Clinical trial NCT05893862
Conditions: Schizophrenia
Sponsor: Merck Sharp & Dohme LLC
Start date: 2023-06-26; Completion date: 2024-02-22
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary purpose of this study to evaluate the effect of a supratherapeutic dose of 80 mg MK-8189 on the QT interval corrected for heart rate (QTc interval) and to assess the safety and tolerability of multiple once-daily doses of MK-8189 in participants with schizophrenia. The effects of 3 treatment sequences 1) MK-8189 (48 mg \[Day 1\] and 80 mg \[Day2\]); 2) standard image placebo (Day 1) and moxifloxacin 400 mg (Day 2); and 3) MK-8189 placebo (Day 1 and Day 2) were assessed with 5-day washout intervening sequence. Participants received all treatments in a counter-balanced order according to 1 of 6 possible treatment sequences.

The primary hypothesis is that the administration of an 80 mg MK-8189 dose on Day 2 does not prolong the QTc interval to a clinically significant degree. Specifically, the true mean difference (MK-8189 - placebo) in QTc change from baseline is less than 10 milliseconds (msec).

Detailed description:

Arms: arm 1: Participants receive a sequence of Treatment A in Period 1 followed by Treatment B in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. arm 2: Participants receive a sequence of Treatment B in Period 1 followed by Treatment C in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. arm 3: Participants receive a sequence of Treatment C in Period 1 followed by Treatment A in in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. arm 4: Participants receive a sequence of Treatment B in Period 1 followed by Treatment A in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. arm 5: Participants receive a sequence of Treatment A in Period 1 followed by Treatment C in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. arm 6: Participants receive a sequence of Treatment C in Period 1 followed by Treatment B in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2.
Interventions: intervention 1: MK-8189 intervention 2: Moxifloxacin intervention 3: Placebo
Intervention descriptions: intervention 1: Oral Tablet intervention 2: Oral Tablet intervention 3: Oral Tablet

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT05893862
Document Date:           16-Aug-2023
A Double-Blind, Cross-Over Placebo-Controlled 
and Active-Controlled Trial To Evaluate The 
Effect Of A Supratherapeutic Dose Of MK-8189 
On The QTc Interval In Participants With 
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 Double-Blind, Cross-Over Placebo-Controlled and Active-Controlled Trial 
To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In 
Participants With Schizophrenia
Protocol Number: 019-02
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
NA
EU CT
NA
EudraCT
NA
JAPIC-CT
NA
WHO
NA
UTN
NA
IND
118,986
Approval Date: 16 August 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 2
16-AUG-2023
Clarified predose hCG pregnancy testing
Amendment 1
03-MAY-2022
Increased sample size from 54 to 84
Original Protocol
03-MAR-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
Clarification of predose hCG pregnancy testing for consistency with inclusion criteria #14. A 
previous PCL incorrectly clarified the hCG timepoints.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.3 
Schedule of 
Activities
hCG pregnancy test moved from Day -2 to 
Day -1 and note updated to be consistent with
inclusion criteria #14.
This change corrects a previous PCL error and 
ensures predose hCG pregnancy testing is 
obtained within 24 (urine) or 72 (serum) hours 
predose per inclusion criteria #14.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.3, 
Schedule of 
Activities
Blood for Plasma MK-8189 – added Days 3, 4, 
and 5 timepoints
Protocol inconsistency. Footnote ‘k’ indicated 
blood collection through 72 hours (Day 5).
Section 1.3, 
Schedule of 
Activities
Blood for Plasma Moxifloxacin – added Days 3, 
4, and 5 timepoints
Protocol inconsistency. Footnote ‘l’ indicated 
blood collections through 72 hours (Day 5).
Section 1.3, 
Schedule of 
Activities
Randomization number assignment updated 
from Day -1 to Day 1
This represents the day the participant is deemed 
eligible to receive the first dose of study 
intervention and will occur prior to dosing on 
Period 1 Day 1. 
Section 1.3, 
Schedule of 
Activities
UDS was added to Day -6 and note was updated 
to provide additional clarification of UDS 
predose testing.
Predose UDS will be done at the time of 
admission to the clinic (Day -6 or Day -2).
Section 1.3, 
Schedule of 
Activities
24-Hour Holter ECG Extraction on Day 4 was 
removed. 
Protocol inconsistency. Footnote ‘e’ indicated 
Holter ECG extractions through Day 2 24 hours 
(Day 3). No extractions will occur on Day 4.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.3, 
Schedule of 
Activities
Footnote ‘i’ was updated to clearly indicate 
triplicate HR measurements are required at all 
timepoints, including screening and poststudy, 
and at the timepoints indicated on specific days.
Additional clarification provides consistency 
with Section 8.3.2.1 of the protocol that more 
clearly specifies the triplicate HR measurements.
Section 1.3, 
Schedule of 
Activities
In footnote ‘k’, the bullet “Leftover main study 
plasma will be stored for future biomedical 
research’ was removed.
In amendment (01), storage of leftover main 
study plasma was clarified to indicate for main 
study use and FBR as previously indicated in 
Section 8.9. The footnote should have been 
removed in the protocol amendment.
Section 1.3, 
Schedule of 
Activities
Visit window added for the poststudy visit
(column heading)
To provide flexibility of +/- 2 days
Section 1.3, 
Schedule of 
Activities 
Section 4.1, 
Overall Design
The 5-day washout between periods was 
clarified as it is relative to the last dose of study 
medication (Day 2) in each period.
Washout is based on the terminal half-life of
both MK-8189 and moxifloxacin and the not the 
actual end of the period (Day 5)
Section 1.3, 
Schedule of 
Activities
Added text to footnote ‘c’ clarifying
participants not currently being treated with 
antipsychotic therapy will also remain 
domiciled through 72 hours post the last dose in 
Period 3.
Domiciling requirement for all participants is 
through 72 hours post the last dose in Period 3.
Section 5.2, 
Exclusion 
Criteria
EC 17 – removed 2 paragraphs referring to 
eGFR 
eGFR is not being used to calculate CrCl in the 
protocol
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................23
2.2.1
Pharmaceutical and Therapeutic Background .............................................23
2.2.2
Preclinical and Clinical Studies ...................................................................24
2.2.3
Ongoing Clinical Studies.............................................................................25
2.2.3.1
Protocol 010.......................................................................................25
2.2.3.2
Protocol 013.......................................................................................26
2.2.3.3
Protocol 014.......................................................................................28
2.2.3.4
Protocol 017.......................................................................................29
2.2.3.5
Protocol 008.......................................................................................30
2.2.4
Completed Clinical Studies..........................................................................30
2.2.4.1
Protocol 011.......................................................................................30
2.2.4.2
Protocol 012.......................................................................................36
2.2.4.3
Protocol 016.......................................................................................36
2.2.5
Information on Other Study-related Therapy ..............................................39
2.3
Benefit/Risk Assessment......................................................................................40
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................43
4.1
Overall Design......................................................................................................43
4.2
Scientific Rationale for Study Design.................................................................44
4.2.1
Rationale for Endpoints ...............................................................................45
4.2.1.1
Efficacy Endpoints.............................................................................45
4.2.1.2
Safety Endpoints................................................................................45
4.2.1.3
Pharmacokinetic Endpoints ...............................................................46
4.2.1.4
Pharmacodynamic Endpoints.............................................................46
4.2.1.5
Planned Exploratory Biomarker Research.........................................46
4.2.1.5.1
Planned Genetic Analysis ........................................................46
4.2.1.6
Future Biomedical Research..............................................................47
4.2.2
Rationale for the Use of Comparator/Placebo .............................................47
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................48
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4.3
Justification for Dose...........................................................................................48
4.3.1
Starting Dose for This Study........................................................................48
4.3.2
Maximum Dose Exposure for This Study ...................................................48
4.3.3
Rationale for Dose Interval and Study Design ............................................51
4.4
Beginning and End-of-Study Definition ............................................................52
4.4.1
Clinical Criteria for Early Study Termination .............................................52
5
STUDY POPULATION ................................................................................................53
5.1
Inclusion Criteria.................................................................................................53
5.2
Exclusion Criteria................................................................................................55
5.3
Lifestyle Considerations......................................................................................58
5.3.1
Meals and Dietary Restrictions....................................................................58
5.3.1.1
Diet Restrictions.................................................................................58
5.3.1.2
Fruit Juice Restrictions ......................................................................59
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................59
5.3.2.1
Caffeine Restrictions..........................................................................59
5.3.2.2
Alcohol Restrictions...........................................................................59
5.3.2.3
Tobacco Restrictions..........................................................................60
5.3.3
Activity Restrictions ....................................................................................60
5.4
Screen Failures.....................................................................................................60
5.5
Participant Replacement Strategy......................................................................60
6
STUDY INTERVENTION............................................................................................61
6.1
Study Intervention(s) Administered...................................................................61
6.2
Preparation/Handling/Storage/Accountability .................................................63
6.2.1
Dose Preparation..........................................................................................63
6.2.2
Handling, Storage, and Accountability........................................................63
6.3
Measures to Minimize Bias: Randomization and Blinding..............................64
6.3.1
Intervention Assignment..............................................................................64
6.3.2
Stratification.................................................................................................64
6.3.3
Blinding........................................................................................................64
6.4
Study Intervention Compliance..........................................................................65
6.5
Concomitant Therapy..........................................................................................65
6.5.1
Rescue Medications and Supportive Care ...................................................66
6.6
Dose Modification (Escalation/Titration/Other)...............................................67
6.7
Intervention After the End of the Study............................................................67
6.8
Clinical Supplies Disclosure................................................................................67
6.9
Standard Policies..................................................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................68
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7.1
Discontinuation of Study Intervention...............................................................68
7.2
Participant Withdrawal From the Study...........................................................69
7.3
Lost to Follow-up .................................................................................................69
8
STUDY ASSESSMENTS AND PROCEDURES........................................................70
8.1
Administrative and General Procedures ...........................................................70
8.1.1
Informed Consent.........................................................................................70
8.1.1.1
General Informed Consent.................................................................71
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................71
8.1.2
Inclusion/Exclusion Criteria ........................................................................71
8.1.3
Participant Identification Card.....................................................................71
8.1.4
Medical History ...........................................................................................72
8.1.5
Prior and Concomitant Medications Review...............................................72
8.1.5.1
Prior Medications...............................................................................72
8.1.5.2
Concomitant Medications..................................................................72
8.1.6
Assignment of Screening Number...............................................................72
8.1.7
Assignment of Treatment/Randomization Number.....................................73
8.1.8
Study Intervention Administration ..............................................................73
8.1.8.1
Timing of Dose Administration.........................................................73
8.1.9
Discontinuation and Withdrawal .................................................................73
8.1.9.1
Withdrawal From Future Biomedical Research ................................73
8.1.10
Participant Blinding/Unblinding..................................................................74
8.1.11
Domiciling ...................................................................................................74
8.1.12
Calibration of Equipment.............................................................................75
8.2
Efficacy Assessments ...........................................................................................75
8.3
Safety Assessments...............................................................................................75
8.3.1
Physical Examinations.................................................................................75
8.3.2
Vital Signs....................................................................................................76
8.3.2.1
Resting Vital Signs ............................................................................76
8.3.2.2
Orthostatic Vital Signs.......................................................................76
8.3.3
Electrocardiograms ......................................................................................76
8.3.4
Clinical Safety Laboratory Assessments .....................................................78
8.3.5
Pregnancy Testing........................................................................................79
8.3.6
Suicidal Ideation and Behavior Monitoring.................................................79
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................79
8.3.7
Rater Expectations and Training for Clinical and Cognitive 
Assessments.................................................................................................80
8.3.8
Monitoring of Extrapyramidal Symptoms...................................................80
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8.3.9
Assessment of Neuropsychological Effects.................................................80
8.3.10
Photograph of Rash......................................................................................80
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................80
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................81
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......83
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...83
8.4.4
Regulatory Reporting Requirements for SAE .............................................83
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................84
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................84
8.4.7
Events of Clinical Interest............................................................................84
8.5
Treatment of Overdose........................................................................................85
8.6
Pharmacokinetics.................................................................................................85
8.6.1
Blood Collection for Plasma MK-8189 and Moxifloxacin..........................85
8.7
Pharmacodynamics..............................................................................................85
8.8
Biomarkers ...........................................................................................................86
8.8.1
Planned Genetic Analysis Sample Collection..............................................86
8.9
Future Biomedical Research Sample Collection...............................................86
8.10
Visit Requirements...............................................................................................86
8.10.1
Screening......................................................................................................86
8.10.2
Treatment Period..........................................................................................87
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................87
8.10.4
Poststudy......................................................................................................87
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......87
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................88
9
KEY STATISTICAL CONSIDERATIONS ...............................................................90
9.1
Hypotheses/Estimation ........................................................................................90
9.2
Analysis Endpoints...............................................................................................90
9.2.1
Cardiodynamics ...........................................................................................90
9.2.2
Pharmacokinetic Endpoints .........................................................................92
9.2.3
Safety Endpoints..........................................................................................93
9.3
Analysis Populations............................................................................................93
9.3.1
Safety Analysis Populations ........................................................................93
9.4
Statistical Methods...............................................................................................93
9.4.1
Statistical Methods for Cardiodynamics Analyses ......................................93
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9.4.1.1
Adequacy of QT Correction Method.................................................94
9.4.1.2
Primary Analysis................................................................................94
9.4.1.3
Sensitivity Analysis ...........................................................................96
9.4.1.4
C-QTc Analysis for MK-8189...........................................................97
9.4.1.5
Exploratory Analyses – Other..........................................................100
9.4.1.6
Categorical Analysis of QTc............................................................100
9.4.2
Statistical Methods for Pharmacokinetics and Safety Analyses................100
9.5
Interim Analyses ................................................................................................101
9.6
Multiplicity .........................................................................................................101
9.7
Sample Size and Power Calculations ...............................................................101
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................102
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......102
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................102
10.1.2
Financial Disclosure...................................................................................105
10.1.3
Data Protection...........................................................................................106
10.1.3.1
Confidentiality of Data ....................................................................106
10.1.3.2
Confidentiality of Participant Records.............................................106
10.1.3.3
Confidentiality of IRB/IEC Information..........................................107
10.1.4
Publication Policy......................................................................................107
10.1.5
Compliance with Study Registration and Results Posting Requirements .107
10.1.6
Compliance with Law, Audit, and Debarment ..........................................108
10.1.7
Data Quality Assurance .............................................................................108
10.1.8
Source Documents .....................................................................................109
10.1.9
Study and Site Closure...............................................................................110
10.2
Appendix 2: Clinical Laboratory Tests............................................................111
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................112
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................112
10.3.2
Definition of AE ........................................................................................112
10.3.3
Definition of SAE ......................................................................................113
10.3.4
Additional Events Reported.......................................................................114
10.3.5
Recording AE and SAE .............................................................................114
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................117
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................119
10.5
Appendix 5: Contraceptive Guidance..............................................................120
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10.5.1
Definitions..................................................................................................120
10.5.2
Contraceptive Requirements......................................................................121
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................122
10.7
Appendix 7: Country-specific Requirements..................................................126
10.8
Appendix 8: Blood Volume Table ....................................................................127
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................128
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...130
10.11 Appendix 11: General and Targeted Neurological Examinations ................131
10.11.1
The General Neurological Examination ....................................................131
10.11.1.1
Module 1 – Mental Status Examination...........................................131
10.11.1.2
Module 2 – Cranial Nerve Assessment............................................131
10.11.1.3
Module 3 – Motor System ...............................................................132
10.11.1.4
Module 4 – Reflexes ........................................................................133
10.11.1.5
Module 5 – Coordination and Gait ..................................................133
10.11.1.6
Module 6 – Sensory .........................................................................134
10.11.2
The Targeted Neurological Examination...................................................134
10.11.2.1
Module 1 – Mental Status Examination...........................................134
10.11.2.2
Module 2 – Cranial Nerve Assessment............................................134
10.11.2.3
Module 3 – Motor System ...............................................................135
10.11.2.4
Module 5 – Coordination and Gait ..................................................135
10.11.2.5
Module 6 – Sensory .........................................................................135
10.12 Appendix 12: Abbreviations .............................................................................136
11
REFERENCES.............................................................................................................141
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LIST OF TABLES
Table 1
Study Interventions.......................................................................................62
Table 2
Sample Allocation Schedule.........................................................................64
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events..............................................................................82
Table 4
Protocol-required Safety Laboratory Assessments.....................................111
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LIST OF FIGURES
Figure 1
Study Schema................................................................................................16
Figure 2
Predicted Mean ΔΔQTcF Versus the Observed Geometric Mean Cmax 
for Each Dose Level Along With 90% Confidence Band ............................51
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Double-Blind, Cross-Over Placebo-Controlled and Active-Controlled Trial 
To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In 
Participants With Schizophrenia
Short Title: MK-8189 Thorough QT Study in Participants with Schizophrenia
Acronym: TQT
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants with schizophrenia.
Primary Objective
Primary Endpoint
To evaluate the effect of a supratherapeutic 
dose of 80-mg MK-8189 on the QTc 
interval
Hypothesis: Administration of an 80-mg 
MK-8189 dose on Day 2 does not prolong 
the QTc interval to a clinically significant 
degree. Specifically, the true mean 
difference (MK-8189 - placebo) in QTc 
change from baseline is less than 10 msec
QTc (QT interval corrected for heart rate) 
change from baseline at post dose time 
points
To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-8189 
in participants with schizophrenia
Adverse events leading to discontinuation 
of study intervention
Adverse events
Secondary Objectives
Secondary Endpoints
To evaluate the effect of moxifloxacin on 
the QTc interval 
Hypothesis: Administration of a single 
400-mg dose of moxifloxacin is associated 
with an increase in QTc interval. 
Specifically, the true mean difference 
(Moxifloxacin-placebo) in QTc change 
from baseline is greater than 5 msec at least 
at one time point
QTc (QT interval corrected for heart rate) 
change from baseline at post dose time 
points
To estimate the pharmacokinetics of 
MK-8189 following multiple doses of 
MK-8189 in participants with schizophrenia
AUC0-24, AUC0-last, Cmax, C24, Tmax, 
t1/2 of MK-8189
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Schizophrenia
Population
Participants with schizophrenia or 
schizoaffective disorder
Study Type
Interventional
Intervention Model
Cross-Over
This is a multi site study
Type of Control
Placebo
Active Control
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects, Investigator, 
Monitor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 8 months 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 84 participants with schizophrenia will be allocated/randomized to 1 of 6
treatment sequences, such that approximately 10 to 14 participants are evaluable and 
complete the study in each treatment sequence as described in Section 9.
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Intervention Groups and Duration:
Arm 
Name
Intervention Name
Unit Dose Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Sequences 
1 to 6
MK-8189
12 mg
48 mg
Oral
Treatment A 
Day 1
Test 
Product
Sequences 
1 to 6
MK-8189
12 mg
4 mg
80 mg
Oral
Treatment A 
Day 2
Test 
Product
Sequences 
1 to 6
Moxifloxacin
400 mg
400 mg
Oral
Treatment B 
Day 2
Diagnostic 
– to assess 
endpoints
Sequences 
1 to 6
MK-8189 Matched 
Placebo
0 mg
0 mg
Oral
Treatment C 
Days 1-2
Placebo
Sequences 
1 to 6
Standard image 
placebo
0 mg
0 mg
Oral
Treatment B 
Day 1
Placebo
Total Number of Intervention Groups/Arms
4
Duration of Participation
Each participant will participate in the study 
for approximately 11 weeks from the time 
the participant provides documented 
informed consent through the final contact.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical and study governance 
considerations are outlined in Appendix 1.
Study accepts healthy participants: 
No
A list of abbreviations is in Appendix 12.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
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1.3
Schedule of Activities
All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
Administrative/Study Procedures
Informed Consent
X
Section 5.1, 8.1.1.1
Informed Consent for FBR
X
Section 5.1, 8.1.1.2
Participant ID Card
X
Section 8.1.3
Inclusion/Exclusion Criteria
X
X
Specific criteria may be reviewed before 
randomization in Period 1
Section 5.1 & Section 5.2
Medical History (includes 
psychiatric history and substance 
abuse)
X
Substances: Drugs, alcohol, tobacco, and 
caffeine
Prior/Concomitant Medication 
Review
X----------------------------------------------------------------------------X
Section 5.2, 6.5, 8.1.5
Assignment of Screening 
Number
X
Section 8.1.6
Washout from current 
antipsychotics therapy
X
Medication discontinued at least 5 days or at 
least 3 half-lives (whichever is longer) prior to 
Day -1
Section 8.1.5.1
Assignment of Randomization 
Number
X
Period 1 only
Section 5.5, 8.1.7
Study Medication 
Administration/Dispensing
X
X
Section 4.1
Standard Mealsb
X------------------------------------------------X
Section 5.3.1
Domicilingc
X------------------------------------------------X
Section 8.1.11
Follow Up Phone call – Period 3 
only
X
Should occur 5-7 days after discharge
Section 8.10.2
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All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
Safety Procedures
Full physical examination
X
X
X
X
Day -1: Period 1 only
Day 5: Period 3 only 
Section 8.3.1
Height
X
Weight
X
X
X
X
BMI to be taken only at Screening
Full Neurological Examination
X
X
Performed at Screening and 
Day -1: Period 1 only 
Section 10.11
Targeted Neurological 
Examinationd
X
X
X
X
X
X
X
Day -1: Period 2 and Period 3 only
Day 5: Period 3 only
All other intervention days: Up to 3 hours 
predose
Section 10.11
Vital Signs (heart rate, blood 
pressure)e
X
X
X
X
X
X
X
X
Period 1 Day -1: may be done on Day -2 
Section 8.3.2
Orthostatic Vital Signs (heart 
rate, blood pressure) f
X
X
X
X
X
X
X
Period 1 Day -1: may be done on Day -2
Section 8.3.2
Vital Signs (respiratory rate, 
temperature) e
X
X
Xg
Xg
Xg
Xg
Xg
X
Period 1 Day -1: may be done on Day -2
Section 8.3.2
12-lead Safety ECGh
X
X
X
X
X
X
X
X
Period 1 Day -1: may be done on Day -2
Section 8.3.3
24-Holter ECG Extractioni
X
X
X
X
Section 8.3.3
Serum hCG (as needed in 
POCBP only)
X
X
Section 5.1 & Section 8.3.5
Urine or Serum hCG (as needed 
in POCBP only)
X
Predose hCG testing should be per IC #14.
Sections 5.1, 8.3.5, & 10.2
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All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
Serum FSH - (PONCBP only)
X
Postmenopausal participants only
Section 10.2
HIV, Hepatitis B and C screen 
(per site SOP)
X
Section 10.2
UDS/BDS (per site SOP)
X
X
X
To be completed once upon admission (Day -6 
or Day -2)
Additional UDS/BDS are conducted per site 
SOP
Laboratory Safety Tests 
(hematology, chemistry, 
urinalysis)
X
X
X
X
Period 1 Day -1: up to 72h prior to dosing.  
Per I/E, results must be reviewed prior to Period 
1 dosing.  In Periods 2 and 3, results are not 
required to be reviewed prior to dosing.
Day 5: Period 3 only
Section 10.2
AE/SAE review
X----------------------------------------------------------------------------X
BPRSd
X
X
X
The assessment can be done at any time during 
the day however an attempt should be made for 
consistent timing across days and periods.
Day 5: Period 3 only
Section 8.3.9
C-SSRS Baseline Version
X
Section 8.3.6.1
C-SSRS Since Last Assessment 
Versiond
X
X
X
X
X
Up to 3 hours predose
Section 8.3.6.1
Barnes Akathisia Rating Scale 
(BARS) j
X
X
X
X
The assessment can be done at any time during 
the day however an attempt should be made for 
consistent timing across days and periods.
Day 5: Period 3 only
Section 8.3.7
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All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
Abnormal Involuntary 
Movement Scale (AIMS) j
X
X
X
X
The assessment can be done at any time during 
the day however an attempt should be made for 
consistent times across days and periods.
Day 5: Period 3 only
Section 8.3.7
Simpson Angus Scale (SAS) j
X
X
X
X
The assessment can be done at any time during 
the day however an attempt should be made for 
consistent times across days and periods.
Day 5: Period 3 only
Section 8.3.7
Pharmacokinetics
Blood for Plasma MK-8189 
and/or Metabolites Assayk
X
X
X
X
X
Sample to be collected within 10 minutes of end 
of ECG extraction window. Plasma for MK-
8189 will be collected in Treatment A & C 
Periods Days 1 and 2
Blood for Plasma Moxifloxacin 
Assayl
X
X
X
X
Sample to be collected within 10 minutes of end 
of ECG extraction window. Plasma for 
moxifloxacin will be collected in Treatment B 
Period Day 2 only
Section 8.6.1
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All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
Biomarkers
Blood for Genetic Analysis
X
Period 1 only
Collect predose from enrolled participants only
Section 8.8
AE=adverse event; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BDS=blood drug screen; BP=blood pressure; BPRS=Brief 
Psychiatric Rating Scale; C-SSRS=Columbia Suicide Severity Rating Scale; CRU=clinical research unit; DNA=deoxyribonucleic acid; ECG=electrocardiogram; FBR=future 
biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HR=heart rate; ID=identification; 
PK=pharmacokinetic; SAE=serious adverse event; SAS=Simpson Angus Scale; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs; 
POCBP=participant of childbearing potential; PONCBP=participant of non-childbearing potential.
a.
There will be a 5-day washout between Periods 1 and 2 & 2 and 3. The 5-day washout between periods is relative to the last dose of study medication (Day 2) in each 
period. 
b.
Meals should be given at approximately the same time every day starting from time of domiciling through last dose including breakfast will be given at ~1-hour postdose, 
lunch at ~4-hour postdose; a snack at ~6-hour postdose and dinner at ~9-hour postdose. On non-dosing days, meals will be time-matched to mealtimes on dosing days. It is 
important that meal timing is standardized relative to Holter ECG extractions. If a mealtime and Holter ECG extraction/PK assessment coincide, the Holter ECG extraction 
will be conducted prior to the meal.
c.
Participants currently treated with antipsychotic therapy will be domiciled from Day -6 prior to Period 1 (to start washout period) and will remain in the CRU until 72 hours 
post the last dose in Period 3. Participants not currently being treated with antipsychotic therapy may be domiciled minimally starting on Day -2 through 72 hours post the 
last dose in Period 3. Participants may stay longer at PIs discretion.
d.
During the intervention period on days when a dose is not given, assessment should be time-matched to the predose or postdose time point. Poststudy assessments are not 
required to be time-matched.
e.
All HR measurements will be in triplicate. VS (HR, BP and RR) - On the following days, specific timepoints are noted:
• Day -1: time-matched to predose and 9 hours postdose. BP will also be taken in triplicate at both timepoints.
• Days 1 & 2: 9 hours postdose. 
• Days 3 & 4: time-matched to predose and 9 hours postdose
• Day 5: time-matched to predose
Temperature will only be taken on Day -1 time-matched to 9 hours postdose.
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All Sequences
Prior to Period 1
All Periodsa
After 
Period 3
Study Period:
Screening
Washout 
Check-In
Pre-
dose
Intervention
Poststudy
Notes
Scheduled Day:
Up to -42
-6
-2
-1
1
2
3
4
5
+14 post last 
dose (+/-2)
f.
Orthostatic VS (HR, BP) - On the following days, specific timepoints are noted:
• Day -1: time-matched to predose and 9 hours postdose
• Days 1 & 2: 9 hours postdose
• Days 3 & 4: time-matched to predose and 9 hours postdose
• Day 5: time-matched to predose
g.
Respiratory rate only
h.
12-Lead safety ECG measurements - On the following days, specific timepoints are noted:
• Day -1: Triplicate measurements, time-matched to 9 hours postdose
• Days 1 & 2: 9 hours postdose
• Days 3 & 4: time-matched to 9 hours postdose 
• Day 5 (Period 3 only): Upon discharge from the clinic
i.
Continuous Holter ECG measurements will be performed on Day -1 (Period 1 only) for approximately 24 hours.  No rest or extraction times are specified. Moderate 
ambulation and physical activity are encouraged to show a range of heart rate on Day -1 of Period 1 only.
In each Period, continuous 24-hour Holter ECG measurement will be performed from approximately 70 minutes prior to first dose administration and until 24 hours post
last dose administration. Replicate 12-lead Holter ECG recordings will be extracted over a 5-minute interval following 15 minutes of rest.
• Day 1: Predose (-50 min, -30 min, -10 min), 0.5, 1, 2, 3, 4, 6, 8, 12, 14 hours postdose
• Day 2: Predose, 1, 2, 3, 4, 8, 11, 14, 16, 24 hours postdose
j.
Additional BARS, AIMS, and SAS assessments should be conducted, as soon as reasonably possible, when there are observed or reported complaints of dystonia and/or 
akathisia
k.
PK for MK-8189 (Treatments A & C)
• Day 1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 14 hours postdose
• Day 2: Predose, 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, 72 hours postdose
l.
PK for Moxifloxacin:(Treatment B)
• Day 1: none
• Day 2: Predose, 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, 72 hours postdose
• Blood samples will be archived.
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2
INTRODUCTION
MK-8189 is a selective inhibitor of PDE10A that is in development for the treatment of 
schizophrenia.
2.1
Study Rationale
This study is being conducted to support efforts to de-risk the potential for MK-8189 to 
prolong QT as required by International Council for Harmonisation (ICH E14). The study 
will assess the potential effect of a supratherapeutic dose of MK-8189 on QTc prolongation 
in participants with schizophrenia in a randomized, double-blind (MK-8189 and placebo) 
placebo-controlled and active-controlled, crossover design. Participants will receive 
open-labeled moxifloxacin as an active control.
To appropriately interrogate the potential for a drug to prolong QT, a TQT study requires the 
administration of a supratherapeutic dose that is expected to cover the high clinical exposure 
scenario; this reflects the exposure of the drug when affected by the intrinsic or extrinsic 
factor that causes the greatest increase in plasma concentrations. Thus, this study will 
evaluate safety, tolerability, and PK of MK-8189 at a dose that will result in concentrations 
that are greater than those expected when MK-8189 is co-administered with a cytochrome 
P450 (CYP) 3A inhibitor 
 increase in maximum plasma concentration [Cmax], 
P006), the factor which is expected to cause the greatest increase in MK-8189 
concentrations.
 
