model will be used to generate confidence intervals and p-values for change-
from-baseline means within treatment as well as for change-from-baseline means between 
treatments. This model assumes a different mean for each treatment at each of the repeated 
time points in the analysis. In this model, time is treated as a categorical variable so that no 
restriction is imposed on the trajectory of the means over time.
 
 
 
In addition, the model will 
also include the interaction terms of week-by-treatment and week-by-baseline. The treatment 
difference in terms of the mean change from baseline at a given time point will be estimated, 
and as appropriate, tested from this model. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. The Kenward-Roger approximation 
will be used to compute the degrees of freedom [Kenward, M. G. and Roger, J. H. 1997].
Treatment comparisons, via confidence intervals and p-values, for each active treatment arm 
(MK-8189 16 mg, MK-8189 24 mg, risperidone) will be performed against placebo at Week 
6. These statistics will also be separately provided for the comparison of each MK-8189 dose 
against risperidone for PANSS total score, PANSS-PSS, PANSS-NSS, CGI-S, and Weight at 
Week 6 and Week 12. 
Model-based analyses pertaining to the acute period will only include data from the acute 
period, whereas model-based analyses pertaining to the extension period will use data from 
both the acute period and the extension period. This approach will reduce the potential for 
nonconvergence as a function of sparse data in the acute period analyses, which would 
require the removal of covariates. If the model does not converge for a given analysis, 
covariates will be removed one-by-one in the following order until convergence is achieved: 
cohort, stratum, gender, age, and duration of illness.
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Table 8
Analysis Strategy for Key Efficacy Variables
Endpoint
Approacha
Statistical Methodb
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis 
PANSS Total Score –
CFB at Week 6
P
Longitudinal ANCOVA
FAS
Model-Based
S
Longitudinal ANCOVA, 
assessments after prohibited 
medication initiation or SM 
cessation included
FAS
Model-Based
S
Longitudinal ANCOVA, with 
Control-Based Mean Imputation
FAS
Model-Based
Key Secondary Endpoints
PANSS-PSS Score –
CFB at Week 6
P
Longitudinal ANCOVA
FAS
Model-Based
S
Longitudinal ANCOVA, 
assessments after prohibited 
medication initiation or SM 
cessation included
FAS
Model-Based
S
Longitudinal ANCOVA, with 
Control-Based Mean Imputation
FAS
Model-Based
CGI-S – CFB at 
Week 6
P
Longitudinal ANCOVA
FAS
Model-Based
S
Longitudinal ANCOVA, 
assessments after prohibited 
medication initiation or SM 
cessation included
FAS
Model-Based
S
Longitudinal ANCOVA, with 
Control-Based Mean Imputation
FAS
Model-Based
Weight at Week 12
P
Longitudinal ANCOVA
FAS
Model-Based
S
Longitudinal ANCOVA, 
assessments after prohibited 
medication initiation or SM 
cessation included
FAS
Model-Based
S
Longitudinal ANCOVA, with 
Control-Based Mean Imputation
FAS
Model-Based
ANCOVA=analysis of covariance; CFB=change from baseline; CGI-S=Clinical Global Impression-Severity; FAS=full 
analysis set; PANSS=Positive and Negative Syndrome Scale; PANSS-PSS= PANSS Positive subscale; SM=study 
medication.
a P=Primary; S=Supportive
  b
 
 
. In addition, the model will also include the interaction terms of week-by-treatment 
and week-by-baseline.
Two sensitivity analyses will be conducted for the primary and key secondary endpoints. 
These sensitivity analyses will not be conducted for any other endpoints.
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The strategy to address multiplicity issues regarding multiple treatment comparisons, 
multiple efficacy endpoints and interim analyses is described in Section 9.7 and in Section 
9.8.
Weight
For weight, 95% confidence intervals for the mean treatment difference (MK-8189 vs. 
placebo and MK-8189 vs. risperidone in the acute period and MK-8189 vs. risperidone in the 
extension period) in percent-change from baseline will be constructed using the primary 
efficacy ANCOVA model.
 