 
2.2
Background
Refer to the Investigator’s Brochure (IB/approved labeling) for detailed background 
information on MK-8189.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8189 is a potent and selective inhibitor of PDE10A that is being developed as a novel 
therapeutic for the treatment of schizophrenia. The PDE10A enzyme metabolically 
inactivates the ubiquitous second messengers, cyclic adenosine monophosphate (cAMP) and 
cyclic guanosine monohydrate) (cGMP) [Bender, A. T. and Beavo, J. A. 2006] and is highly 
expressed in the target nucleus of the corticostriatal pathway, the striatum [Seeger, T. F., et al 
2003].
Preclinical pharmacology studies demonstrate that PDE10A inhibition increases cAMP/ 
cGMP signaling in pathways that have been associated with underlying pathology 
(glutamate) as well as clinically validated therapeutics (dopamine D2 receptor antagonists) 
for schizophrenia. Enhanced signaling in these pathways is hypothesized to restore 
behavioral inhibition that is impaired in schizophrenia [Grauer, S. M., et al 2009] [Schmidt, 
C. J., et al 2008]. PDE10A inhibitors may potentially be an alternative treatment as 
monotherapy and/or adjunct treatment in schizophrenia patients who have inadequate 
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response to first line atypical antipsychotic (AAP) or second-generation antipsychotic (SGA) 
treatment.
2.2.2
Preclinical and Clinical Studies
Preclinical and clinical study information can be found in the MK-8189 IB.
Summary of Completed Phase 1 Clinical Studies
Three single-dose clinical studies (P001, P002, P004) in healthy participants, a single dose 
study in healthy participants and participants with moderate hepatic impairment (P012) two 
CYP3A drug-drug interaction (DDI) studies in healthy participants (P006, P015), and four 
multiple- dose clinical studies in participants with schizophrenia and healthy participants 
(P003, P007, P011 and P016) have been completed with MK-8189. P011 included elderly 
(>60 years of age, n=12) participants with schizophrenia and healthy elderly (> 60 years of 
age, n=18) participants. Overall, across the completed studies, 231 participants have received 
at least one dose of MK-8189; 124 participants without schizophrenia and 107 participants 
with schizophrenia. Please see IB and section 2.2.4 for a summary of completed studies.
Overview of Pharmacokinetics:
 
 Based on completed studies, data suggest that 
the exposures at steady state for a given dose are generally comparable between healthy 
participants and participants with schizophrenia administered MK-8189 as monotherapy. 
MK-8189 is a CYP3A substrate and in a DDI study (P006) the coadministration of extended 
release 240-mg diltiazem, a moderate CYP3A inhibitor, increased MK-8189 area under the 
curve (AUC) and Cmax by approximately 
 respectively. Additionally, a 
subsequent DDI study (P015) demonstrated that coadministration of itraconazole, a strong 
CYP3A inhibitor, increased MK-8189 AUC and Cmax by approximately 
 
 respectively, and these results were generally consistent with the results observed 
in the diltiazem study. Collectively, these results confirm that MK-8189 is a CYP3A 
substrate. Data collected from a single-dose hepatic impairment study (P012) demonstrated 
that MK-8189 AUC and Cmax were approximately 
 in participants with 
moderate hepatic impairment compared to healthy matched controls, respectively. Results 
collected from a study in adult and elderly participants (P011) suggest that 1) the PK of 
MK-8189 in elderly participants with and without schizophrenia were generally similar to 
one another and 2) the PK of MK-8189 in young and elderly participants with schizophrenia 
were generally similar to one another.
Overview of Safety:
Across completed and ongoing studies, MK-8189 was generally well tolerated up to 24 mg in 
healthy participants and up to 80 mg in participants with schizophrenia. The most common 
treatment-related adverse events (AEs) (≥5%) following treatment of MK-8189 (n=231) 
across the completed Phase 1 studies which included, healthy participants (non-elderly and 
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elderly), participants with schizophrenia (non-elderly and elderly) and participants with 
hepatic impairment, were headache (13.0%) somnolence (13.4%), dystonia (10.4%), 
decreased appetite (9.5%), nausea (8.7%), fatigue (5.6%), dizziness (6.5%), vomiting (6.1%),
diarrhea (4.8%), akathisia (6.1%), anxiety (5.2%) and insomnia (5.2%). Most AEs were mild 
to moderate in severity. There were no deaths and one treatment-related SAE across the 
Phase 1 studies; In P007, one participant discontinued due to a treatment-related SAE of 
increased psychosis which resulted in hospitalization. The SAE occurred following treatment 
with the 36-mg dose. The AE was considered severe and had a duration of 6 days. The SAE 
resolved following initiation of an antipsychotic and benzodiazepine.
Participants with schizophrenia (n=107) were only evaluated in multiple-dose studies. The 
most commonly (≥ 5%) reported treatment-related AEs reported in participants with 
schizophrenia administered MK-8189 as monotherapy (n=75) or adjunct therapy (n= 32) 
were headache (16.8%), somnolence (15.0%), decreased appetite (12.1%), nausea (9.3%), 
dystonia (8.4%), akathisia (7.5%), dizziness (6.5%), vomiting (6.5%), and constipation 
(5.6%). In comparison, the most commonly reported AEs in participants administered 
placebo (n=37) were somnolence (13.5%), headache (10.8%), anxiety (5.4%), decreased 
appetite (5.4%), dizziness (5.4%), nausea (5.4%), and rash (5.4%). There is no clear trend for 
a relationship between MK-8189 dose and specific AEs.
In a Phase 2 POC trial (P005), MK-8189 was generally well tolerated by the 90 participants 
who received at least one dose of the once daily MK-8189 (
 
 Participants were dosed after they were able to taper off 
psychotropic medications. Adverse Events, that occurred in ≥5% of participants in the 
MK-8189 intervention group and had greater incidence than placebo, were diarrhea, nausea, 
vomiting, decreased appetite, akathisia, dystonia, headache, sedation, somnolence, anxiety, 
and insomnia. No deaths were reported in the P005 study. No SAEs were reported for 
participants on MK-8189. Eight participants (8.9%) had an AE of dystonia and 2 participants 
(2.2%) had an AE of oromandibular dystonia. Detailed PK and safety information from 
individual completed studies are summarized in the IB.
2.2.3
Ongoing Clinical Studies
As of January 1, 2023, 4 Phase 1 trials and one Phase 2 trial are ongoing (includes clinically 
complete) and 3 Phase 1 trials completed. All data presented for ongoing trials are 
preliminary.
2.2.3.1
Protocol 010
P010 was a Phase 1 study to evaluate the Absorption, Metabolism and Excretion of a single 
4.5-mg IR/~ 50 μCi dose of [14C]MK-8189 in healthy adults. This study is clinically 
complete and preliminary results are provided below.
The study was a non-randomized, single-site, open-label, 1-period study of MK-8189 dosed 
in 6 healthy adult males. Participants received a single-oral dose of 4.5-mg (~50-μCi) of 
[14C]MK-8189, fasted. Blood (plasma), urine, and fecal samples were collected at specified 
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timepoints. Total radioactivity and metabolite profiling was assessed in plasma, urine, and
fecal samples. MK-8189 concentrations were also measured in plasma.
In general, a single dose of 4.5-mg (~ 50-μCi) of [14C]MK-8189 was generally well 
tolerated in healthy male participants. Six (100.0%) participants experienced 1 or more AEs 
during the study and 5 (83.3%) reported AEs that were considered related to study 
intervention by the investigator. Four of 6 participants experienced mild extrapyramidal 
symptoms. All AEs were mild in intensity except 1 moderate AE of lethargy and all AEs 
resolved by study completion. AEs reported by >1 participant were akathisia (n=4), fatigue 
and hyperhidrosis (n=2 each).
Four participants experienced intervention-related mild akathisia starting within 20 minutes 
(minutes) after dosing with a duration ranging from 15 to 50 minutes. All events resolved 
without intervention. One participant experiencing akathisia also experienced lethargy 
(moderate for 3.82 hours followed by mild for 18.25 hours), mild irritability for 20 minutes 
and euphoric mood for 9.92 hours on Day 1. One participant experiencing akathisia also 
experienced mild hyperhidrosis for 45 minutes, fatigue for 22.83 hours and dyskinesia for 39 
minutes on Day 1.
There were no clinically meaningful abnormalities (i.e., reported as AEs) in routine 
laboratory safety, ECG, vital signs, or physical examinations. There were no deaths or SAEs 
reported and no discontinuations due to an AE.
2.2.3.2
Protocol 013
P013 was a multiple-dose clinical study to evaluate the safety, tolerability, and 
pharmacokinetics of MK-8189 in healthy Chinese participants.
This study enrolled 16 healthy Chinese male and female participants and were randomized to 
receive MK-8189 8 mg or placebo (Days 1-3), MK-8189 12 mg or placebo (Days 4-6), 
MK-8189 16 mg or placebo (Days 7-9) and MK-8189 24 mg or placebo (Days 10-12). 
MK-8189 oral administration of titrated doses up to 24 mg was generally tolerated in healthy 
Chinese participants. No reports of serious adverse events (SAEs) or deaths were identified. 
All 12 participants treated with MK-8189 reported 1 or more AEs and the investigator found 
at least 1 event related. These events were generally mild to moderate in severity and 
recovered without concomitant medication.
All 12 participants had 1 or more AE considered related to MK-8189 by the investigator. The 
most frequently reported (> n=1) treatment related AEs after MK-8189 were somnolence 
(n=10, 83.3%), insomnia (n=9, 75.0%), decreased appetite (n=5, 41.7%), nausea (n=4, 
33.3%), dystonia (n=4, 33.3%), tremor (n=3, 25.0%), anxiety (n=3, 25%), blood bilirubin 
increased (n=2, 16.7%), akathisia (n=2, 16.7%), headache (n=2, 16.7%), hyperhidrosis (n=2, 
16.7%). Of the 2 participants who discontinued the study, 1 discontinued due to a treatment 
related AE of moderate delusions (15.5 hours duration) after MK-8189 8 mg. Another 
participant discontinued due to other reason (no longer wanted to take the study drug) and is 
described below.
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Five participants reported dystonia (n=4 after MK-8189 and n=1 after placebo), an ECI:
•
One participant experienced dystonia (mild, related) after MK-8189 8 mg. Signs and 
symptoms included difficulties in closing eyes, tremor around eyes after closing them, 
abnormal muscle tension around mouth and unnatural occlusion and restricted mouth and 
eye movement, abnormal head and facial muscle tone. The participant remained under 
observation (no laboratory tests were performed, or treatment given) and recovered from 
dystonia after 7 hours and 30 minutes.
•
One participant experienced occlusal muscle dystonia (mild) after placebo. The occlusal 
muscle was abnormal and could not be closed for 6 seconds; the participant reported it 
was difficult to close the eyes, and the eyes trembled after closing the eyes. The 
participant remained under observation (no laboratory tests were performed, or treatment 
given) and the event had self-remission after 6 seconds.
•
One participant experienced dystonia (mild, related) after the last dose of MK-8189 16 
mg. There was no complaint of discomfort, and a physical examination found increased 
muscle tension of the limbs, and the arm fell slightly slowly. No treatment was given, and 
no laboratory tests were performed. Another physical examination was performed with 
no abnormalities and the symptoms resolved after 59 minutes.
•
One participant experienced dystonia (mild, related) and akathisia (mild, related) after 
MK-8189 8 mg. The participant had difficulty closing eyes, stiff wrists, and poor arm 
movement. A physical examination showed no abnormalities. On that day, SSAS 
assessment showed that the subject had slow falling arms, stiff swinging shoulders, stiff 
elbows, stiff wrists, slight swinging of the legs, and slight resistance to head rotation. 
BARS assessment showed akathisia. AIMS showed slight restriction of facial muscle 
movement. No laboratory tests were taken, and no treatment given. The participant 
remained under observation and symptoms of dystonia and akathisia resolved after 1 hour 
40 minutes. The day after the participant experienced thinking sluggish (mild, 1 day 
duration) and anxiety (mild, 8 hours duration).
•
One participant experienced dystonia (mild, related) after MK-8189 8 mg. The 
participant presented numb mouth, difficulty closing eyes, tight mouth, and difficulty 
opening mouth. Also present was abnormal perioral muscle tone when looking up. The 
physical examination showed no abnormalities. The investigator conducted AIMS, which 
showed slightly increased tongue movement, the BARS showed the inner restlessness, 
and the SAS assessment report indicated that when the subject walked, the swing was 
slightly reduced, the arm dropped slightly slowly, the contact sound was weak, and the 
rebound was weak. The participant was under observation and received trihexyphenidyl 
hydrochloride (benzhexol hydrochloride). The symptoms of dystonia resolved 2 hours 
and 4 minutes later. This participant reported a second episode of dystonia (mild, related) 
after MK-8189 12 mg. The participant claimed their eyes were trying to look up 
involuntary, and also noted difficulty closing the eyes. The BARS, SAS and AIMS were 
conducted, and the SAS indicated gait obvious diminution in swing, arm fall slowed 
slightly with less audible contact and little rebound, shoulder shaking slight stiffness, 
elbow rigidity slight stiffness, wrist rigidity slight stiffness, head rotation slight resistance 
to movement although the time to rotate may be normal. The participant was kept under 
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observation and received trihexyphenidyl hydrochloride (benzhexol hydrochloride) to 
treat the dystonia. A physical examination was completed and showed no abnormality. 
Symptoms of dystonia recovered after 23 hours and 30 minutes. This participant also 
reported the following AEs and ultimately discontinued from the study after the Day 6 
dose due to Other reason (as noted above): 3 occurrences of dizziness (11.5 hours, 5.5 
hours and 1 week duration), 3 occurrences of headache (11.5 hours, 5.5 hours and 5 days 
duration), 2 occurrences of vomiting (1 hour and 7 hour duration), somnolence (5 days 
duration), anxiety (5 days duration), insomnia (3 days duration), decreased appetite (3 
days duration), nausea (4 days duration) and diarrhea (4 days duration). All AEs were 
considered related to study intervention except the diarrhea which occurred a day after 
study intervention was stopped.
•
One participant reported suicidal ideation (mild) after MK-8189 24 mg. It was reported 
that after a dream the participant had mood swings and was crying. The concept of 
transient suicide appeared. The participant was observed during the clinical course and 
did not receive treatment for the event. The suicidal ideation lasted for 5 seconds, and the 
moderate mood swings (related) recovered after 21 minutes. As the outcome was 
recovered, no further follow-up information was reported. The investigator considered 
the suicidal ideation related to study intervention as the participant had not reported 
previous suicidal thoughts.
There were no clinically meaningful trends for study-intervention related changes in the vital 
sign measurements, physical examination assessments, or other observations related to safety 
in this study.
2.2.3.3
Protocol 014
P014 is a randomized, placebo-controlled, parallel-group, multisite, double-blind, multiple-
panel study of MK-8189 in participants with schizophrenia to support efforts to de-risk the 
potential for MK-8189 to prolong QT as required by ICH E14. Thus, this study is being
conducted to 1) evaluate a supratherapeutic dose regimen in participants with schizophrenia 
to support, if required, a TQT in participants with schizophrenia and 2) perform a 
concentration-QTc analysis in participants with schizophrenia receiving supratherapeutic 
doses.
Panel A and A-1 are clinically complete. Panel A enrolled 11 participants who were 
randomized to receive MK-8189 48 mg or placebo (Day 1) and MK-8189 60 mg or placebo 
(Day 2). Panel A-1 enrolled 10 participants who were randomized to receive MK-8189 
48 mg or placebo (Day 1) and MK-8189 80 mg or placebo (Day 2).  Panel C is ongoing and 
will enroll up to 30 participants who will be randomized to receive MK-8189 or placebo; 
MK-8189 48 mg or placebo (Days 1 to 2) and MK-8189 80 mg or placebo (Day 3).
To date, no SAEs or deaths have occurred. In Panel A, 11 schizophrenic participants enrolled 
in Panel A have completed dosing per protocol. Four participants reported a total of 5 
treatment-emergent adverse events. All AEs were considered mild in intensity. Discomfort, 
tremor, restlessness, somnolence, and headache were considered related to study 
intervention; exacerbation of insomnia and musculoskeletal pain were considered unrelated 
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to study intervention. All AEs resolved without interruption to study intervention.  In 
Panel A-1,10 participants were randomized and completed dosing per protocol. Five
participants reported at least one treatment-emergent AE. All AEs were mild and resolved. 
AEs reported included headache (n=1), constipation (n=1), insomnia (n=1), nausea (n=1), 
asthenia (n=1), somnolence (n=2), anxiety (n=1), feeling jittery (n=1) and akathisia (n=1). 
The AE of akathisia began following the 80 mg dose, no treatment was provided, and the AE 
lasted for approximately 3 weeks.
To date, in Panel C, 28 participants have been randomized, 26 have completed dosing per 
protocol, and 25 have completed the study. Two participants have discontinued due to an AE, 
and 1 participant withdrew consent. Treatment emergent AEs have been reported in 10 
participants and include dry mouth (n=1), increased appetite (n=1), dizziness (n=1), headache
(n=3), vaginal discomfort (n=1), fatigue (=1), anxiety (n=1) dyspepsia (n=1), lip twitching 
(n=1), somnolence (n=1), asthenia (n=1), and vomiting (n=1). One participant was reported 
to have mild nystagmus and miosis which began ~ 1 day following their last dose with a 
duration of 2 days. The participant who experienced the vaginal discomfort (unrelated to 
study treatment) following completion of study treatment was discontinued from the study as 
the participant was prescribed fluconazole and metronidazole. Two participants experienced 
dystonia: One participant experienced moderate oromandibular dystonia with a duration of 
~16 hours which began 4 hours following their first 48 mg dose of MK-8189/placebo. The 
participant withdrew consent due to this AE and the participant was treated with a single 
dose of benztropine 1 mg. A second participant also experienced mild dystonia 
approximately 7 hours following their first dose of MK-8189/placebo. The participant 
complained of intermittent stiffening of her neck shoulders hands and jaws for approximately 
4 hours. No treatment was administered. No dystonia symptoms were reported the following 
day and the participant completed study treatment pre protocol. The participant also 
experienced intermittent episodes of vomiting following administration of MK-8189/placebo. 
With the exception of the moderate oral mandibular dystonia, all AEs were mild, and all AEs 
with the exception of vaginal discomfort (participant lost to follow-up) were resolved.
Across the panels there have been no trends for clinically significant changes, in safety 
laboratory parameters, vitals or ECGs.
2.2.3.4
Protocol 017
P017 is an ongoing Phase 1 randomized, placebo-controlled, parallel-group, multisite, 
double-blind study of MK-8189 in participants with Alzheimer’s Disease with and without 
neuropsychiatric symptoms.
Preliminary blinded safety data from the ongoing Phase 1 study (P017) in participants (n=29) 
with AD, suggest that MK-8189 doses titrated from 8 mg to 24 mg were generally well 
tolerated. An initial cohort of 8 participants (6 active: 2 placebo) received. Based on good 
safety and tolerability data from those first 8 participants, all additional participants (n=21) 
were to be titrated up to MK-8189 24 mg/placebo as follows: MK-8189 8 mg/placebo Days 1
to 3 MK-8189 16 mg/placebo Days 4 to 6 and MK-8189 24 mg/placebo Days 7 to 28.  Based 
on available data to date, 13 men and 15 women were enrolled, 19 were White and 9 were 
Black or African American and participants were between the ages of 65 and 85 years. There 
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were no deaths or treatment-related SAEs.  Of the 29 participants, 27 completed study 
treatment for 28 days and of those 26 completed study treatments per protocol. One 
participant down-dosed from MK-8189 24 mg/placebo to MK-8189 8 mg/placebo due to an 
AE first reported on Day 8 but experienced since Day 6 and this participant completed 
28 days of dosing. One participant withdrew consent, and one participant withdrew following 
administration of the MK-8189 16 mg/placebo dose due to AEs (duration) of moderate 
nausea (4 days), mild diarrhea (2 days) and mild dizziness (3 days). Eleven participants 
reported at least one AE. Most AE reported were mild, and one AE was severe (intermittent 
electrical shock sensation with duration of 8.5 hours following administration of 
16 mg/placebo dose) which resulted in down dosing as described above. No participant 
reported AEs of EPS. There have been no trends for clinically meaningful changes in 
laboratory safety values, vital signs or ECGs.
2.2.3.5
Protocol 008
P008 is an ongoing Phase 2B randomized, double-blind, placebo- and active controlled trial 
of the efficacy and safety of MK-8189 in adult participants 18 to 50 years of age who are 
experiencing an acute episode of schizophrenia according to DSM-V™ criteria.
A total of 576 participants from approximately 80 sites across the USA, Europe and Asia will 
be recruited into this trial. Recruitment was initiated in December 2020. Treatment duration 
will be for a period of 12 weeks and includes a 6-week acute treatment period followed by a 
6-week extension period. Eligible participants will be randomized to receive one of five 
treatment sequences with target doses of MK-8189 (8 mg, 16 mg, and 24 mg QD), 
risperidone (6 mg QD), or placebo. Placebo completers at 6 weeks will be allocated to 
receive MK-8189 24 mg for the remainder of the trial. This trial is being conducted in a 
hospital/acute care setting followed by an outpatient setting.
2.2.4
Completed Clinical Studies
2.2.4.1
Protocol 011
P011 was a Phase 1 multiple-dose randomized, double-blind, placebo-controlled, 
multicenter, 2-part study. Part 1 (Panels A/B/C) evaluated the safety and tolerability of 
different titration regimens or initiating MK-8189 treatment without titration in participants 
≤60 years of age with schizophrenia. Part 2 (Panels D/E/F/G) evaluated the multiple dose 
safety, tolerability, and PK of MK-8189 in elderly participants with schizophrenia (Panel D 
and Panel E) and healthy elderly participants (Panel F and Panel G) between 61 and 80 years 
of age (inclusive). Panel E and Panel G were to explore the safety and tolerability at different 
titration regimens and were only to be initiated after a safety and tolerability review from 
Panel D and Panel F, respectively.
Part 1 Panel A: Participants with schizophrenia. Intervention MK-8189 16 mg/placebo 
(Days 1 to 3), 24 mg/placebo (Days 4 to 10).
Overall, multiple oral doses of MK-8189 titrated from 16 mg to 24 mg were generally well 
tolerated in participants with schizophrenia. Of the 8 participants included in the safety 
analysis in Panel A, 6 (75%) experienced 1 or more AEs during the study; 5 participants 
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(83.3%) after MK-8189 and 1 participant (50%) after placebo. All AEs were mild or 
moderate in intensity and resolved prior to the end of the study. No participants were 
discontinued from the study intervention due to an AE.
Five participants (62.5%) reported 1 or more AEs that the investigator considered study 
intervention related; 4 participants (66.7%) after MK-8189 and 1 participant (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
decreased appetite (n=1 [16.7%] following MK-8189 24 mg and n=1 [50.0%] following 
placebo), dystonia (n=2 [33.3%] following MK-8189 16 mg), and somnolence (n=2 [33.3%] 
following MK-8189 16 mg).
Dystonia and new or worsening tardive dyskinesia per protocol were defined as ECIs. There 
were 2 (33.3%) participants administered MK-8189 who experienced a nonserious ECI. One 
participant, who prior to the study was being treated with benztropine to prevent EPS, 
experienced mild intermittent bilateral dystonia of the upper extremities after MK-8189 16 
mg. The investigator treated the participant with benztropine 1 mg and symptoms resolved 
after 2 days. The participant had also experienced moderate somnolence (3-day duration; 
related to MK-8189) which resulted in this participant remaining at the 16 mg dose for all 7 
days of dosing. This participant was also taking a sedating antihistamine, hydroxyzine, for 
the duration of the AE. One participant had moderate dystonia of the tongue, lips, facial 
muscles, and left hand after MK-8189 16 mg. The investigator treated the participant with 
benztropine 1 mg and symptoms resolved after 22 h. The participant was titrated to MK-8189 
24 mg per protocol and completed the study without recurrence of dystonia. The investigator 
considered both events related to study intervention.
Part 1 Panel B: Participants with schizophrenia. Intervention MK-8189 24 mg/placebo 
(Days 1 to 7)
Overall, multiple oral doses of MK-8189 24 mg were generally well tolerated in participants 
with schizophrenia. Of the 18 participants included in the safety analysis in Panel B, 
10 (55.6%) experienced 1 or more AEs during the study; 9 participants (64.3%) after 
MK-8189 and 1 participant (25%) after placebo. All AEs were mild or moderate in intensity. 
One participant had a moderate ligament sprain continuing at the end of the study. The 
investigator considered the event not related to study intervention. All other AEs resolved 
prior to the end of the study.
Five (35.7%) participants administered MK-8189 24 mg reported 1 or more AEs that the 
investigator considered study intervention related. The most commonly (>1 participants) 
reported study intervention related AE was somnolence (n=2, [14.3%] following treatment 
with MK-8189 24 mg).
One (7.1%) MK-8189 treated participant, who had a history of gastroesophageal reflux 
disease, discontinued intervention due to mild vomiting following administration of MK-
8189 24 mg. The investigator treated the participant with ondansetron 4 mg and symptoms 
resolved after 3 days. This participant also reported nausea on Day 2. The investigator 
considered both AEs not related to intervention.
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One (7.1%) participant had a mild AE of increased alanine aminotransferase (ALT) 
(116 IU/L; normal range [NR] 7-52 IU/L) following treatment of MK-8189 24 mg that the 
investigator considered related to study intervention. This participant had mildly elevated 
screening (61 IU/L) and predose (98 IU/L) values of ALT which continued to increase during 
the study. The AE was reported on the last day of study intervention and resolved in 
~2 weeks. Alkaline phosphatase followed a similar pattern. Aspartate aminotransferase was 
normal at screening and predose but the participant experienced an elevation throughout the 
study. Bilirubin remained within normal range throughout the study.
Part 1 Panel C: Not initiated
Part 2 Panel D: Elderly participants with schizophrenia. Intervention MK-8189 
8 mg/placebo (Days 1 to 3), 16 mg/placebo (Days 4 to 6), 24 mg/placebo (Day 7 to 13)
Overall, multiple oral doses of MK-8189 titrated from 8 mg to 24 mg were generally well 
tolerated in elderly participants with schizophrenia. Of the 16 participants included in the 
safety analysis in Panel D, 10 (62.5%) experienced 1 or more AEs during the study; 
7 participants (58.3%) after MK-8189 and 3 participants (75%) after placebo. The majority 
of AEs were mild or moderate in severity; an AE of severe intensity is discussed below. One 
participant (8.3%) in the MK-8189 intervention group had a mild skin disorder (verbatim 
term: small bump on the left side of the forehead) not resolved at the end of study. The AE 
was reported following the last dose of study intervention (MK-8189 24 mg) and the 
investigator considered this event not related to study intervention. All other AEs resolved 
prior to the end of the study.
Six participants (37.5%) reported 1 or more AEs that the investigator considered study 
intervention related; 4 participants (33.3%) after MK-8189 and 2 participants (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
somnolence (n=2 [16.7%] following MK-8189 8 mg, and 24 mg and n=1 [25%] following 
placebo), dystonia (n=1 [8.3%] following MK-8189 8 mg and n=1 [25.0%] following 
placebo) and restlessness (n=2 [16.7%] following MK-8189 8 mg and 16 mg).
One participant (8.3%) in the MK-8189 intervention group experienced an AE of severe 
intensity (somnolence) and a nonserious related ECI (dystonia). On Day 1 following 