 It is noted that confidence intervals will 
only be produced for a given comparison if both treatment arms have at least 25 participants 
(~20% of the total sample size per arm).
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
Analyses will be conducted separately for the acute period and the extension period. Unless 
otherwise noted, all assessments and events within 14 days of the last dose of study 
medication from a given period will be included in the analyses for that period, noting that 
any assessments or events taking place after the first dose of extension study medication are 
precluded from being phased to the acute period.
The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet PDLCs in laboratory, vital signs, and ECG parameters are 
either prespecified as “Tier 1” endpoints or will be classified as belonging to “Tier 2” or 
“Tier 3” based on the number of events observed.
Tier 1 Events
There are no Tier 1 events for this protocol as no inferential testing is planned.  
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (via the Miettinen and 
Nurminen method) [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 3% of participants (corresponding to 2 
participants in the risperidone arm and 4 participants in the MK-8189 and placebo arms) in 
any treatment arm show the event. The threshold of at least 3% was chosen because the 95% 
confidence interval for the between-group difference in percent incidence will always include 
zero when treatment arms of equal size each have less than 4 events (and when a treatment 
arm of half-allocation has less than 2 events) and thus would add little to the interpretation of 
potentially meaningful differences. To avoid overreporting, and since the final number of 
subjects that will ultimately be randomized to the curtailed MK-8189 8 mg arm is unknown 
(but is known to be smaller than all other arms), membership in Tier 2 for the MK-8189 8 mg 
arm requires at least 2 participants.
Because many 95% confidence intervals for Tier 2 events may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical
significance of the between-group differences in AEs and safety parameters that meet 
predefined limits of change.
In addition to individual events that occur in 3% or more of participants in any treatment 
group, the broad AE categories consisting of the proportion of participants with any AE, a 
drug-related AE, a serious AE, an AE that is both drug-related and serious, and 
discontinuation due to an AE will also be considered Tier 2 endpoints.  
As mentioned in Section 9.4.2, composite AEs for dystonia, dyskinesia, akathisia, 
parkinsonism, and EPS will also be constructed. These composite AEs will be analyzed as 
Tier 2 AEs.
Since all CIs generated for safety analyses will be constructed as comparisons against 
placebo, and since the extension period does not have a placebo arm, no CIs will be provided 
for the extension period.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment arm are provided for Tier 3 safety parameters.
Categorical Safety Measures 
C-SSRS
The percentage of participants with any treatment-emergent suicidal ideation or with any 
treatment-emergent suicidal behavior will be analyzed per the tiered analysis strategy 
outlined above, and will be considered as either Tier 2 or Tier 3 events, depending on the 
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number of participants with an event observed within each treatment group. Additionally, the 
11 prespecified categories of suicidal ideation and behavior will be summarized. Participant
counts (and cumulative counts) for each category will be based on the most severe treatment-
emergent event observed during the assessment period.  
In constructing the treatment-emergent C-SSRS analyses, a pretreatment reference period is 
required, from which a baseline score for each of the 3 categories (ideation, behavior, 
nonsuicidal self-injury) is derived. For this study, the baseline score for each of the 3 
categories will be taken as the maximum score arising from the 2 predose C-SSRS 
administrations. The first predose administration references lifetime history. The second 
predose administration references the timeframe between the first and second predose 
administrations. 
It is noted that the first predose administration is actually comprised of 2 separate 
administrations; one using lifetime as the reference period and another using fixed-time 
intervals (6 months for behavior and 2 months for ideation). The fixed-time administration is 
solely included for inclusion/exclusion purposes (noting that the contemporaneous maximum 
lifetime baseline score may not be less than the maximum fixed-time baseline score by 
definition).
BARS
The number and percent of participants with at least 2-point worsening on the BARS total 
score will be summarized by treatment group and time point.
In addition, the number and percent of participants transitioning from a baseline global score 
to a postdose global score will be summarized by treatment and time for the following 
transitions: (0 or 1) to (2 or 3), (0 or 1) to (4 or 5), and (2 or 3) to (4 or 5).
AIMS
Basic summary statistics for both the raw values and the change-from-baseline values will be 
provided by treatment and time point for the AIMS composite score (sum of Items 1-7; 
ranging from 0-28). Also, the number and percent of participants with at least a 2-point 
worsening on the AIMS composite score will be summarized by treatment group and time 
point.
In addition, the number and percent of participants transitioning from a baseline global score 
to a postdose global score will be summarized by treatment and time for the following 
transitions: (0 or 1) to 2, (0 or 1) to (3 or 4), and 2 to (3 or 4).
SAS
Basic summary statistics for both the raw values and the change-from-baseline values will be 
provided by treatment and time point for the total score (0 to 4).
In addition, the number and percent of participants with a total score ≥0.7 will be 
summarized by treatment group and time point.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on treatment, and change from baseline values 
will be provided by treatment arm.