administration of the MK-8189 8 mg dose, the participant experienced severe somnolence 
which resolved after 3 days with continued dosing. No action was taken regarding study 
intervention. On Day 3 following the 8 mg dose, this participant experienced moderate 
bilateral upper extremity dystonia. The event lasted for 3 days and resolved with 
cyclobenzaprine 10 mg. This participant also reported moderate akathisia beginning on 
Day 3 with a duration of 3 weeks. This same participant did not receive the Day 6 dose 
(MK-8189 16 mg) due to moderate AEs of conjunctivitis (3-day duration) and a maculo-
papular rash (4-day duration). The investigator considered all AEs related to study 
intervention. The participant did not titrate to the MK-8189 24-mg dose and was dosed with 
16 mg on Day 7. The participant withdrew consent on Day 8 and discontinued from study 
intervention.
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Three participants (n=2 [16.7%] following MK-8189 and n=1 [25.0%] following placebo) 
were discontinued from study intervention due to an AE. One participant discontinued 
intervention due to moderate pain that the investigator did not consider related to study 
medication. The AE started on Day 3 following administration of MK-8189 8 mg and 
resolved after ~ 1.5 weeks. The subject discontinued prior to the 16 mg intervention 
administration on Day 5. One participant discontinued intervention due to moderate 
restlessness after administration of MK-8189 16 mg (Day 3). This participant also 
experienced moderate dyskinesia (verbatim: involuntary movement of lower extremities) 
(Day 6). Both AEs resolved after 23 hours with no action taken. The investigator considered 
both AEs related to study intervention. One participant discontinued intervention due to mild 
dystonia (described below) after administration of placebo.
Two participants (n=1 [8.3%] following MK-8189 and n=1 [50.0%] following placebo) 
reported ECIs. One participant experienced moderate dystonia following treatment with 
MK-8189 8 mg and is described above. One participant had mild dystonia of the throat after 
placebo study intervention (Day 3) which initially responded to treatment with benztropine 
but then recurred. The event resulted in discontinuation from study intervention and resolved 
after 2 weeks. The investigator considered the event related to study intervention.
One participant (25.0%) in the placebo treatment group had 2 laboratory AEs: mild decreased 
estimated glomerular filtration rate (eGFR) on 2 occasions. One reported on Day 4 with a 
duration of 4 days. The other reported after the last dose of study intervention along with a 
mild increased blood glucose. The increased blood glucose resolved in 2 weeks however the 
decreased eGFR lasted around 1.25 months and was considered recovered/resolved with 
sequelae. The participant had a screening eGFR value of 55 mL/min/1.73 (NR: >59) with a 
creatinine of 1.23 mg/dL (NR: 0.76 to 1.27). The eGFR was low at screening but within 10% 
of the lower limit of normal permitted by the protocol. The participant had a medical history 
of diabetes and hypertension. The investigator felt the eGFR decreases were due to the 
poorly controlled diabetes, hypertension, and reluctance to hydrate. All AEs were not related 
to study intervention.
Part 2 Panel E: Not initiated.
Part 2 Panel F: Healthy elderly participants. Intervention MK-8189 8 mg/placebo (Days 1 to 
3), 16 mg/placebo (Days 4 to 6), 24 mg/placebo (Day 7 to 13)
Overall, multiple oral doses of MK-8189 titrated from 8 mg to 24 mg were generally well 
tolerated in healthy elderly participants. Of the 6 participants included in the safety analysis 
for Panel F, 4 of 5 participants administered MK-8189 (80%) experienced 1 or more AEs 
during the study. The 1 participant that received placebo did not report an AE. All AEs were 
mild or moderate in intensity and all but 1 AE resolved prior to the end of the study as 
described below.
Three (60%) participants after MK-8189 reported 1 or more AEs that the investigator 
considered study intervention related. No specific related AEs were reported in more than 
1 participant.
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One participant (20%) administered MK-8189 discontinued from study intervention due to 
an AE of moderate nausea after administration of MK-8189 24 mg. This participant had 
multiple AEs throughout the course of the study. Following treatment with MK-8189 8 mg, 
the participant had an AE of mild decreased appetite (~ 1-week duration) considered related 
by the investigator. Following the third dose of MK-8189 24 mg, this participant reported 
AEs of moderate dizziness (~ 8-hour duration), moderate nausea (5-day duration; reason for 
discontinuation), mild vomiting on 2 occasions (1- and 2-min durations), mild dyspepsia 
(3.5-hour duration), and mild ongoing hyponatremia (133 mmol/L on Day 10 and 
130 mmol/L at discharge [NR 135-146] mmol/L). The investigator considered all AEs after 
MK-8189 24 mg related to study intervention. This participant also had mild diarrhea 
(considered unrelated to study intervention) beginning on Day 6 (16 mg) with a duration of 
5 days which may have contributed to the hyponatremia. The participant also experienced a 
mild macule (verbatim: asymptomatic macular erythematous lesions on upper left chest) on 
Day 5 which was considered unrelated to treatment.
One participant reported moderate involuntary muscle contractions (3.5-hour duration) along 
with moderate EPS (~ 2-week duration) following MK-8189 16 mg (Day 5). The participant 
also experienced a second episode of moderate involuntary muscle contractions on Day 6 
(~2-week duration). Following the participant’s first MK-8189 24 mg dose and due to the 
ongoing EPS, the participant did not feel comfortable continuing at the 24-mg dose and was 
down-titrated to 16 mg for the duration of the study. The EPS was characterized by 
intermittent internal and visible tremor, intermittent stiffness and intermittent cogwheeling. 
The participant was given benztropine as needed until these AEs resolved. This participant 
also reported mild salivary hypersecretion (2-hour duration) following MK-8189 16 mg 
(Day 10). The investigator considered all AEs related to study intervention.
Part 2 Panel G: Healthy elderly participants. Intervention MK-8189 16 mg/placebo (Days 1 
to 3), 24 mg/placebo (Days 7 to 13)
Overall, multiple oral doses of MK-8189 titrated from 16 mg to 24 mg in healthy elderly may 
be less well tolerated than initiating titration of MK-8189 at a dose of 8 mg. Of the 
15 participants included in the safety analysis for Panel G, 12 (80%) experienced 1 or more 
AEs during the study; 11 participants (84.6%) after MK-8189 and 1 participant (50%) after 
placebo. The majority of AEs were mild or moderate in intensity; AEs of severe intensity are 
described below. All AEs resolved prior to the end of the study.
Ten participants (66.7%) reported 1 or more AEs that the investigator considered study 
intervention related; 9 participants (69.2%) after MK-8189 and 1 participant (50%) after 
placebo. The most commonly (>1 participants) reported study intervention related AEs were 
somnolence (n=4 [30.8%] following MK-8189 16 mg), akathisia (n=3 [23.1%] following
MK-8189 16 mg [n=2] and 24 mg [n=1]), tremor (n=3 [23.1%] following MK-8189 24 mg), 
myalgia (n=2 [15.4%] following MK-8189 16 mg and 24 mg), headache (n=2 [15.4%] 
following MK-8189 24 mg), hypertonia (n=1 [7.7%] following MK-8189 24 mg and n=1 
[50%] placebo), and oromandibular dystonia (n=2 [15.4%] following MK-8189 16 mg and 
24 mg).
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Three participants (23.1%) administered MK-8189 experienced 1 AE of severe intensity. 
One participant experienced severe somnolence on Day 1 (MK-8189 16 mg) which resolved 
after 8.75 hours. The participant also reported mild akathisia (3-hour duration), mild 
dyspepsia (3-hour duration) and restlessness (~ 1-week duration) also on Day 1 and an AE of 
mild tremor (4-day duration) on Day 5 (MK-8189 24 mg). One participant experienced 
severe somnolence on Day 1 (MK-8189 16 mg) which resolved after 10 hours. This 
participant had no other reported AEs. The investigator considered all AEs for both 
participants related to study intervention. No action was taken with study intervention for 
these 2 participants. One participant experienced a severe hypnagogic hallucination after 
MK-8189 24 mg (discussed below).
Three (23.1%) participants administered MK-8189 discontinued study intervention due to an 
AE. One participant discontinued due to a severe hypnagogic hallucination on Day 8. This 
participant experienced mild akathisia (20-hour duration) and moderate headache (8-hour
duration) on Day 7 after MK-8189 24 mg. The participant was treated with benztropine 1 mg 
as needed for the akathisia. Overnight, prior to the Day 8 24-mg administration, the 
participant experienced moderate tactile hallucination (5-min duration), moderate 
hyperhidrosis (5-hour duration) and mild palpitations (2-min duration). Early morning upon 
waking on Day 8, the participant experienced a severe hypnagogic hallucination (5-min 
duration). The participant did not receive the Day 8 dose due to these AEs. Later that day 
(Day 8), the participant experienced moderate tactile hallucination (15-min duration), 
moderate hyperhidrosis (15-min duration), mild hypertonia (5-day duration) and moderate 
sinus tachycardia (39-min duration). Since similar AEs reoccurred on Day 8, the participant 
decided not to continue dosing due to the possibility of a reoccurrence of the hypnagogic 
hallucination. This participant also reported a mild ECI of oromandibular dystonia (30-min 
duration) on Day 1 (MK-8189 16 mg) and a mild headache on Day 10 (MK-8189 24 mg). 
The investigator considered all AEs related to study intervention except the mild headache on 
Day 10. One participant discontinued intervention due to mild akathisia following Day-3 
administration of MK-8189 16 mg. The investigator treated the participant with benztropine 
1 mg and symptoms resolved after 2 days. The investigator considered the AE related to 
study intervention. This participant also reported mild fatigue (6-day duration) and moderate 
wheezing (2-day duration) 8 days following intervention discontinuation. The investigator 
considered these AEs not related to study intervention. One participant discontinued 
intervention due to moderate ECI of oromandibular dystonia of the jaw on Day 4 following 
administration of MK-8189 24 mg. The investigator treated the participant with benztropine
1 mg and symptoms resolved after 6.5 hours. The participant also reported moderate anxiety 
(~11-hour duration; treated with lorazepam 1 mg), mild myalgia (14.5-hour duration; treated 
with ibuprofen 800 mg) and mild apathy (23-hour duration) on Day 4. The investigator 
considered all Day-4 AEs related to study intervention. Prior to the Day-4 AEs, the 
participant experienced on Day 2 moderate apathy (2-day duration), mild dysphonia (6-day 
duration), mild involuntary muscle contractions (verbatim: fasciculation, 2-day duration) and 
mild parosmia (~1-week duration), all considered related to intervention by the investigator. 
On Day 3, the participant experienced mild back pain (3-day duration; treated with 
paracetamol 1000 mg), salivary hypersecretion (3-day duration) and mild muscle tightness of 
the legs (10.5-hour duration). The only AE considered related to intervention on Day 3 by the 
investigator was the salivary hypersecretion.
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One participant (7.7%) had a mild laboratory AE of decreased eGFR on Day 12 after 
MK-8189 24 mg which was not considered related to study intervention. The decreased 
eGFR lasted around 1.5 months and was considered recovered/resolved with sequelae by the 
investigator. The participant had a normal screening eGFR value of 75 mL/min/1.73 (NR: 
>59) with a creatinine value of 0.81 mg/dL (NR: 0.76-1.27). The eGFR fluctuated between 
65 and 75 mL/min/1.73 throughout the study but was never below the NR until Day 12 
(eGFR value of 58 mL/min/1.73; creatinine value of 1.01 mg/dL). The participant had a 
history of hypertension, and the investigator felt the eGFR decrease was related to their 
baseline hypertension. The investigator referred the participant to their primary care 
physician (PCP) for further treatment of hypertension (participant was prescribed lisinopril 
by the PCP).
Across all Panels, there were no dose-related trends for increases in specific AEs. There 
were no clinically meaningful trends for MK-8189-treatment related changes in safety 
laboratory values, vital signs, including orthostatic vital signs, ECGs, or physical exams. 
There were no SAEs or deaths reported and no participant reported suicidal ideation or 
behavior per the C-SSRS.
2.2.4.2
Protocol 012
P012 was an open-label single-dose Phase 1 study to evaluate the safety, tolerability, and PK 
in participants with hepatic impairment and matched healthy participants.
Overall, MK-8189 4 mg was generally well tolerated in the moderate hepatic impairment and 
healthy participants in the study. No deaths or serious adverse events or events of clinical 
interest were reported. No participant discontinued from the study due to an AE. Of the 
14 participants included in the safety analysis, 4 (28.6%) experienced 1 or more AEs during 
the study: 4 (57.1%) in the moderate hepatic impairment group and none in the healthy 
participants group. Ten (71.4%) participants did not report an AE. All AEs were mild in 
intensity and all AEs resolved by the end of the study. The most frequently (>1 participant) 
reported AE amongst the moderately hepatic impaired participants was vomiting (n=2/7; 
28.6%). One participant vomited on Day 1, ~5 hours after dosing and another participant on 
Day 3. All other AEs were reported by 1 participant only.
Intervention-related AEs were reported by 2 of 14 (14.3%) participants as detailed below. Six 
AEs (2 of 7 [28.6%] participants with moderate hepatic impairment) were considered 
intervention-related by the investigator: One participant developed mild AEs of vomiting, 
~5 hours after dosing (1 episode, 1 min), muscle spasm (10 minutes), and hot flush 
(40 minutes). One participant had mild AE of headache (19.5 hours) on Day 1, followed by 
anxiety (30 minutes) and affect lability (30 minutes) on Day 2.
No clinically meaningful trends were observed as a function of study intervention for 
laboratory safety tests, vital signs, or ECGs.
2.2.4.3
Protocol 016
P016 was a randomized, placebo-controlled, parallel-group, single-site, double-blind,
multiple-ascending dose study of MK-8189 in healthy participants. Up to approximately 
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25 healthy participants were planned to be enrolled to ensure 20 participants completed the 
study. Participants were randomized to receive single rising doses of MK-8189 or placebo on 
Days 1 through 6 (Day 1=8 mg, Day 2=16 mg, Day 3=24 mg, Days 4, and 5=48 mg, and 
Day 6=72 mg). Participants were domiciled from Day -2 until Day 9.
Adverse Events: In general, MK-8189 up to doses of 24 mg was well tolerated in healthy 
male and female participants in the study. The rapid titration regimen above 24 mg was not 
generally well tolerated due to central nervous system and gastrointestinal AEs.
Of the 12 participants included in the safety analysis, 100.0% (n=12/12) experienced 1 or 
more AEs during the study. In general, more AEs were observed with higher doses of 
MK-8189, and all participants receiving placebo reported AEs; 28.6% (n=2/7) for MK-8189 
8 mg (Day 1), 57.1% (n=4/7) for 16 mg (Day 2), 42.9% (n=3/7) for 24 mg (Day 3), 100.0% 
(n=6/6) for 48 mg (Days 4 and 5), 100% (n=4/4) for 72 mg (Day 6), and 100.0% (n=5/5) for 
placebo. Most AEs were mild or moderate in intensity; one AE of akathisia was rated severe. 
All but 1 unrelated AE of leukocyturia resolved by study completion. There were no deaths 
or other serious AEs.
Three participants receiving MK-8189 discontinued study intervention due to AEs that were 
considered related to study intervention by the investigator: One participant experienced a 
moderate AE of vomiting (duration 23.17 hours) following administration of the second 
48-mg dose and was not titrated further by decision of the investigator. This participant also 
experienced mild nausea (2 days) following the second dose of 48 mg. One participant 
experienced a moderate AE of anxiety (duration 9.92 hours) following administration of the 
second 48-mg dose and was not titrated further by decision of the investigator. This 
participant also experienced moderate vomiting (duration 10 minutes) following the second 
dose of 48 mg. One participant discontinued study intervention following the 24-mg dose due 
to severe akathisia that started 23.5 hours after dosing (duration 22.5 hours) and was treated 
with 3 doses of 10-mg propranolol hydrochloride. This participant also experienced moderate 
affect lability which began after the 16-mg dose (duration 4 days) and a few days later 
(Day 9) mild affect lability with a duration of 3.43 weeks, as well as mild restlessness which 
started after the 24-mg dose (duration 3 days).
One participant receiving placebo had a dose reduction when still blinded (from 48 mg on 
Day 4 to 24 mg MK-8189/placebo on Days 5 and 6) due to AEs of mild restlessness and 
moderate somnolence, both assessed by the investigator as related to study intervention, that 
started on Day 4 and lasted 40 min and 7 hours, respectively.
AEs reported by >1 participant treated with MK-8189 or placebo were: nausea (MK-8189: 
71.4%, placebo: 40.0%); decreased appetite (MK-8189: 71.4%, placebo: 20.0%); insomnia 
(MK-8189: 57.1%); headache (MK-8189: 42.9%, placebo: 40.0%); nightmare (MK-8189: 
42.9%, placebo: 20.0%); diarrhea and pyuria (MK-8189: 42.9% each); restlessness 
(MK-8189: 28.6%, placebo: 20.0%); vomiting, eructation, increased systolic blood pressure, 
hematuria, and leukocyturia (MK-8189: 28.6% each); dizziness and somnolence (placebo: 
40.0% each). AEs in the system organ classes of gastrointestinal disorders, metabolism and 
nutrition disorders, and psychiatric disorders were most frequently reported, by 6 participants 
each.
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A total of 83.3% (n=10/12) participants reported AEs that were considered related to study 
intervention by the investigator. In general, more AEs were observed with higher doses of 
MK-8189; 14.3% (n=1/7) for MK-8189 8 mg, 42.9% (n=3/7) for 16 mg, 28.6% (n=2/7) for 
24 mg, 83.3% (n=5/6) for 48 mg, 100% (n=4/4) for 72 mg, and 60.0% (n=3/5) for placebo. 
Study-intervention-related AEs reported by >1 participant treated with MK-8189 or placebo 
were: nausea (MK-8189: 71.4%, placebo: 40.0%); decreased appetite (MK-8189: 71.4%, 
placebo: 20.0%); insomnia (MK-8189: 57.1%); headache (MK-8189: 42.9%, placebo: 
40.0%); nightmare (MK-8189: 42.9%, placebo: 20.0%); diarrhea (MK-8189: 42.9%); 
restlessness (MK-8189: 28.6%, placebo: 20.0%); vomiting, eructation, increased systolic 
blood pressure (MK-8189: 28.6% each); dizziness and somnolence (placebo: 40.0% each).
Dystonia was an event of clinical interest. One participant experienced an AE of dystonia in 
the legs approximately 14 hours after receiving MK-8189 72 mg on Day 6 with a duration of 
17 minutes. Earlier in the day (~6-hours postdose), this participant experienced intermittent 
tremors in the legs (duration 40 minutes) and 10 minutes later also muscle twitches in the 
right leg (duration 7.67 hours). All AEs were of mild intensity, considered related to study 
intervention and resolved without intervention. Although not considered dystonia, the 
following dystonic-like reactions were also observed. One participant receiving MK-8189 
experienced AEs of intermittent muscle tightness in the arms on Day 2 ~30 minutes predose 
(ie, 23.5 hours after the 8-mg dose) (duration 3 hours), muscle spasms in the right hand on 
Day 2 44 minutes after the 16-mg dose (duration 1 minute) and blepharospasm on Day 4 
after the first 48-mg dose (duration 3 days). The participant also experienced orofacial 
dyskinesia on Day 2 predose. All AEs were of mild intensity, considered related to study 
intervention and resolved without intervention. This participant discontinued study 
medication after the second dose of MK-8189 48 mg due to an AE of vomiting. One 
participant receiving placebo experienced mild muscle spasms in the calves on Day 7 with a 
duration of 5 days. This participant also developed moderate intermittent akathisia on Day 7 
with a duration of 5 days that was treated with 60-mg propranolol hydrochloride on Days 7 to 
11. Both events were considered related to study intervention and resolved. Two other 
participants randomized to MK-8189 received propranolol hydrochloride to treat AEs. One 
participant to treat severe akathisia (see above). Another participant received a single dose of 
10-mg propranolol hydrochloride on Day 7 to treat an acute stress disorder of moderate 
intensity that started 33 hours after the last dose (72 mg on Day 6) and resolved in 4 hours. 
The AE was not considered related to study intervention.
Laboratory Safety Tests and Physical Examination: Overall there were no clinically 
meaningful trends observed as a function of study intervention for laboratory safety tests and 
physical examination. Although there were some AEs reported related to laboratory safety 
tests, none of these were considered related to study intervention.
12-lead ECGs and semi-automated Holter ECGs: 12-lead ECGs were collected from 
Day 1 to Day 6 24 hours with Day 1 predose as baseline. Semi-automated Holter ECGs were 
collected on Days 1, 3, and 6 (up to 72-hours postdose) with time-matched baseline. QTcF 
categorical analyses were performed for the Holter ECGs only.
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QT corrected using Fridericia’s formula (QTcF): Mean change from time-matched baseline 
for QTcF from the semi-automated Holter ECGs was similar for MK-8189 and placebo. A 
similar pattern was observed for the 12-lead ECGs. All QTcF values during the study were 
≤450 msec (Holter). All changes in QTcF from time-matched baseline (Holter) were <30 
msec, except for 1 participant receiving MK-8189 8 mg who had an increase >30 msec and 
≤60 msec on Day 1 8 hours (actual increase: 33 msec, time-matched baseline value: 395 
msec) and 14 hours (actual increase: 40 msec, time-matched baseline value 391 msec). This 
participant continued dosing up to 72 mg without any further QTcF increases of >30 msec.
12-lead ECG parameters were generally similar for MK-8189 and placebo. However, mean 
change from baseline for ventricular rate was higher for MK-8189 than for placebo at higher 
doses (starting on Day 5 10 hours) up to 72 hours after the 72-mg dose, which was also 
present on the Holter ECGs on Day 6. The rationale for the ventricular/heart rate increase is 
unknown. 
Mean change from time-matched baseline for resting systolic and diastolic blood pressure 
was generally similar for MK-8189 and placebo. It was numerically higher from Day 6 
6 hours onwards, and Day 6 14 hours onwards, respectively.
Orthostatic Hypotension: One participant (MK-8189 48 mg) experienced orthostatic 
hypotension (ie, a decrease of ≥20 mmHg between standing and semi-recumbent systolic 
blood pressure or decrease of ≥10 mmHg between standing and semi-recumbent diastolic 
blood pressure). All events were asymptomatic, and no occurrences were considered AEs.
2.2.5
Information on Other Study-related Therapy
Moxifloxacin is being used as an active control in this trial because it produces a mild but 
robust increase in QTc interval in healthy study participants at Tmax 
 