Though model-based analyses pertaining to weight are considered as efficacy analyses, the 
standard analyses for weight (change-from-baseline summary statistics and predetermined 
limits of change) will be considered as safety analyses. Of note, the predetermined limits of 
change are as follows: Increase of ≥7% and Decrease of ≥7%.
Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs and SOCs (incidence ≥3% participants in at 
least 1 treatment group)
X
X
Composite AE of dyskinesia
X
X
Composite AE of dystonia
X
X
Composite AE of akathisia
X
X
Composite AE of parkinsonism
X
X
Composite AE of extrapyramidal symptoms
X
X
Tier 3
Specific AEs and SOCs (incidence <3% participants in all 
treatment groups)
X
Change from baseline results (labs, ECGs, vital signs)
X
BARS
X
AIMS
X
SAS
X
C-SSRS
X
AE=adverse experience; AIMS=Abnormal Involuntary Movement Scale BARS=Barnes Akathisia Rating Scale; C-
SSRS=Columbia Suicide Severity Rating Scale; CI=confidence interval; ECG=electrocardiogram; SAS=Simpson Angus 
Extrapyramidal Side Effects Scale; SOC=System Organ Class; X=results will be provided
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed using tables and/or graphs. No statistical hypothesis tests will 
be performed on these characteristics.  
The number and percent of participants screened and randomized and the primary reasons for 
screening failure and discontinuation will be displayed. Baseline characteristics and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables. The number and percentage of participants transitioned from inpatient to 
outpatient will be summarized by week and treatment.
9.7
Interim Analyses
Two types of interim analyses may be performed in this study. Results will be reviewed by 
an eDMC.  
The first type of interim analysis will be for safety only and will be conducted approximately 
every 4 to 6 months, with the frequency subject to change per eDMC recommendation.
The second type of interim analysis pertains to futility. This futility IA may be conducted at 
the discretion of the Sponsor, and, if conducted, will occur only once (though it is noted that 
the eDMC has the ability to request efficacy analyses at any time to assess the benefit-risk 
profile). If conducted, this IA will be conducted when ~50% of the randomized participants
in the MK-8189 16 mg, MK-8189 24 mg, and placebo treatment arms (N~=64/arm) are 
estimated to have had the opportunity to treat for 6 weeks. Futility may be declared if the 
BPCP for both primary hypotheses is less than 10%.
The endpoints, timing, and purpose of the interim analyses are summarized in Table 10.
Table 10
Summary of Interim Analysis Strategy
Key Endpoints for
Interim Analysis
Timing of
Interim Analysis
Purpose of
Interim Analysis
Safety Endpoints as requested by 
eDMC
Interim safety analyses will be 
reviewed initially every 4-6 months 
(approximately) by the eDMC. The 
eDMC may change the frequency of 
these analyses based on the results of 
these analyses.  
Safety
Week 6 CFB in PANSS Total Score
If conducted, the futility IA will be 
conducted when ~50% of the 
randomized participants in the MK-
8189 16 mg, MK-8189 24 mg, and 
placebo treatment arms (N=~64/arm)
are estimated to have had the 
opportunity to treat for 6 weeks.
Assess futility
CFB=change from baseline; eDMC=external Data Monitoring Committee; IA=interim analysis; PANSS=Positive and 
Negative Syndrome Scale
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Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators before the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no responsibilities 
associated with the conduct or design of the study.
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician. Additional logistical details will be provided in the eDMC Charter.  
Treatment-level results from the interim analysis will be provided to the eDMC by the 
unblinded statistician. Before final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline, the ITT principle and the CHMP guideline on adaptive designs.
Should the futility IA be conducted, then the decision of whether to terminate the study for 
futility will be based on the BPCP, ie, the likelihood of correctly detecting a treatment 
difference at the end of the study given the results at the interim, corresponding to the 
primary hypotheses. The BPCPs will be computed assuming that the observed trend at the 
interim will continue to the end of the study. Details pertaining to the computation of the 
BPCPs are included in the sSAP.
Consideration may be given to terminate the study for futility if the BPCP for the primary 
endpoint for both doses is less than 10%. The probability of incorrectly stopping the study, β, 
at the IA would be approximately 1% under the primary set of assumptions.
The usefulness of the futility criterion may be assessed by examining the probability of 
terminating the study in the presence of a no or a nonmeaningful drug effect. Assuming no 
treatment effect for both doses results in a 40.2% probability of terminating the study at the 
futility IA and assuming a 1-point treatment effect for both doses (thought to not be clinically 
meaningful), results in a 29.2% probability of terminating the study at the futility IA.
9.8
Multiplicity
Since there are 2 active doses (MK-8189 16 mg and MK-8189 24 mg) and 4 endpoints
(PANSS vs. Placebo at Week 6, PANSS-PSS vs. Placebo at Week 6, CGI-S vs. Placebo at 
Week 6, Weight vs. Risperidone at Week 12) on which strong control is desired, there are 8
total hypotheses on which strong Type 1 error control must be maintained at a familywise 
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α=0.05 level. This control will be achieved by utilizing a Bonferroni approach in conjunction 
with a closed testing sequential approach. Specifically, a separate hypothesis family will be 
created for each of MK-8189 16 mg and MK-8189 24 mg. Each family will be comprised of 
4 hypotheses corresponding to the primary endpoint and the 3 key secondary endpoints. 
Using a Bonferroni approach, each family will be tested independently at the α=0.025 level
(two-sided).
Within each of the 2 dose families, the primary hypothesis will be tested at a two-sided 
 