Moxifloxacin is a synthetic broad-spectrum antibacterial agent that is frequently used as an 
active control in TQT trials such as this.
Moxifloxacin is metabolized via glucuronide and sulfate conjugation. The CYP P450 system 
is not involved in moxifloxacin metabolism and is not affected by moxifloxacin. In vitro 
studies with CYP P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, 
CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter 
the PK of drugs metabolized by these enzymes.  Moxifloxacin, given as an oral tablet, is well 
absorbed from the gastrointestinal tract. The mean (± standard deviation [SD]) elimination 
 
Adverse reactions (AR), judged by investigators to be at least possibly drug-related, 
occurring in greater than or equal to 3% of moxifloxacin treated patients were: nausea (7%), 
diarrhea (6%), and dizziness (3%). See the moxifloxacin hydrochloride package insert for 
additional information [U.S. Prescribing Information 2020].
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2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine.
The data generated will be used to inform the cardiac safety profile of MK-8189.
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.
The following objectives will be evaluated in participants with schizophrenia.
Primary Objective
Primary Endpoint
To evaluate the effect of a supratherapeutic 
dose of 80-mg MK-8189 on the QTc 
interval
Hypothesis: Administration of an 80-mg 
MK-8189 dose on Day 2 does not prolong 
the QTc interval to a clinically significant 
degree. Specifically, the true mean 
difference (MK-8189 - placebo) in QTc 
change from baseline is less than 10 msec
QTc (QT interval corrected for heart rate) 
change from baseline at post dose time 
points
To evaluate the safety and tolerability of 
multiple once-daily oral doses of MK-8189 
in participants with schizophrenia
Adverse events leading to discontinuation 
of study intervention
Adverse events
Secondary Objectives
Secondary Endpoints
To evaluate the effect of moxifloxacin on 
the QTc interval 
Hypothesis: Administration of a single 
400-mg dose of moxifloxacin is associated 
with an increase in QTc interval. 
Specifically, the true mean difference 
(Moxifloxacin-placebo) in QTc change 
from baseline is greater than 5 msec at least 
at one time point
QTc (QT interval corrected for heart rate) 
change from baseline at post dose time 
points
To estimate the pharmacokinetics of 
MK-8189 following multiple doses of 
MK-8189 in participants with schizophrenia
AUC0-24, AUC0-last, Cmax, C24, Tmax, 
t1/2 of MK-8189
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4
STUDY DESIGN
4.1
Overall Design
This is a three-period, randomized, double-blind, active-controlled and placebo-controlled, 
3-way crossover, multisite study of participants with schizophrenia.
The study will consist of 6 sequences and 3 treatment periods with 5-day washout between 
doses in each period in a cross-over design. The 5-day washout period is selected based on
the terminal half-lives of both MK-8189 and moxifloxacin.
Participants will be randomized to 1 of 6 sequences according to a randomized allocation 
schedule. In each treatment sequence, the dosing periods will consist of:
•
Treatment A: MK-8189 48 mg on Day 1, MK-8189 80 mg on Day 2
•
Treatment B: Standard image placebo on Day 1 and moxifloxacin 400 mg on Day 2
•
Treatment C: MK-8189 matched placebo on Day 1 and Day 2
If applicable, participants will be washed off their current antipsychotic therapy. The washout 
may start with a down titration of the antipsychotic treatment during the screening phase per 
direction of the investigator. Participants should not receive antipsychotic therapy for at least 
5 days or 3 half-lives (whichever in longer) prior to Day -1. For longer half-life 
antipsychotics (eg, aripiprazole and brexpiprazole), if deemed appropriate by the 
investigator, a participant may stop treatment of the antipsychotics as an outpatient but
should be confined to the clinical research unit within a week of stopping treatment and 
minimally beginning on Day -6. If participants are not currently receiving antipsychotic 
therapy, they may be domiciled as late as Day -2 prior to Period 1.
Participants will be domiciled approximately 5 days (or 1 day if no washout required) prior
to Day -1 of Period 1 through 72 hours following the last dose administration in Period 3 
(including all washout periods) to facilitate the intensive PK sampling and Holter recordings. 
On Day -1 of Period 1 only, participants will have Holter recordings for approximately 24
hours without prespecified extraction periods to generate a wide range of heart rate and QT 
values that will be used to generate an individualized heart rate correction for QT. These data 
may be required if the Fridericia heart rate correction is not considered sufficient. In addition, 
Holter monitoring recordings and blood sample for PK will be conducted on days and 
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timepoints specified in the SoA up to 24 hours and 72 hours, respectively, following the last 
dose administration in each Period. Blood sampling for PK will be within 10 minutes of the 
end of ECG extraction period. The ECG reader will be blinded to all treatment (placebo, 
study intervention and active positive control) groups.
Following 72-hour assessments in Period 3, antipsychotic standard of care may be restarted, 
and participants may be discharged from the unit. At the investigator’s discretion, the 
participants may be domiciled for a longer duration if further observation is required.
Participants will return to the clinical research unit for a follow-up visit approximately 
14 days following the last dose administration of the study intervention.
Because this is a Phase 1 assessment of MK-8189 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
A thorough assessment of the cardiac safety of MK-8189 is required as part of drug 
development and registration. Some non-antiarrhythmic drugs have the potential to delay 
cardiac repolarization, prolonging the QT interval on the ECG. Such QT prolongation has 
been associated with development of potentially life-threatening cardiac arrhythmias, in 
particular Torsades de Pointes (TdP). There is in general a qualitative relationship between 
substantial QT prolongation and the risk of TdP [ICH Expert Working Group 2005]. This 
study is being conducted, therefore, to rigorously characterize the effect of MK-8189 on the 
QT and heart rate corrected QT (QTc) intervals. The study design will accomplish this 
objective consistent with ICH E14 guidelines.
The study will be a 6-treatment sequence arm, 3-period, double-blind (to MK-8189 treatment 
arm), randomized cross-over design. Participants will be randomized to 1 of 6 sequence 
arms, and will receive MK-8189, placebo, and moxifloxacin. This 3-period, cross-over 
design is selected as each participant receives all 3 treatments and serves as their own 
control, thus a smaller number of patients are required as compared to a parallel group study.
Based on the half-life of MK-8189 
) and moxifloxacin (~12 hours), a 5-day
washout should be sufficient between periods. While the positive control, moxifloxacin, will 
be administered in an open-label manner, the central ECG reader will be blinded to all 
treatments. The standard image placebo to moxifloxacin is included to ensure study 
procedures are followed uniformly.
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Further, the following design features prescribed in the ICH E14 guidance have been 
incorporated into this study:
1. A supratherapeutic dose of MK-8189 will be administered to assess the effect of 
MK-8189 on QTc at concentrations in excess of those anticipated when the maximum 
clinical dose is administered under steady-state conditions and the influence of the 
intrinsic or extrinsic factor that causes the greatest increase in exposure as described
in Section 4.3.2.
2. Moxifloxacin will be included as a positive control with an expected mean effect on 
the QT/QTc interval of 5 msec.
3. To reduce variability in the QT interval measurements, replicate ECGs will be 
extracted from 24-hour Holter tracings and a centralized core laboratory will be used 
to assess the QT interval. Readings at this core reading facility will be by a skilled 
reader and to the extent possible, all measurements from a single individual will be 
made by the same reader.
4. To reduce bias, the reader will be blinded to treatment, time, and subject identifier. 
Furthermore, as food can affect QT, mealtimes will be standardized across treatment periods. 
In addition, as this study will also explore the relationship between MK-8189 concentration 
and QTc, there is an attempt to achieve a wide range of concentrations during the initiation of 
dosing and the washout period, therefore sampling will be collected early following the first
dose through 72 hours following the final dose. Blood sampling for PK will be within 
10 minutes of the end of the ECG extraction period to support this analysis.
As all participants are domiciled throughout the trial, there is adequate monitoring for any 
safety concerns and participants will be continued to be domiciled for 72 hours following the
last dose of study intervention.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints in this study.
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
clinical AEs as well as through the conduct of neurological exams, physical exams, ECGs, 
VS, and laboratory safety tests. The C-SSRS will be administered to monitor mood and 
suicidal ideation and behavior in all trial participants (see Section 4.2.). In addition, scales 
will be included to evaluate extrapyramidal symptoms (EPS) and general well-being.
As EPS are associated with antipsychotics and have been observed in the MK-8189 clinical 
program, the (Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement 
Scale (AIMS) and Simpson Angus Scale (SAS) will be used to quantify any EPS observed in 
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the study. The BARS is an akathisia rating scale with objective and subjective measures and 
an overall rating from 0 to 5. A score of 0 presents no evidence for akathisia, a score of 3 is 
moderate akathisia and a score of 5 is severe akathisia. The AIMS evaluates 12 items and 
uses a 5-point scale to assess abnormal movement in 3 areas (orofacial, extremities, trunk). 
The SAS evaluates 10 items and uses a 5-point scale to measure symptoms of parkinsonism 
or parkinsonian side effects (including rigidity, tremor, akinesia, and salivation).
In case moderate EPS symptoms in an individual participant persist, the dose will not be 
further up titrated for this participant. Participants with severe EPS symptoms will be 
discontinued if not attenuated with dose reduction, dose titration and/or medical 
management.
The BPRS rating scale will be used to measure psychiatric symptoms such as depression, 
anxiety, hallucinations, and unusual behavior in a range of psychotic and affective symptoms 
in participants with schizophrenia. The BPRS has been used in clinical research as a tool to 
measure treatment effects and are effective scales to monitor the general well-being of the 
psychiatric patients. The BPRS consists of 18 symptom constructs and takes 20 to 30 minutes 
for the interview and scoring. The rater should enter a number ranging from 1 (not present) to 
7 (extremely severe). Zero is entered if the item is not assessed. Participants who experience 
severe psychosis during the study will be discontinued and referred for additional treatment 
as indicated.
4.2.1.3
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK of MK-8189. Therefore, individual 
plasma concentration and actual sample collection times of MK-8189 will be used to derive 
the PK parameter values AUC0-24, AUC0-last, Cmax, C24, Tmax and t1/2. MK-8189 
concentrations are being collected to also support a concentration-QTc analysis.
4.2.1.4
Pharmacodynamic Endpoints
The primary objective of this trial is to evaluate the potential effect of a supratherapeutic 
dose of MK-8189 on the QTc in participants with schizophrenia. 
Thus electrocardiogram data (eg, QT, QRS, RR and PR intervals and heart rate [HR]) will be 
obtained with a digital Holter device on study days specified in the SoA. An approximate 24-
hour Holter will also be conducted on Day -1 to support the determination of QTCI as 
discussed in Section 4.1.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
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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 multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, polymorphs of CYP2C9 will 
specifically be investigated for association with the pharmacokinetic (PK) and 
pharmacodynamic endpoints of MK-8189, since MK-8189 is partially metabolized by 
CYP2C9. Genetic variation in CYP2C9 may be analyzed for association with any laboratory 
or clinical data collected in this study.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on 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.
4.2.2
Rationale for the Use of Comparator/Placebo
Moxifloxacin is included as a positive control with an expected mean effect on the QT/QTc 
interval of 5 msec. Use of a positive control with this magnitude of effect is recommended by 
the E14 guidelines to ensure that a thorough QT study is conducted in such a way as to be 
adequately sensitive to detect a change in QT/QTc that meets the definition of being of 
regulatory concern.
Placebo to moxifloxacin will be used in an open-labeled manner, as the reading of ECGs is 
performed in a blinded manner. The placebo to moxifloxacin is included to ensure that
specified study procedures are followed uniformly.
Placebo to MK-8189 will be used to blind study participants and site staff to study treatment. 
This ensures an unbiased safety assessment.
Furthermore, ECGs collected following administration of placebo will be used to provide 
off-drug assessments at the same timepoints and under similar conditions (eg, in relation to 
food, activity and time of day all known to affect the QT interval) to those obtained 
following administration of study drug.
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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 an NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
The rationale for dose regimen selection is detailed in Section 4.3.1 and Section 4.3.2.
As this is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.3.1
Starting Dose for This Study
The starting dose for this study will be MK-8189 48mg/placebo. This starting dose, 
 
 has been shown to be generally well 
tolerated in an ongoing protocol, P014: See Section 2.2.3.5 for a summary of the study 
design for P014 as well as the preliminary blinded safety data associated with this starting 
dose.
A starting dose of 48 mg will allow for a shortened titration scheme and duration of treatment 
while achieving the target supratherapeutic dose to support a thorough QT study as discussed 
in section 4.3.2.
4.3.2
Maximum Dose Exposure for This Study
To ensure the risk of QT prolongation is appropriately evaluated, the maximum dose selected 
for this study should provide a Cmax value that would exceed the Cmax anticipated 
following administration of the highest clinical dose at steady-state under the condition of the 
intrinsic or extrinsic factor that results in the greatest increase in Cmax concentrations. The 
anticipated maximum therapeutic dose of MK-8189 is 
 with 
accumulation observed at steady state resulting in a predicted median steady-state Cmax of 
(geometric mean (GM) Cmax =
 Under conditions of CYP3A inhibition, 
the factor anticipated to cause the greatest increase (
) in MK-8189 PK, the median
steady state Cmax is predicted to be 
(GM Cmax = 
Based on 
preliminary results from P014 in Panel A-1 (48 mg Day 1/80 mg Day 2), the observed 
median Cmax on Day 2 following the 80 mg dose was
(GM Cmax =
providing an 
 relative to the median Cmax at the highest clinical dose under 
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steady state conditions. Preliminary data from P014 demonstrated that administration of an 
80 mg dose is generally well tolerated as described in Section 2.2.3.5.
Based on preliminary results from P014 in Panel A-1 (48 mg Day 1/80 mg Day 2), the 
observed GM AUC0-24 exposure at 80 mg was
 and therefore the margin to 
the AUC0-24 for an 80 mg dose, as derived from the 6-Week and chronic toxicology studies, 
would be 
 and 
, respectively, further supporting evaluation of this 
supratherapeutic dose. Brief summaries of the 6-Week and chronic toxicology studies 
supporting dose escalation are provided below:
In the 6-Week rat study, doses of 25, 50 and 1000 mg/kg/day of MK-8189 were evaluated.  
There were no adverse findings in the study; therefore, the no observed adverse effect level 
(NOAEL) was
 (AUC0-24hr = 
 
) and 
 
in males (AUC0-24hr = 
 
) over the supratherapeutic GM exposure of 
. The functional observational battery (FOB) evaluation 
conducted on Study Day 1 showed findings at all dose levels that consisted of non dose-
dependent decreases in the mean number of line crosses and rears, and very slight, dose-
dependent decreases in mean body temperature. In addition, an absence of motor activity 
(akinesis) was noted in 1 of the 6 high-dose animals tested. Collectively, these observations 
are consistent with mild sedation. Importantly, these animals retained normal ability to 
respond to external stimuli as evidenced by normal responses to the noise, touch, and 
approach stimuli. These findings were considered transient as they were not present before 
the subsequent dose on Study Day 2.
In the 6-Week monkey study, doses of 10, 30 and 300 mg/kg/day were administered. 
Pharmacologically-mediated physical signs were observed across all dose groups and 
consisted of somnolence, increased/decreased activity, unsteady gait, increased 
licking/chewing/chomping motion, vocalization, intermitted recumbency, intermitted whole 
body trembling, and/or salivation. These physical signs were considered transient, reversible,
and consistent with the expected pharmacology of PDE10A inhibition. The NOAEL in this 
study was 
 (AUC0-24hour = 
 
) providing an exposure margin of 
over the supratherapeutic GM exposure of 
.
In the 6-month rat study, doses of 0, 25, 100 and 750 mg/kg/day were evaluated.
 
 
Therefore the 
mg/kg/day dose was considered the NOAEL for this study (AUC0-24hr = 
 
providing an exposure margin of 
over the supratherapeutic GM exposure of 
In the 9-month monkey study, doses of 0, 30/10/3, 150 or 600/300 mg/kg/day of MK-8189
were administered. Similar to the 6-Week study, pharmacologically-mediated transient and 
reversible physical signs were observed in all dose groups in the study. In addition, beginning 
in Study Week 8 of this study, reversible physical signs of uncoordinated movements were 
observed down to the low-dose level. Due to the severity of the uncoordinated movements, 
the low-dose level had to be lowered (30 to 3 mg/kg/day) to increase tolerability of the test 
article.  Based on these findings, the NOAEL 
. Renal 
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tubular degeneration was observed in the high-dose group (600/300 mg/kg/day). The 
NOAEL
), providing 
an exposure margin of
over the 
 
The effects of MK-8189 on measures of cardiac conduction and repolarization were assessed 
in both in vitro (hERG current [IKr] evaluation) and in vivo (anesthetized guinea pigs and 
conscious telemetered monkey models). MK-8189 inhibited hERG current with an 
 
. The IC50 value is 
 over the unbound mean Cmax (
 at the 
anticipated 
 and 
 over the 
unbound mean Cmax (
) at a supratherapeutic dose of MK-8189 of 80 mg QD, based 
on preliminary results from P014 in Panel A-1 (48 mg Day 1/80 mg Day 2).
The M3 metabolite decreased hERG current amplitude in a concentration-dependent manner 
(
 
 however, an IC50 value could not be determined. Assuming IC50 
, the 
margin over the estimated unbound M3 Cmax concentration at 80 mg QD (
, 
, based 
on preliminary results from P014 in Panel A-1 (48 mg Day 1/80 mg Day 2).
In an anesthetized guinea pig study, MK-8189 had no effects on HR and ECG parameters. 
Average peak plasma concentrations of MK-8189 measured during the 20 min infusions of 
10, 30 and 60 mg/kg 
 respectively.  Thus, the NOEL/NOAEL in 
this study 
 providing an exposure margin of 
over the estimated GM 
 at the anticipated 
 
 and 
 relative to the GM clinical Cmax at the 80 mg dose of 
 In 
anesthetized rhesus monkeys, MK-8189 had no effect on CV parameters during rising 
intravenous (IV) doses up to a 
 plasma concentration (~
In a telemetry study in monkeys, single oral doses of 2, 5, and 20 mg/kg were evaluated and 
 
were observed. In a second study at lower oral doses of 0.03, 0.1 and 0.3 mg/kg, there were 
no test article-related effects. Thus, the no-observed effect level was a single oral dose of 
 
mg/kg 
 estimated from a 6-week toxicity study 
 
the 
 
 and 
 value of
at a dose of 
MK-8189 of 80 mg). Several studies were conducted to determine the underlying cause (see 
MK-8189 IB for additional details). The general conclusion from these studies was that 
 likely occur due to a 
 
 subsequent to PDE10A target engagement in conscious rhesus monkeys and 
therefore, these changes in 
 are not relevant to humans.
Furthermore, a concentration-QTc analysis was conducted in P007 and as shown in Figure 2
there is no evidence for a relationship between concentration and QTc at MK-8189 exposures 
achieved with the 48 mg dose. Therefore, preclinical and clinical data support dose escalation 
to 80 mg in the current study.  In addition, during the study safety and tolerability will be 
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carefully assessed. Dose escalation may be stopped within an individual or the study based 
on tolerability.
4.3.3
Rationale for Dose Interval and Study Design
MK-8189 is formulated as a controlled-release tablet intended for QD administration. To 
date most multiple ascending dose studies have been conducted as a within participant 
titration. The within participant titration was introduced based on results from the single-
ascending dose trial (P001) in healthy participants, where following treatment with the 3-mg 
and 6-mg IR formulation, dystonia was observed around the time of peak MK-8189 
concentration (See IB for details). 
 
 In addition to successfully reducing 
 
through development of the CR formulation (
 a titration 
approach in the target patient population was implemented in the multiple ascending dose 
studies (P003 and P007) and the POC (P005) study, which significantly reduced the rate of 
observed EPS and dystonia and permitted evaluation of doses and exposures significantly 
greater than could be achieved tolerably with the IR formulation. Of note, in P007, where the 
 as well as supratherapeutic doses up to 48 mg have been 
evaluated, no MK-8189-related dystonia has been reported in healthy participants or 
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participants with schizophrenia. The peak concentration values at the 
dose are 
 those observed following 
 of the IR formulation, suggesting the absolute 
concentration is not a driver of dystonia. Across P003 and P007 the starting dose of the CR 
formulation has increased from 2 mg to 4 mg to 8 mg without an increase in the incidence in 
dystonia. Furthermore, Part 1 of P011 was conducted to evaluate the need for titration in 
participants with schizophrenia. As described in section 2.2.3 4, initiating dosing at 
 