 
 
 
Figure 2
Testing Strategy to Address Multiplicity  
CFB=change from baseline; CGI-S=Clinical Global Impression-Severity; PANSS=Positive and Negative Syndrome Scale; 
PANSS-PSS= PANSS Positive subscale; Pbo=placebo; RSP=risperidone
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9.9
Sample Size and Power Calculations
9.9.1
Efficacy Parameter Estimates
Parameter estimates and other required assumptions were primarily based on data from MK-
8189 P005, which featured a 4-week acute period and a 12-mg dose of MK-8189. Since the 
primary endpoints for the current study pertain to the 16-mg and 24-mg doses (at which 
efficacy higher than 12 mg is assumed) at Week 6 (at which efficacy higher than Week 4 is 
assumed), assumptions about the effect of dose and time were required. Details pertaining to 
the derivation of the parameter assumptions are in the sSAP. Table 11 displays the assumed 
Week 6 CFB treatment differences (MK-8189 – Placebo). This table also displays the 
assumed Week 6 CFB standard deviations. 
9.9.2
Efficacy Sample Size and Power Calculations
Sample size was determined based on the PANSS total score. Power was estimated via 
simulations which took the 1 planned futility IA into account, using a futility bound of 10%. 
Sample size was computed using the multiplicity approach outlined in Section 9.8 to have at 
least 90% power to reject the null hypothesis for at least 1 dose (MK-8189 16 mg or MK-
8189 24 mg). 
Table 12 provides the probability of declaring success on at least 1 dose (16 mg and/or 24 
mg) and at each dose separately for a variety of underlying assumptions with 128 randomized 
participants per arm. With 128 randomized participants per arm, there is approximately a 
91% probability of declaring success on PANSS total score for at least 1 dose under the 
primary assumptions.
All sample size and power calculations have been conducted assuming that 65% of 
randomized participants will have a Week 6 efficacy measurement.
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Using the assumptions provided in Table 11, marginal power calculations for the PANSS-
PSS and CGI-S were computed (not simulated) and are presented in Table 13. These 
marginal calculations do not incorporate the sequential nature of the multiplicity approach 
over the endpoints nor do they incorporate the potential futility analysis. 
In a similar fashion, marginal power calculations for weight were computed (not simulated) 
and are presented in Table 14. It is noted that power calculations are provided assuming 2 
different completer rates (65% and 50%), meant to approximate the percentage of completers 
at Week 6 and Week 12 respectively. It is also noted that the power calculation 
corresponding to the Week 12 completion rate was computed using a 2:1 sample size ratio 
(since risperidone is the comparator).
As noted in Figure 2, testing will only proceed to the respective key secondary hypotheses if 
all null hypotheses preceding the given hypotheses are successfully rejected. Therefore, the 
actual probabilities corresponding to the key secondary hypotheses are lower than the 
corresponding presented marginal probabilities.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect (with a nominal 95% CI) for the primary endpoint (PANSS 
total score) and key secondary endpoints (PANSS-PS, CGI-S, and Weight) will be estimated 
and plotted within each category of each subgroup. The primary model will be used for all 
subgroup analyses, applied to the given subset of participants. It is noted that some of the 
covariates in the primary model may need to be removed either of necessity (eg, removing 
gender from the model when analyzing the male subgroup) or to facilitate convergence (in 
which case terms will be removed in the same order as that specified for the primary 
analysis). Confidence intervals will only be produced if both treatment arms have at least 25 
participants (~ 20% of the total sample size per arm).
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In addition, a Forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant, the number tablets/capsules remaining in study packaging will be counted, 
reviewed, and recorded at regular intervals. Study intervention records will be used to 
calculate participant compliance.
A day within the study will be considered an “On-Therapy” day if the participant takes the 
required number of tablets/capsules of each type as noted in Section 6.6. It is noted that a 
participant will be considered as “On Therapy” for a given day if they took the correct 
number of tablets/capsules, even if the tablets/capsules taken were intended for a different 
study day (eg, during 1 of the titration weeks). Therefore, it is possible for a participant to be 
considered as “On Therapy” for a given day, even if the participant mistakenly took incorrect 
study intervention on that day. 
For a participant who is followed for the entire study period, the “Number of Days Should be 
On Therapy” is the total number of days from randomization to the last day of treatment 
administration for that participant. For a participant who discontinued from the study 
permanently, the “Number of Days Should be On Therapy” is the total number of days from 
randomization to the date of the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the APaT 
population.
9.12
Extent of Exposure
The extent of exposure to study intervention will be evaluated by summary and cumulative 
frequencies by treatment group or treatment sequence.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
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clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
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10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
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.
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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.
10.1.10
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 15 will be performed by the central laboratory.
Use of local vs. central laboratory test results:

If a local sample is required for timely decision-making, then a sample for central 
analysis should be obtained at the same time. Local laboratory results should be 
entered into the relevant CRF if a central result is not available.

In the event of unforeseen issues leading to delayed or missing screening laboratory 
samples, duplicate laboratory specimens may be collected, with 1 specimen being 
sent to the local laboratory for immediate analysis of all screening parameters and the 
other processed at the central laboratory. The local laboratory results will be used as a 
guide to determine participant eligibility. 

At any time during the study, if the investigator determines that immediate local 
laboratory results for protocol-specified parameters are needed to further evaluate the 
participant’s condition, a duplicate set of sample(s) should be collected and sent to the 
central laboratory.
Screening/Baseline laboratory notes:

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5.1 and 5.2 of the protocol.

Screening laboratory tests are not to be repeated if the initial tests results meet the 
exclusionary criteria. For example, if the screening eGFR is <50 mL/min/1.73m2
(CKD-EPI formula), the laboratory test is not repeated, and participant is a screen 
failure.

If screening insulin values are still pending at time of the planned baseline visit, and 
the investigator considers the pending insulin value unnecessary to judge participant 
eligibility, the investigator may go forward with the baseline visit and potential 
randomization with insulin values pending.

Fasting blood draws at screening are encouraged.
Additional notes:

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

It is anticipated that laboratory blood samples should be obtained fasting while the 
participant is an inpatient. For outpatients, they will be instructed and encouraged to 
fast overnight before clinical laboratory sample collection. Note that it is recognized 
that samples may be collected in a nonfasting state. The self-reported 
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fasting/nonfasting state of the participant will be noted on the laboratory requisition 
form (ie, no food or drink other than water ≥10 hours is considered fasting).

In the event of a positive or ambiguous urine test for pregnancy, refer to Sections 10.5 
and 7.1. 

Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.

A participant must be discontinued if the participant has a persistent eGFR of <40
mL/min/1.73m2 as measured by CKD-EPI formula (see Section 7.1). eGFR of <40 
mL/min/1.73m2 is considered persistent if the values are met for 2 consecutive blood 
draws at 2-week intervals. If an eGFR of <40 mL/min/1.73m2 is met at the baseline 
visit (V2), an unscheduled blood sample should be collected at Visit 4 and sent to 
central laboratory for analysis.

Prolactin values are masked post baseline. The investigator will be alerted by the 
central laboratory if a postbaseline value is >10X ULN. If the investigator finds it 
necessary to unmask a prolactin value to understand an AE (ie, those potentially 
associated with prolactin dysregulation), the investigator may contact central 
laboratory to be provided with prolactin value. Requests for actual prolactin values 
are to be recorded in the source documents. 

Prolactin levels are not to be determined by local laboratory testing. The prohibition
in local prolactin level testing is in place until the follow-up period is completed.

Note: follow-up visits will run concurrently with routine scheduled visits if 
participants continue with study visits after last dose (see Section 8.10.3). The 
prohibition in local prolactin level testing is lifted after the participant completes the 
follow-up period.
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Table 15
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet Count 
White blood cell (WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen (BUN)
Potassium
Sodium
Chloride
Bicarbonate
Creatinine
eGFR (CKD-EPI formula)
Phosphorous
Magnesium 
Calcium
Creatine Phosphokinase (CK)
AST/SGOT
ALT/SGPT
Albumin
Total protein
Alkaline phosphatase
Lactate 
Dehydrogenase
Total bilirubin 
Direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of normal
Glucose (fasting)
•
Lipid Panel:
Total cholesterol
High Density 
Lipoproteins
•
(HDL)
Low Density 
Lipoproteins
(LDL)
Triglycerides
•
Insulin 
Prolactin 
(postbaseline results 
to be masked)
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood (RBC count), ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick
•
Microscopic examination (if macroscopic examination is abnormal, i.e., 
blood or protein is abnormal), includes casts, crystals, epithelial cells, RBC, 
WBC
•
Albumin to creatinine ratio
Other Screening Tests
•
FSH (as needed in women of nonchildbearing potential only)
•
Highly sensitive serum or urine β-human chorionic gonadotropin
•
(hCG) pregnancy test (as needed for WOCBP)
•
HbA1c
•
TSH
•
Free Thyroxine (T4) (if reflex Thyroid-stimulating hormone [TSH] is abnormal)
•
Urine alcohol and drug screen includes:
•
Amphetamines
•
Barbiturates  
•
Benzodiazepines (Urine)
•
Cannabinoids  
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Laboratory Assessments
Parameters
•
Cocaine Metabolites  
•
Methadone 
•
Opiates  
•
Phencyclidine 
•
Propoxyphene
•
Separate test for ETG/alcohol run centrally.
•
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C 
virus [HCV] antibody) 

Serologies are at the discretion of the investigator
10.2.1
Alcohol and Drug Screen
Provided there is no exclusionary evidence of moderate to severe substance use disorder 
(Section 5.2), a positive finding of alcohol, cannabinoid drugs, or prohibited psychotropic 
medications at screening will not necessarily exclude the participant from the study.
However, the investigator should interview the participant and ensure that the participant
understands that they must refrain from using cannabinoid drugs and prohibited psychotropic 
medications throughout the study. Alcohol use during the study should also be discouraged. 
This discussion must be noted in the source documents or on the laboratory report. The 
investigator may enroll the participant if they feel confident that the participant will comply 
with instructions. Additional tests may be scheduled postscreening at the discretion of the 
investigator. If a participant is considered to be under the influence of illegal drugs or is 
believed to have taken a prohibited psychoactive drug, or if they meet the DSM-5™criteria 
for substance use disorder (excluding nicotine) within a 1-week period, the investigator may 
consider the participant for discontinuation.
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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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
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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 
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.
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Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
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◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE
and document this in the medical notes.
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
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).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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 follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with 2 FSH measurements 
in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:

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 2
FSH measurements in the postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive 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 subdermal contraceptive implantc,d
IUSc,e
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
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   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  abstinence (any method), withdrawal (coitus interruptus), Periodic spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
After the initiation of treatment, additional pregnancy testing will be performed according to 
the SoA, and as required locally.
Additional pregnancy testing will be performed whenever an expected menstrual cycle is 
missed or when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AAPs
atypical antipsychotics
AE
adverse event 
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
all participants as treated
AST
aspartate aminotransferase
AUC
area under the curve
BARS
Barnes Akathisia Rating Scale
BMI
body mass index
BPCP 
Bayesian predictive conditional probability 
C24
plasma concentration at 24 hours
CAC
Clinical Adjudication Committee
cAMP
cyclic adenosine monophosphate
CFB
change from baseline
CGI-S
Clinical Global Impression-Severity of Illness
cGMP
cyclic guanosine monophosphate
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
Cmax
maximum plasma concentration
CNS
central nervous system 
CRF
Case Report Form 
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale 
CTFG
Clinical Trial Facilitation Group 
C-VISA™
Clinical Validation Inventory for Study Admission
CYP
Cytochrome P450
088GYV
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PRODUCT: MK-8189
144
PROTOCOL/AMENDMENT NO.: 008-05
MK-8189-008-05 FINAL PROTOCOL
16-MAR-2023
Abbreviation
Expanded Term
DC
discontinuation; visit when participant discontinues from the study after 
end of treatment
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DSM-5™
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECT
electroconvulsive therapy
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EO
enzyme occupancy
EOC
Executive Oversight Committee 
EOT
end of treatment; visit when participant discontinues from study 
intervention 
EPS
extrapyramidal symptoms
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
HbA1c
Hemoglobin A1C
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
088GYV
08TZTT


PRODUCT: MK-8189
145
PROTOCOL/AMENDMENT NO.: 008-05
MK-8189-008-05 FINAL PROTOCOL
16-MAR-2023
Abbreviation
Expanded Term
ICF
informed consent form 
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
identification
IEC
Independent Ethics Committee
IND
investigational new drug 
IRB
Institutional Review Board 
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
Lactational Amenorrhea Method
LDL
low density lipoprotein
LFT
liver function test
LOCF
Last Observation Carried Forward
MAD
multiple ascending dose
MAO
monoamine oxidase
MINI
Mini International Neuropsychiatric Interview for Schizophrenia and 
Psychotic Disorders
NDA
New Drug Application 
PANSS
Positive and Negative Syndrome Scale
PANSS-GSS
PANSS General Psychopathology subscale
PANSS-NSS
PANSS Negative subscale
PANSS-PSS
PANSS Positive subscale
PCL 
Protocol Clarification Letter
PDE10A
phosphodiesterase 10A
PDLC
predefined limits of change
PET
positron emission tomography 
PI
primary investigator
PK
pharmacokinetic
POC
proof of concept
088GYV
08TZTT


PRODUCT: MK-8189
146
PROTOCOL/AMENDMENT NO.: 008-05
MK-8189-008-05 FINAL PROTOCOL
16-MAR-2023
Abbreviation
Expanded Term
PP
per protocol
PR
pulse rate
PSP
Personal and Social Performance Scale
qd
once a day
QRS
QRS complex
QTc
Heart rate-corrected QT interval 
QTcF
Fridericia formula
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAD
single ascending dose
SAE
serious adverse event 
SAS
Simpson Angus Extrapyramidal Side Effects Scale, Statistical Analysis 
System
SDE
Sponsor-designated expert; medically qualified Sponsor representative 
who consults with sites on protocol-specific activities, such as the 
review of the screening C-VISA™ and PANSS to verify participant 
eligibility. An “external” SDE refers to a vendor SDE.
SLAB
Supplemental laboratory case report form
SoA
schedule of activities
SOP
standard operating procedure
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TC
telephone or virtual contact
TM
trademark
TSH
thyroid-stimulating hormone
UDS
urine drug screen
ULN
upper limit of normal
US
United States
V
visit
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential 
088GYV
08TZTT


PRODUCT: MK-8189
147
PROTOCOL/AMENDMENT NO.: 008-05
MK-8189-008-05 FINAL PROTOCOL
16-MAR-2023
11
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