was generally well tolerated in participants with schizophrenia. In this panel of participants, 
no AEs of EPS were reported. Furthermore, as described in Section 2.2.3, the titration 
regimen in this study was demonstrated to be generally well tolerated in P014, an ongoing 
study. As described in Section 4.3.5, this regimen should provide appropriate exposures to 
evaluate the potential of MK-8189 to prolong QT.
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). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the 
DSM-5 criteria with the onset of the first episode being no less than 2 years prior to 
screening and monotherapy with antipsychotics for treatment should be indicated.
Participants on more than 1 antipsychotic will need to be reviewed and approved by PI 
and Sponsor.
2. Has a total BPRS score of <48 with a BPRS score <4 for #10 (hostility) and #14 
(uncooperativeness) at the screening visit.
3. Is in the non-acute phase of their illness and clinically stable for 3 months prior to 
screening as demonstrated by:
a.
no clinically significant change in dose of prescribed antipsychotic medication, or 
clinically significant change in antipsychotics medication to treat symptoms of 
schizophrenia for two months prior to screening.
b. no increase in level of psychiatric care due to worsening of symptoms of 
schizophrenia for three months prior to screening.
Note: Participants that are stable but not currently taking antipsychotic 
medications are eligible.
4. Be in good health based on medical history, physical examination, and laboratory safety 
tests obtained at the screening visit and prior to randomization. Appendix 2 provides a 
table of laboratory safety tests to be performed. Appendix 10 provides an algorithm for 
the assessment of out-of-range laboratory values.
5. Have a Body Mass Index (BMI) ≥18.5 kg/m2 and ≤40 kg/m2 inclusive and total body 
weight of ≥50 kg (110 lbs) at screening. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
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6. Have no clinically significant abnormality on 12-lead ECG performed at the screening 
visit and prior to randomization. The assessment prior to randomization is based on the 
mean of the triplicate measures. Note: The QTcF duration must be ≤450 msec, the QRS 
duration <120 msec and the PR interval <200 msec. Repeat 12-lead safety ECGs may be 
performed in participants whose parameters are, per investigator discretion, minimally 
outside the designated range. Appendix 9 provides a table of the 12-Lead 
Electrocardiogram Abnormality Criteria, however the more restrictive criteria of this 
Appendix and Inclusion/ Exclusion criteria will be followed.
7. Have a normal resting blood pressure (systolic blood pressure is ≥90 mmHg and 
≤140 mmHg; diastolic blood pressure is ≥60 mmHg and ≤90 mmHg) and normal resting 
heart rate (≥45 bpm and ≤100 bpm) in the supine position at the pre-trial (screening) visit 
and prior to randomization. Repeat evaluations may be done if the values for a participant 
are, per investigator discretion, minimally outside of the triplicate measures. The 
assessment prior to randomization is based on the mean of the triplicate measures. In 
addition, orthostatic vital sign changes should be asymptomatic with a standing systolic 
blood pressure of ≥90 mmHg.
8. Has a history of receiving and tolerating antipsychotics medication within the usual dose 
range employed for schizophrenia.
9. Has a stable living situation in which the participant or contact person can be reached by 
the investigator if there is a need for follow up.
10. Participants with hypothyroidism, diabetes, high blood pressure, chronic respiratory 
conditions or other medical conditions could be considered as a candidate for study 
enrollment if their condition is stable and the prescribed dose and regimen of medication 
is stable for at least 3 months prior to screening and there are no expected changes in co-
medication during the study.
11. Has regular bowel movements and, in the opinion of the investigator, no clinically 
significant diarrhea or constipation.
12. Participants is able to discontinue the use of all antipsychotic medication at least 5 days 
or 3 half-lives (which ever in longer) prior to the start of the treatment period and during 
the study.
Demographics
13. Participant is an individual of any sex/gender, from 18 years to 60 years of age inclusive, 
at the time of providing the informed consent.
14. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
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•
Is a POCBP and:
-
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 14 days after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of
contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the 
first dose of study intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5 and Appendix 2.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
15. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
16. Is willing to comply with the study restrictions (see Section 5.3 for a complete summary 
of study restrictions).
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than 
schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria with one month 
of screening.
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2. Has evidence or history of intellectual disability, borderline personality disorder, anxiety 
disorder, or organic brain syndrome.
3. Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia 
(TD).
4. Has a substance-induced psychotic disorder or behavioral disturbance thought to be due 
to substance abuse.
5. Has a DSM-5 defined substance abuse or dependence disorder (excluding nicotine and 
caffeine) within 3 months of screening.
6. Has a history of seizure disorder beyond childhood or is receiving treatment with any 
anticonvulsant to prevent seizures.
7. Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, 
respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, 
immunological, or cerebrovascular disease, malignance, allergic or other chronic and/or 
degenerative process at screening.
8. Has any clinically significant abnormal laboratory, vital signs, physical examination, or 
12-lead safety ECG findings at screening or changes from baseline that may interfere 
with the interpretation of PK or safety parameters or, in the opinion of the investigator, 
would make the participant inappropriate for entry into this study.
9. Is at imminent risk of self-harm, based on clinical interview and responses on the C-
SSRS, or of harm to others in the opinion of the investigator. Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method (eg, 
positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the 
past 2 months or suicidal behavior in the past 6 months.
10. History of cancer (malignancy). Participants with adequately treated disease deemed as 
“cured,” or who, in the opinion of the study investigator, are highly unlikely to sustain a 
recurrence for the duration of the study may be enrolled at the discretion of the 
investigator.
11. Has a clinically significant history or presence of sick sinus syndrome, first, second, or 
third degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, 
cardiac arrhythmia, prolonged QTc interval, or conduction abnormalities.
12. The participant meets any of the following cardiac parameters: a history of risk factors 
for Torsades de Pointes (e.g, heart failure/cardiomyopathy or family history of long QT 
syndrome), is taking concomitant medications that prolong the QT/QTc interval.
13. At Screening or prior to randomization has uncorrected hypokalemia or 
hypomagnesemia, or abnormal serum calcium.
14. Has a history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures.
15. Has a family history of sudden cardiac death.
16. Has a history of any illness that, in the opinion of the investigator or Sponsor, might 
confound the results of the study or poses an additional risk to the participant by their 
participation in the study.
17. Participant has an estimated CrCl ≤80 mL/min based on the Cockcroft-Gault Equation.
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Cockcroft-Gault Equation:
When creatinine is measured in µmol/L, use this formula:
For females, multiply the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
Participants who have a measured CrCl of up to 10% below 80 mL/min may be enrolled in 
the study at the discretion of the investigator.
18. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or nonprescription drugs or food.
19. Has a positive test(s) for HBsAg, hepatitis C antibodies or HIV.
20. Had major surgery, donated, or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
21. Has received or is currently receiving treatment with clozapine for any length of time. 
Has received treatment with monoamine oxidase inhibitors within 3 months of screening 
or cariprazine within 2 months of screening.
22. Is unable to be washed off their parenteral depot antipsychotic medication prior to
screening or requires a dose of a parenteral depot antipsychotic medication during the
study
23. Is unable to refrain from the use of co-medication that is a moderate or strong inhibitor or 
inducer of CYP3A or moderate or strong inducer of CYP2C9 beginning approximately 2 
weeks or 5 half-lives, whichever is longer, prior to administration of the initial dose of 
trial drug and throughout the trial (Section 6.5).
24. Has received any non-live vaccine starting from 14 days prior to study intervention or is 
scheduled to receive any non-live vaccine through 30 days following study intervention. 
Exception: COVID-19 vaccine may be administered. Study intervention must be given at 
least 72 hours following or at least 48 hours prior to any COVID-19 vaccination. 
Investigational COVID-19 vaccines (ie, those not licensed or approved for Emergency 
Use) are not allowed.
CrCl = (140 −age<yr>)(body wt <kg>)
(72)(serum creatinine <mg/dL>)
CrCl =
(140 −age<yr>)(body wt <kg>)
(72)(serum creatinine <μmol/L> × 0.0113)
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Prior/Concurrent Clinical Study Experience
25. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
Not applicable
Other Exclusions
26. Under the age of legal consent.
27. Has been in incarceration or imprisonment within 3 months prior to screening.
28. Consumes greater than 3 servings of alcoholic beverages (1 serving is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume 4 servings of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
29. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
30. Is a regular user of cannabis (in the opinion of the PI; cannabis use >2x per month 
requires Sponsor consultation), a user of any illicit drugs or has a history of drug 
(including alcohol) abuse within approximately 3 years. Participants must have a negative 
urine drug screen (UDS) (with the exception of prescribed medications permitted at the 
discretion of the PI and Sponsor and/or cannabis) prior to randomization.
31. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions). Presents any concern by the investigator regarding safe 
participation in the study or for any other reason the investigator considers the participant 
inappropriate for participation in the study.
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
5.3.1.1
Diet Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours before study 
intervention administration. Approximately 240 mL of water will be provided during study 
drug administration but will be restricted 1 hour prior to and 1 hour after study drug
administration.
Meals and snack(s) will be provided by the investigator at time points indicated in the SoA
after any coinciding Holter and/or PK procedure. Participants will fast from all food and 
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drinks, except water, between meals and snacks. Meals and snacks should be standardized in 
caloric content, composition, and timing and the meal content will be consistent within a 
given clinical site. After the 48-hour postdose procedures have been completed in each 
period, subsequent meals and snacks will be unrestricted in caloric content, composition, and 
timing except Day 5 breakfast which will be served after all 72-hour postdose procedures.
Meal and water restrictions on Day -1 will be time-matched to days when treatment is 
administered. Similarly, on the days following the last dose in each per period, meal and 
water restrictions will be time-matched to days when treatment is administered.
Fasting requirements for laboratory safety evaluations are at least 8 hours prior to collection.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention, throughout the study and until the poststudy visit.
Participants will refrain from the consumption of all fruit juices 24 hours before study drug
administration and through the completion of the 72-hour postdose procedures in each 
period.
On all other days, the consumption of all fruits and fruit juices (except for grapefruit, 
grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours before the prestudy and poststudy visits.
Participants will be permitted to consume approximately 2 units of caffeinated beverages or 
xanthine-containing products only between 1 hour and 2 hours postdose on study 
intervention administration days and time-matched on non-study intervention administration
days.
After 72 hour postdose procedures, caffeinated beverages or xanthine-containing products 
will be limited to no more than 6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits. During the in-house period, consumption of alcohol is not allowed. At all 
other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent servings (1 serving is approximately equivalent to: beer [354 
mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
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5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the clinical research unit (CRU).
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods), and until the poststudy visit. Note: On Day -1 of Period 1, moderate ambulation and 
physical activity are encouraged to show a range of HR.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention withdraws from the study a replacement 
participant may be enrolled if deemed appropriate by the investigator and Sponsor. The 
replacement participant will generally receive the same intervention or intervention sequence 
(as appropriate) as the participant being replaced. The replacement participant will be 
assigned a unique treatment/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
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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, MK-8189 and matching placebo and standard image placebo for
moxifloxacin will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted before dosing the replacement participant. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/AxMP
Sourcing
Sequences 
1 to 6
Experimental
MK-8189
Drug
Tablet
12 mg
48 mg
Oral
Treatment A 
Day 1
Test Product
IMP
Provided 
centrally by 
the Sponsor
Sequences 
1 to 6
Experimental
MK-8189
Drug
Tablet
12 mg
4 mg
80 mg
Oral
Treatment A 
Day 2
Test Product
IMP
Provided 
centrally by 
the Sponsor
Sequences 
1 to 6
Active 
Comparator
Moxifloxacin
Drug
Tablet
400 mg
400 mg
Oral
Treatment B 
Day 2
Diagnostic –
to assess 
endpoints
NIMP/AxMP
Provided 
locally by 
the site
Sequences 
1 to 6
Placebo 
Comparator
MK-8189 
Matched 
Placebo
Drug
Tablet
0 mg
0 mg
Oral
Treatment C 
Days 1-2
Placebo
NIMP/AxMP
Provided
centrally by 
the Sponsor
Sequences 
1 to 6
Placebo 
Comparator
Standard image 
placebo
Drug
Tablet
0 mg
0 mg
Oral
Treatment B 
Day 1
Placebo
NIMP/AxMP
Provided
centrally by 
the Sponsor
IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (e.g, not applicable in 
the case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
The sample allocation schedule is depicted in Table 2.
Table 2
Sample Allocation Schedule
Treatment 
Sequences
n
Period 1
Period 2
Period 3
Sequence 1
14
A
B
C
Sequence 2
14
B
C
A
Sequence 3
14
C
A
B
Sequence 4
14
B
A
C
Sequence 5
14
A
C
B
Sequence 6
14
C
B
A
Treatment A (MK-8189)
Day 1: 48-mg MK-8189 (4 x 12 mg) = 4 tablets
Day 2: 80-mg MK-8189 (6 x 12 mg, 2 x 4 mg) = 8 tablets
Treatment B (Moxifloxacin)
Day 1: Standard image placebo = 1 tablet
Day 2: 400-mg Moxifloxacin = 1 tablet
Treatment C (MK-8189 Placebo)
Day 1: MK-8189 Placebo matching 48-mg MK-8189 = 4 tablets
Day 2: MK-8189 Placebo matching 80-mg MK-8189 = 8 tablets
6.3.2
Stratification
The allocation schedule will be stratified to females and males. Female participants will be 
assigned the low allocation range and male participants will be assigned the upper allocation 
range to attempt to enroll at least 30% females.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-8189 and MK-8189 
matched placebos will be prepared and/or dispensed in a blinded fashion by an unblinded 
pharmacist or qualified study site personnel The participant, the investigator, and Sponsor 
personnel or delegate(s) who are involved in the study intervention administration or clinical 
evaluation of the participants are unaware of the intervention assignments.
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The administration of moxifloxacin will be open label therefore, the Sponsor, investigator, 
and participant will know the moxifloxacin intervention administered. A standard image 
placebo will be administered on Day 1 of the moxifloxacin period (Treatment B).
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study-site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the case 
report form (CRF). The dose of study intervention and study participant ID will be confirmed 
at the time of dosing by a member of the study-site staff other than the person administering 
the study intervention. Study-site personnel will examine each participant’s mouth to ensure 
that the study intervention was ingested.
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
•
Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 5 days after the last dose of study 
intervention.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines.  These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Non-live vaccines may only be administered in consultation with the Sponsor prior to or 
following the receipt of study intervention according to the time frames specified in 
Exclusion Criteria (Section 5.2).
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•
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrollment or receives during the study must be 
recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
Paracetamol/acetaminophen (up to 4 g per day), ibuprofen (up to 1.2 g per day) and antacids 
(e.g. magnesium hydroxide) may be used for minor ailments without prior consultation with 
the Sponsor.
Medications to treat mild chronic conditions such as hypothyroidism, diabetes, high blood 
pressure, chronic respiratory conditions or other mild medical conditions are allowed during 
the study if the prescribed dose and regimen of medication are stable for at least 3 months 
prior to screening and there are no expected changes in co-medication during the study. 
Inclusion of participants being administered concomitant medications that have not been 
stable for 3 months must be discussed with the Sponsor. Moderate to strong inhibitors or 
inducers of CYP3A and/or CYP2C9 are not allowed as MK-8189 is being metabolized by 
these CYP enzymes and co-administration of inhibitors or inducers may potentially alter the 
metabolism and PK of MK-8189.
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
For the treatment of EPS, such as acute dystonia, all participants may be treated with an 
anticholinergic. If the symptoms are unresponsive to anticholinergic treatment, a 
benzodiazepine can be used. CRUs will be staffed with medically trained personnel with 
appropriate access to full service acute-care hospitals to facilitate rapid institution of medical 
intervention.
In case the participant presents with signs of akathisia without signs of dystonia, the 
participant can be treated with a β-adrenergic blocker. If symptoms do not resolve with the β-
adrenergic blocker, treatment with an anticholinergic may be used.  An anticholinergic may 
be used as first-line treatment in the case that a β-adrenergic blocker is not a preferred 
treatment based on a participant’s medical history and/or concomitant medication.
Anticholinergics, benzodiazepines and β-adrenergic blockers are often used in the treatment 
of EPS and are considered standard practice. Oral anticholinergic treatment is also used as 
concomitant medication to prevent EPS symptom with antipsychotic medication.
Participants will be washed off from their antipsychotic treatment (Section 8.1.5.1). The
duration of washout period should be at least 5 days or cover at least 3 half-lives of the drug 
(whichever is longer) prior to Day -1 assessments. During the washout and treatment period, 
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a benzodiazepine and zolpidem may be used to treat withdrawal symptoms. The drugs 
indicated above should not be inhibitors or inducers of CYP3A and CYP2C9 (see Section 6.5 
for further details), thus no effect on the PK of MK-8189 would be expected during co-
administration.
6.6
Dose Modification (Escalation/Titration/Other)
If, as judged by the Sponsor and/or investigator, the safety and tolerability data do not justify 
dose titration, the dose will not be increased as planned. Instead, participants may:
•
Skip a single dose and dosing may continue at the same dose level
•
Receive the same dose level to further explore safety and tolerability at that level
•
Dosing may be stopped
If appropriate medical care necessitates dosing to be stopped or a lower dose given, the 
investigator may do so without consultation with the Sponsor. Participant discontinuation 
criteria are outlined in Section 7.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). The 
Sponsor will not provide random code/disclosure envelopes or lists with the clinical supplies.
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 period
will still continue to participate in the study as specified in Section 1.3 and Section 8.1.9, or 
if available, a protocol clarification letter (PCL).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
Participants with severe EPS symptoms will be discontinued if not attenuated with dose 
reduction, titration, or medical management.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen (with the exception of prescribed 
medications permitted and/or cannabis at the discretion of the PI and Sponsor) at any 
time during the course of the study. The drug screen can be confirmed by a recheck at the 
discretion of the investigator after discussion with the Sponsor.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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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.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the volume mentioned in Appendix 8.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented 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.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
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, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history, including psychiatric history and substance abuse, will be obtained by the 
investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 3 months of starting the study. Use of any prescription or nonprescription medication 
during the washout period should first be discussed between the investigator and Sponsor 
unless appropriate medical care necessitates that therapy or vaccination should begin before 
the investigator and Sponsor can consult. Note: medications permitted under Section 6.5 of 
the protocol do not need to be discussed prior to use.
Washout from Antipsychotics:
All participants will be washed out from their antipsychotic medication at least 5 days or at 
least 3 half-lives (whichever is longer) prior to Day -1 in Period 1. The washout may start 
with a down titration of the antipsychotic treatment during the screening period per direction 
of the investigator. For longer half-life antipsychotics (eg, aripiprazole and brexpiprazole), if 
deemed appropriate by the investigator, a participant may stop treatment (ie, cessation of 
AAP) as an outpatient, but should be confined to the clinical research unit within a week of 
stopping treatment and minimally beginning on Day -6.
Participants may restart their antipsychotics therapy following completion of the 72-hour
postdose study procedures in Period 3.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
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Any individual who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment/allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff. Participants 
will fast from all food and drinks, except water, for at least 8 hours prior to study drug 
administration. Approximately 240 mL of water will be provided during study drug 
administration but will be restricted 1 hour prior to and 1 hour after study drug 
administration. Details on water and dietary restrictions are outlined in Section 5.3.1. Site 
staff will ensure that participants have swallowed study treatment.
8.1.8.1
Timing of Dose Administration
All doses of the study medication will be given in the morning at approximately the same 
time in each treatment period and will occur after an 8-hour overnight fast, as described in 
the SoA.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.10.4 to have the applicable procedures conducted. However, the 
investigator may decide to perform the poststudy procedures at the time of discontinuation or 
as soon as possible after discontinuation. If the poststudy visit occurs prior to the safety 
follow-up time frame as specified in Section 8.4.1, the investigator should perform a 
follow-up telephone call at the end of the follow-up period (Section 8.4.1) to confirm if any 
AEs have occurred since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
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. 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.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the 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 must be discontinued from study 
intervention but should continue to be monitored in the study.
8.1.11
Domiciling
Participants currently treated with antipsychotic medication will be domiciled in the CRU
from Day -6 prior to Period 1 (to start the washout period of current antipsychotic 
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medication) and will remain in the CRU until 72 hours post the last dose in Period 3.
Participants not currently being treated with antipsychotic medication may be domiciled 
minimally starting on Day -2. At the discretion of the investigator, participants may be 
requested to remain in the CRU longer.
Participants may be permitted to leave the unit, for emergency situations only, during the 
domiciling period at the discretion of the investigator after discussion with the Sponsor. The 
decision how to monitor the participant will be at the discretion of the investigator after 
discussion with the Sponsor.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
There are no direct efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Body Mass Index (BMI)
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI = kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
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Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed at 
prespecified timepoints noted in the SoA (Section 1.3).
•
Blood pressure and heart rate measurements will be assessed in a supine position as well 
as orthostatic positions with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a supine position for at 
least 10 minutes before having VS measurements obtained. Supine VS will include HR, BP
and respiratory rate (RR). The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements.
In each Period, the predose (baseline) BP will be in triplicate measurements, obtained at least 
1-2 minutes apart on Day -1 as per the SoA. The mean of these measurements will be used as 
the baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed). Postdose BP measurements will be single measurements. In each Period (all 
timepoints), and at screening and poststudy, HR will be measured in triplicate, obtained at 
least 1-2 minutes apart.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.2.2
Orthostatic Vital Signs
Orthostatic VS (HR and systolic and diastolic BP) will also be obtained at timepoints per the 
SoA. Participants should be supine for at least 10 minutes and then stand upright for 
approximately 2 minutes before measurement of orthostatic VS.
8.3.3
Electrocardiograms
Triplicate 12-lead ECG on Day -1 will be obtained and reviewed by an investigator or 
medically qualified designee (consistent with local requirements) as outlined in the SoA 
using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
QTc intervals. Refer to Inclusion/Exclusion criteria and Appendix 9 for eligibility assessment 
and potentially significant findings.
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Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the supine for at least 10 minutes before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
Predose ECGs, in each period, will be obtained in triplicate at least 1 to 2 minutes apart per 
the schedule of activities on Day -1. These measurements will be used as the baseline to 
calculate change from baseline for safety evaluations (and for rechecks, if needed).
During each treatment period, if a participant demonstrates an increase in QTc interval ≥60 
msec compared with mean predose baseline measurement, the ECG will be repeated twice 
within 5 minutes. The mean value of the QTc interval from the 3 ECGs will represent the 
value at that time point. If the mean QTc interval increase from baseline (Day -1) for any 
postdose time point is ≥60 msec, the participant will continue to be monitored by repeat 12-
lead ECGs every 15 minutes for at least 1 hour or until the QTc is within 60 msec of 
baseline. If prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
During each treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The mean value of the QTc 
interval from the 3 ECGs will represent the value at that time point. If the mean QTc interval 
is ≥500 msec, the Sponsor should be notified, and the ECGs should be reviewed by a 
cardiologist. The participant should be telemetry monitored (until the QTc is <500 msec) or 
should be considered for transfer to a location where closer monitoring and definitive care 
(eg, a cardiac care unit [CCU] or intensive care unit [ICU]) is available.
If at any time the QRS duration is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
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A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
24-Hour Holter Assessment 
For the entire 24-hour Holter recording duration, participants should not wear metal jewelry 
such as watches, necklaces, and/or bracelets from the waist up. Participants must also not use 
electronic devices such as cell phones, computers/laptops, MP3 players, etc. during Holter 
recording. Holter recording will be turned on approximately 70 minutes prior to trial drug 
administration. Participants will be encouraged to shower according to a schedule agreed 
upon by the Investigator, Sponsor, and Holter vendor so as not to interfere with intensive 
Holter monitoring periods. Details can be found in the procedure manual provided by the 
ECG vendor.
Holter data will be extracted (in replicates) and analyzed using automated and semi-
automated methods by a blinded core ECG laboratory according to a pre-specified algorithm. 
To minimize artifacts, participants must rest quietly in a supine position for ~20 minutes 
prior to the time points specified in the SoA. The extraction window will be ~5 minutes 
following ~15 minutes of rest. No other study assessments or procedures should occur during 
the resting and extraction windows (~20 minutes).
Holters may be removed and reapplied (same Holter used by the same participant) per 
instructions provided by the ECG vendor.  Lead placement must be marked anytime 
electrodes are removed.
See the procedure manual provided by the ECG vendor for specific instructions.
Procedures for transfer, archiving, and review of ECGs will be specified by the ECG vendor.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.6
Suicidal Ideation and Behavior Monitoring
8.3.6.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the 
C-SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior at screening, the 
assessor should also inquire and document if this is also present at the time of the Screening 
Visit.
Participants who, at any time during this study, report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). After that evaluation, only those participants whose suicidal ideation is considered by 
the evaluator to be passive, and who expressly deny any intent to act, and who, after 
evaluation, are not judged to be at serious risk for self-harm during the course of the study 
may continue in the study; other participants must be discontinued from study participation 
and receive appropriate clinical follow-up care to ensure their safety.
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In addition, all AEs of suicidal ideation or behavior must be recorded as an ECI (see 
Section 8.4.7). Sites are to designate which health care professionals are to be responsible for 
acute care on-site and to specify referral center(s) to be used for further evaluation.
8.3.7
Rater Expectations and Training for Clinical and Cognitive Assessments
For this study, potential raters of clinical assessments (BARS [Section 8.3.8], SAS 
[Section 8.3.8], AIMS [Section 8.3.8], BPRS [Section 8.3.9] and C-SSRS [8.3.6.1]), will be 
identified based on review of their reported credentials against target minimum credentials 
for education, prior experience with schizophrenia or similar populations and direct, hands-
on experience with study-specific or similar assessments. Persons whose credentials meet or 
exceed those targets will then be considered ‘qualified’ as raters in this trial. It is 
recommended that the same rater conducts the same assessments throughout the study for a 
given participant, where feasible.
8.3.8
Monitoring of Extrapyramidal Symptoms
The investigator or qualified designee will complete the BARS, AIMS and SAS at times 
specified in the SoA. Additional assessments at unscheduled times outside of the SoA will be 
conducted by study staff, as soon as reasonably possible, if it is observed or a participant 
reports complaints of dystonia and/or akathisia.
8.3.9
Assessment of Neuropsychological Effects
A general (full) Neurological Exam will be performed at the Screening and Baseline visits. A 
targeted Neurological Exam will be administered at times specified in the SoA.
A BPRS evaluation will be performed at Screening, Baseline and will also be completed at 
times specified in the SoA.
The General and Targeted Neurological Exams are contained in Appendix 11.
8.3.10
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship. See 
Investigator Site Binder for additional guidance.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention randomization through 14 days after cessation of intervention, 
all AEs, SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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 3
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 
24 hours of 
learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities 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
Not applicable
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor’s product, as defined in Section 8.5.
2. 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).
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It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
1. Severe EPS or EPS leading to study discontinuation
2. Treatment-emergent adverse event of new or worsening tardive dyskinesia
3. Suicidal ideation, suicidal behavior
4. Moderate or severe depression
5. Moderate or severe mood swings
6. Dystonia
7. Akathisia
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be measured for 
evaluation of PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, 
samples at lower doses may not be measured if samples at higher doses reveal undetectable 
drug concentrations). If indicated, these samples may also be measured and/or pooled for 
assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
Blood samples collected may be stored and further analysis may be performed, if required.
8.6.1
Blood Collection for Plasma MK-8189 and Moxifloxacin
Blood collection time points for plasma MK-8189 and moxifloxacin are outlined in the SoA 
(Section 1.3). Sample collection, storage, and shipment instructions for plasma samples will 
be provided in the Operations/Laboratory manual.
8.7
Pharmacodynamics
ECG parameter values are extracted from 24-hour Holter monitoring per the SoA.
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8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for 
 and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to
Leftover extracted DNA will be stored for FBR if the participant 
provides documented informed consent for 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 samples are listed in Section 8.8
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 6 weeks before intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention randomization if there are 
Day -1 procedures planned per protocol.
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8.10.2
Treatment Period
Refer to the Schedule of Activities (Section 1.3)
Participants must be washed out from any antipsychotic therapy for at least 5 days or cover at 
least 3 half-lives of the drug (whichever is longer) prior to Day -1. Participants will report to 
the CRU on Day -6 to start their washout period. However, if participants are not currently 
being treated with antipsychotic medications and therefore do not require a washout, they 
may be domiciled on Day -2.
On treatment days participants will be dosed once daily with MK-8189, moxifloxacin or 
standard image placebo and have procedures completed per the SoA. Participants will remain 
in the unit through 72 hours post last dose and completion of all procedures and will be 
discharged at the discretion of the investigator.
Participants will resume the use of their own antipsychotic medication after the completion 
of the last PK sample collection (72h postdose). A phone call should occur 5-7 days after 
CRU discharge to check for any side effects and medication compliance.
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.10.4
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the ECG parameter values extracted from the 24-hour Holter collection, and 
time-matched blood samples for MK-8189/moxifloxacin are the critical procedures. Every 
effort should be made to complete the 20-minute supine resting period at the nominal time 
point. For example, for the 1-hour postdose time point, the supine rest period should begin at 
40 minutes postdose and end at 1-hour postdose. The PK should be collected within 10 
minutes of the end of the supine rest period. For example, if the supine rest period ends at 1 
hour postdose the PK should be collected by 1 hour and 10 minutes postdose.
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All other procedures should be completed as close to the prescribed/scheduled time as 
possible. Study procedures can be performed before or after the prescribed/scheduled time.
1. Holter ECG (extraction period) and blood for plasma PK
2. 12-Lead Safety ECG 
3. Vital signs –
a.
Resting Blood Pressure and Heart Rate
b. Orthostatic BP and HR
4. Laboratory safety tests
5. Neurological exams: C-CSSRS, BPRS, BARS, AIM, SAS
Vitals signs may occur immediately before 12-Lead Safety ECG depending on participant 
positioning.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted:
•
Predose standard safety evaluations: VS and ECG triplicate measurements on Day -1 
timepoint(s) within 1 hour; laboratory safety tests and physical examination within 72 
hours.
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
examination
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time
-
Between 24-hours and 48-hours postdose may be obtained within 1 hour of the 
theoretical sampling time
-
From 48-hours to 72-hours postdose may be obtained within 2 hours of the theoretical 
sampling time
•
Study intervention administration (multiple-dose studies only): at 30 minutes.
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-8189 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
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As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose of the study intervention administered in any given 
period/sequence
•
Repeat of a period/sequence at the same dose regimen or more conservative dosing 
regimen
•
Entire period(s) or sequence(s) may be omitted
•
Decrease in the duration of study intervention administration (eg, number of days)
•
Adjustment of the dosing interval (eg, divided doses <bid to qd, qd to bid, tid, or vice 
versa>)
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data
The PK sampling scheme currently outlined in the protocol may be modified during the study 
based on newly available PK or pharmacodynamic data (eg, to obtain data closer to the time 
of peak plasma concentrations). If indicated, these collected samples may also be assayed in 
an exploratory manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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9
KEY STATISTICAL CONSIDERATIONS
This section details the principal statistical analysis strategy and procedures for the study. If, 
after the study has begun, changes are made to the statistical analysis plan stated below, then 
these deviations to the plan will be listed, along with an explanation as to why they occurred, 
in the Clinical Study Report.
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Department of the Sponsor.
9.1
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3
Primary hypothesis: 
Administration of an 80 mg MK-8189 dose on Day 2 does not prolong the QTc interval to a 
clinically significant degree. Specifically, the true mean difference (MK-8189 – placebo) in 
QTc change from baseline is less than 10 msec.
Secondary hypothesis: 
Administration of a single 400 mg dose of moxifloxacin is associated with an increase in 
QTc interval. Specifically, the true mean difference (Moxifloxacin-placebo) in QTc change 
from baseline is greater than 5 msec at least at one time point.
9.2
Analysis Endpoints
Cardiodynamics, PK and safety endpoints that will be evaluated for within- and/or between-
treatment differences are listed below.
9.2.1
Cardiodynamics
ECG Extractions:
The central ECG laboratory (eResearch Technologies, Inc., a Clario company, Philadelphia, 
PA, USA) will use TQT Plus, an advanced computer-assisted and statistical process utilized 
to extract ECGs from continuous recordings collected in thorough QT (TQT) studies. During 
protocol-specified ECG extraction windows, up to 10 non-overlapping 14-second digital 12-
lead ECG tracings will be extracted from continuous recordings. The TQT Plus method 
enables the extraction of a high-quality data set by identifying periods of recordings with the 
lowest available HR variability and noise.
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The ECGs will be extracted according to the following principles:
•
The actual times of dosing, extraction windows, and PK sampling will be communicated 
to the central ECG laboratory by the study center personnel.
•
The TQT Plus process identifies periods of stable HR on the continuous 12-lead ECG 
tracing within the 5-minute extraction window. Stability will be defined as beat-to-beat 
variation of HR and other ECG parameters lower than a predefined threshold. If the TQT 
Plus method results in a low number of consecutive, readable cardiac cycles in the 5 
minute window, the time point will be fully reviewed manually.
•
Replicate, non-overlapping ECGs will be extracted in close succession within each 
extraction window.
Early Precision QT Analysis
Twelve-lead ECGs will be extracted in up to 10 replicates from each nominal time point pre 
specified in the protocol with TQT Plus methods. The median value of each parameter from 
the set of approximately 100 evaluable beats in each extracted replicate will be calculated, 
and then the mean of all available (up to 10) medians from the nominal time point will be 
used as the participant’s reportable value at that time point.
Early Precision QT analysis will be performed on all analyzable (non-artifact) beats in the 10 
ECG replicates (1 replicate consists of one 14 second ECG). All readable cardiac cycles from 
these ECG replicates will be assessed for multiple quality metrics, including beat stability, 
HR changes, noise, and other parameters, and will be categorized into high and low 
confidence rank. All low confidence beats will be fully reviewed and adjudicated manually 
by Clario technicians using pass-fail criteria. The beats found acceptable by manual review 
will be included in the analysis.
Statistical quality control procedures will be used to review and assess all beats and identify 
“high” and “low” confidence beats using several criteria including:
•
QT or QTc values exceeding or below certain thresholds (biologically unlikely)
•
RR values exceeding or below certain thresholds (biologically unlikely)
•
Rapid changes in QT, QTc, or RR from beat to beat
•
HR derived from RR using the formula HR (bpm)=60000/RR(msec)
The primary analysis lead will be Lead II. If Lead II is not analyzable, then the primary lead 
of analysis will be changed to V5 for the subject’s entire data set. If Lead V5 is not 
analyzable, then Lead V2 will be used for the subject’s entire data set. If both alternate leads 
cannot be used, the Clario cardiologist has the option to deem the data non-analyzable or can 
decide to use the most appropriate lead for the subject’s entire data set. The lead used for 
analysis is listed in the data listings transferred from Clario.
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Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) in 
all recorded beats of all replicates will be performed using the iCOMPAS software. All beats 
that are deemed “high confidence” will not be reviewed by a Clario cardiac safety specialist. 
All low confidence beats will be reviewed manually by a Clario cardiac safety specialist and 
adjudicated using pass-fail criteria. The beats found acceptable by manual review will be 
included in the analysis. The beats confirmed to meet fail criteria will not be included in the 
analysis.
For the purpose of measuring PR and QRS intervals and to assess T-wave morphology and 
presence of U-waves, the TQT Plus algorithm will select the 3 of the 10 ECG replicates with 
the highest quality score from the ECG extraction window. These 3 ECGs will be analyzed 
using a semi-automated process to determine these parameters. If 3 consecutive usable beats 
cannot be identified in at least 2 of the 3 replicates, then all beats in all replicates will be 
reviewed for that time point using a manual analysis.
If manual analysis is required, then all beats in a minimum of 3 replicates will be reviewed 
using the iCOMPAS software. The Clario cardiac safety specialist will review all usable 
beats in Lead II (or an alternate lead) for each replicate and will review and/or adjust the 
fiducial placements (onset of P, onset of Q, offset of S, and offset of T-wave that were 
electronically marked) of each waveform and also document the T wave morphology and the 
presence of U-waves for each beat. 
Endpoints
QTc (QT interval corrected for heart rate) change from baseline is the primary endpoint.  
Fridericia’s correction to the QT interval (QTcF) will be used as the default correction 
method, and is applied by dividing the QT interval by the cube root of the RR interval, QTcF 
= (QT/RR1/3).
Replicates Holter ECG readings will be extracted at each specified time point, and replicate 
values will be averaged before any calculation and model fitting. 
The baseline value for each participant during each period will be defined as the average of 
measurements obtained over three predose time points:  20 minutes, 10 minutes and 5 
minutes prior to Day 1 dosing in that period. Change from baseline at each time point will be 
computed as post-dose minus baseline value for all analyses.
The QTc comparison of MK-8189 to placebo will be conducted at all time points as indicated 
by the study flow chart.  For the comparison of moxifloxacin to placebo, only the time points 
1, 2, 3, and 4 hours post-dose will be considered.  
HR, PR interval, QRS duration, and U and T wave morphology are exploratory endpoints.
9.2.2
Pharmacokinetic Endpoints
Plasma concentrations at ECG-matched time points for MK-8189. (Note: Moxifloxacin 
concentrations will be assessed only if concentration-QTc analysis is required for
moxifloxacin)
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PK parameters (e.g., AUC0-24, AUC0-last, Cmax, C24, Tmax and t1/2) for MK-8189 are the 
PK endpoints of interest.
9.2.3
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory test results, and vital signs.
9.3
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
Per-Protocol (PP) – The population includes the subset of participants who receive study 
treatment and who comply with the protocol sufficiently to ensure that generated data will 
likely exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
measurements and absence of important protocol deviations. Important protocol deviations 
will be identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation. Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the clinical 
study report. At the end of the study, all participants who are compliant with the study 
procedure as aforementioned and have available data from at least one study treatment will 
be included in the PP dataset. This population will be used for the PK and cardiac safety 
analyses.
9.3.1
Safety Analysis Populations
All Participants as Treated (APaT) – Safety Analyses will be conducted in the APaT 
population, which consists of all randomized/allocated participants who received at least one 
dose of study intervention. Participants will be included in the treatment group corresponding 
to the study intervention they actually received for the analysis of safety data using the APaT 
population. This will be the treatment group 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 group corresponding to the study intervention 
actually received. 
Analyses of laboratory test results, vital signs, and ECG measurements will include only 
participants with at least one measurement obtained after at least one dose of study 
intervention. If the analysis will assess change from baseline, a baseline measurement is also 
required.
9.4
Statistical Methods
9.4.1
Statistical Methods for Cardiodynamics Analyses
ECG data will be examined for outliers and unusual values. Any data excluded from the 
analysis will be listed, along with the reason for exclusion, in the report. Replicates QT 
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measurements taken at a prescribed time point will be averaged prior to any further analysis. 
If additional unscheduled ECGs are collected post dose, they will be excluded from the 
analysis. No imputations will be made for missing ECG data.
9.4.1.1
Adequacy of QT Correction Method
Fridericia’s correction to QT is made in order to correct for heart rate. The formula is 
(QTcF(msec)=QT(msec)/[(RR(sec))^(1/3)]). The appropriateness of the correction factor (i.e. 
1/3) will be assessed graphically and via a linear mixed effects model with QTcF as the 
response variable and RR interval as a covariate, and subject as a random effect. Day -1 
readings, pre-dose Day 1 measurements in each period, and placebo data will be used for this 
analysis. Though not to be formally tested, a slope close to 0 indicates that the Fridericia’s 
correction is adequate.  If the above methods provide evidence that Fridericia’s correction is 
inadequate or heart rate is shown to be affected by MK-8189 administration, then additional 
correction methods such as individual correction (QTcI) may be explored.  
If mean change from baseline in HR at any timepoint is above 10 bpm, then analysis will be 
performed using QTcI.  For this analysis, QT and RR values thus obtained from continuous 
ECG measurements on Day -1 for 24 hour period (prior to dosing on Day 1 in period 1) will 
be used to estimate the coefficients for each participant and these coefficients will be used to 
correct QT for HR for the participant. 
9.4.1.2
Primary Analysis
The baseline for the assessment of MK-8189 80 mg, placebo, and moxifloxacin QTc effect 
will be the QTc values obtained at predose on Day 1 in each treatment period. 
A linear mixed effects model will be used to estimate the mean between-treatment difference 
in QTc change from baseline at each time point, using separate models for each pairwise 
treatment comparison of interest (MK-8189 versus Placebo and Moxi versus Placebo) and 
each time point. Post dose data from Day 2 from all six sequences will be included in the 
model.  The dependent variable is QTc (y), and the independent variables in the model 
include fixed effect terms for seqstar, periodstar and treatment; seqstar and periodstar are 
defined for the MK-8189 vs. Placebo comparison in the table below, and analogous 
definitions are used for the moxi vs. Placebo comparisons.  In addition, the between-
periodstar difference in baseline QTc (Xdiffstar) will be used as a covariate in the model 
along with periodstar by Xdiffstar interaction. This approach is an extension of the 
methodology for the analysis of 2x2 crossover designs with period-specific baseline 
measurements [Mehrotra, D. V. 2014]. Of note, this linear mixed effects modeling analysis is 
notably more powerful than a corresponding analysis for a 3x3 crossover design that uses 
change from baseline as the dependent variable with fixed effects terms for sequence, 
treatment and period.
An unstructured covariance matrix will be used to allow for unequal treatment variances and 
to model the correlation between the treatment measurements within each subject via the 
REPEATED statement in SAS PROC MIXED. Kenward and Roger's method will be used to 
calculate the denominator degrees of freedom for the fixed effects (DDFM=KR). The least 
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square mean (95% CI) of QTc for both treatments and the least square difference (90% CI) 
between the two treatments will be obtained from the LSMEANS statement. Sample SAS 
code is given below for the comparison of MK-8189 versus Placebo.
PROC MIXED DATA=all; 
  by timepoint;
  CLASS seqstar periodstar treatment subjid;
  MODEL y=seqstar treatment  periodstar  Xdiffstar  Xdiffstar *periodstar/ ddfm=kr; 
  REPEATED treatment/SUBJECT= subjid(seqstar) TYPE=UN;
  LSMEANS treatment/ DIFF CL ALPHA=0.10;
RUN;
Period
seqstar
periodstar
Sequence
1
2
3
1
2
1
MK-8189
Placebo
Moxi
1
MK-8189
Placebo
2
Placebo
Moxi
MK-8189
0
Placebo
MK-8189
3
Moxi
MK-8189
Placebo
1
MK-8189
Placebo
4
MK-8189
Moxi
Placebo
1
MK-8189
Placebo
5
Moxi
Placebo
MK-8189
0
Placebo
MK-8189
6
Placebo
MK-8189
Moxi
0
Placebo
MK-8189
y=response at post-baseline (at a given time point)
Variable seqstar is derived from the original treatment sequences. For example, when 
comparing MK-8189 with Placebo, seqstar=1 for sequences in which MK-8189 appears 
before Placebo and seqstar=0 for sequences in which Placebo appears before MK-8189, as 
shown in the table above
Variable periodstar is derived by the order of treatments in a sequence. For example, when 
comparing MK-8189 with Placebo, the periodstar=1 for MK-8189 when MK-8189 appears 
before Placebo and periodstar=2 when MK-8189 appears after Placebo, as shown in the table 
above.
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Xdiffstar= difference between the QTc baselines of the consecutive periodstars in which 
MK-8189 can appear before or after Placebo.
Primary Hypothesis
To address the primary hypotheses that administration of an 80 mg dose of MK-8189 does 
not prolong the QTc interval to a clinically significant degree, specifically, means and two-
sided 90% CIs (equivalent to one-sided upper 95% CIs) for the true mean difference 
(MK-8189 – placebo) in QTc change from baseline will be provided at each prespecified 
time point. These CIs will be calculated using the appropriate error term from the above 
mixed effect model and referencing a t-distribution. If all of the upper limits of the 90% CIs 
fall below 10 msec, the primary hypothesis that administration of an 80 mg dose of MK-
8189 does not prolong the QTc interval to a clinically significant degree will be supported. 
However, if any of the upper limits exceed 10 msec, then there will be insufficient evidence 
to accept the primary hypothesis.
Secondary Hypothesis
To address the secondary hypothesis, the one-sided p-value for the mean difference between 
moxifloxacin and placebo in QTc change from baseline compared to 5 msec will be 
computed at each of the following time points (1, 2, 3, and 4 hours post-dose) based on the 
above mixed effect model.  Hochberg’s step-up method will be applied to preserve the 
overall alpha level at 0.05 for the hypothesis testing. The p-values obtained will be ranked in 
ascending order P(1) ≤ P(2) ≤ P(3) ≤ P(4).
If the maximum p-value P(4) is less than or equal to α = 0.05, then it will be concluded that 
the secondary hypothesis has been met.
If the maximum p-value P(4) is greater than α = 0.05, the next largest p-value P(3)  will then 
be compared with α/2 = 0.025.  If P(3) is less than or equal to 0.025, then it will be concluded 
that the secondary hypothesis has been met.  
Testing will continue with P(i) compared to α = 0.05/(n-i+1) in each step, until one time 
point supports the hypothesis, or until all p-values have been evaluated. 
The hypothesis that administration of moxifloxacin is associated with an increase in QTc 
interval will be accepted if there is at least one i such that P(i) is less than or equal to α = 
0.05/(n-i+1). Ninety percent confidence intervals for the mean between-treatment difference 
(moxifloxacin – placebo) will also be provided at each time point.
9.4.1.3
Sensitivity Analysis 
A model-based timepoint by timepoint analysis will also be conducted using a linear mixed 
effects model to estimate the mean between-treatment difference (moxifloxacin – placebo
and MK-8189 80 mg - placebo) in QTc change from baseline at each time point. Data from 
all 6 sequences will be included in the model. The dependent variable is ΔQTcF (change 
from baseline), and the independent variables in the model include treatment (moxifloxacin, 
MK-8189 80 mg, and placebo), sequence, period, time (as a categorical variable), and 
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treatment-by-time interaction as fixed effects and baseline QTcF as a covariate, and subject 
as a random effect.  An unstructured covariance matrix will be used for the repeated within-
period QTcF change from baseline measurements. 
The least square mean (95% CI) of QTcF change from baseline for moxifloxacin, MK-8189 
80 mg, and placebo and the least square difference (90% CI) between treatments 
(moxifloxacin – placebo and MK-8189 80 mg - placebo) will be obtained at each time point
from the LSMEANS statement. 
9.4.1.4
C-QTc Analysis for MK-8189
Before performing the C-QTC analysis, the following model assumptions will be checked
[Garnett, C., et al 2017]. If not specified otherwise, all data including Day 1 data will be used 
in the analysis. 
Graphical data exploration of model assumptions
The assumptions that MK-8189 does not affect HR, that the QT correction method for HR is 
adequate, that there is no delayed effect of PK on QTc (hysteresis), and that the relationship 
between concentration and QTc is in fact linear will first be explored graphically and/or 
statistically. If any of the model assumptions are not met, other models may be considered. 
Assumption 1: No drug effect on HR
The assumption that MK-8189 has no effect on HR will first be assessed by providing an 
exploratory plot of mean change in HR (ΔHR) from baseline versus time by dose. In addition 
to this plot, the mean placebo-corrected change from baseline in heart rate (ΔΔHR) by dose 
will also be evaluated. 
Mean increases or decreases in HR from baseline >10 bpm would be considered indicative of 
a meaningful change.
Assumption 2: QT correction is independent of HR
The adequacy of QT correction for heart rate will be evaluated both statistically and 
graphically. Fridericia’s correction to QT (QTcF = QT / RR1/3) is usually adequate, and this 
correction for HR will be applied first. The appropriateness of the correction factor (i.e., 1/3) 
will be assessed via a linear mixed effects model with QTcF as the response variable and RR 
interval as a covariate and subject as a random effect. Day -1 readings, pre-dose Day 1 
measurements in each period, and placebo data will be used for this analysis. Inclusion of 
zero in the 95% CI of the estimated slope would indicate that Fridericia's correction provides 
an adequate correction to the original QT data; otherwise, an appropriate transformation on 
RR may be further explored for each of the analyses. For the analyses, a scatter plot of 
individual QTc versus RR interval (Day -1 readings, pre-dose Day 1 measurements in each 
period, and placebo data) including the regression line from the above model will be 
provided. 
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A second scatterplot of individual QTc versus RR interval including all data (active, placebo, 
designated by separate symbols) will also be provided. A QTc-RR quantile plot will be 
provided. Individual RR values will be binned into deciles. The median of the RR 
observations in each bin will be plotted against the corresponding mean QTc (with 90% CI). 
Mean QTc will be presented separately for placebo and active treatments, distinguished with 
separate symbols. This plot will be overlaid with separate regression lines for active and 
placebo treatments and 90% confidence bands, which will be obtained from a linear mixed 
effects model having a fixed effect for treatment (active, placebo), RR interval as continuous 
covariate, interaction of treatment and RR, and a random effect for subject. 
If there is increase in HR (mean change from baseline in HR >10 bpm) on intervention, then 
QT will be corrected for HR by applying individual correction.  The QTcI correction factor 
may be derived from linear mixed effects modeling on the natural log scale log(QT) = log(a) 
+ bi ∙log(RR interval) with subject included as a random effect for both slope and intercept. 
This will be done for each participant using baseline data derived from Day-1 and Day 1 
predose from period 1 automated QT and RR readings. The QTcI correction factor (ie, 
log[RR] coefficient) for each participant, bi, will then be used to calculate the individually 
corrected QT for each participant as follows: QTcI = QT/RRbi.  If this model is found to be 
inadequate, then other models may be used.
For C-QTcI analysis, the individual coefficients will be calculated from automated ECG 
readings will be used. For C-QTcF analysis, semi-automated ECG readings will be used.
Note that hereafter, “QTc” will refer to the HR corrected QT interval with the appropriate 
correction method determined through the above procedures. 
Assumption 3: No time delay between drug concentrations
The potential for PK/PD hysteresis will be evaluated with the following plots:
- time course of mean and 90% CI ΔΔQTc by dose
- time course of geometric mean (90% CI) drug concentration by dose
- mean ΔΔQTc versus concentration connected in temporal order by dose
The assumption of a direct temporal relationship between drug concentration and QTc effect 
is supported if the time course of ΔΔQTc is concordant with the PK profile. If, however, 
there is a clear delay between peak concentration and peak QTc or QTc effect, the model 
would be modified to account for the possibility of a delayed temporal effect.
Assumption 4: Linear C-QTc relationship
The adequacy of using a linear model will be assessed by a scatterplot of individual paired 
ΔQTc and concentration data. It will be overlaid with a loess smooth line and 90% 
confidence band.
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Dependent Variable
The dependent variable for analysis will be HR-corrected QTc change (ΔQTc) from baseline 
values with the appropriate correction determined using the methodology in [Sec. 9.5.1]. 
MK-8189 plasma concentration profiles will be examined for outliers and missing values. 
For C-QTc analyses, only paired ECG and PK concentrations will be included in the model. 
Participants on active treatment who have post-dose concentration values below LLOQ will 
have the value set at LLOQ/2 for the analysis. Participants on placebo will have their plasma 
concentration set to zero at each time point for that treatment period.
C-QTC Model
If the assumptions described above are met, C-QTc modeling will be conducted in an 
exploratory manner. PROC MIXED will be used to investigate the relationship between QTc 
and MK-8189 plasma concentrations. The individual QTc change from baseline will be 
evaluated using a linear mixed effects model with fixed effects for treatment (MK-8189, 
placebo) and time point, and continuous effects for QTc baseline and MK-8189 plasma 
concentration as well as random effects for subject and subject by period, and a double 
compound symmetry covariance structure will be assumed [Mehrotra, D. V., et al 2017].
The following is sample SAS code:
proc mixed data=datanew method=reml;
class subjid time trt;
model cfb = trt conc time bsl/ddfm=kr solution;
random subjid;
repeated / subject = subjid*period type=cs;
estimate "ddQTc at 80 mg cmax" trt -1 1 conc cmax_80 mg / alpha=0.1 CL;
run;
where:
cfb = QTc change from baseline
ddQTc = placebo-corrected QTc change from baseline
bsl = QTc baseline 
trt = 0 if treatment is placebo or 1 if treatment is MK-8189
conc = concentration
time = 0.5, 1, 2, 3, 4, 6, 8, 12, 14 on Day 1; predose, 1, 2, 3, 4, 8, 11, 14, 16, and 24 on Day 
2.
The adequacy of the model will be assessed, and other relationships (e.g., nonlinear or 
delayed effect) may be explored if needed.
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9.4.1.5
Exploratory Analyses – Other 
Means and 95% confidence intervals for QTc and QTc change from baseline will be 
descriptively summarized for each treatment by time point. 
In addition to the analyses conducted at prespecified time points, means and two-sided 90% 
CIs for the difference between MK- 8189 and placebo in QTc change from baseline may be 
provided for other time points that are of clinical interest.
Other ECG parameters of interest HR and PR intervals, QRS duration, will be summarized in 
similar fashion. Counts will be provided by treatment and time point for HR > 100 bpm, PR 
> 220 ms and QRS > 110 ms. T wave morphology and U wave will be summarized.
For T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, 
i.e., changes not present at baseline.  For each category of T-wave morphology and of U-
waves, the category will be deemed as present if observed in any replicates at the time point.  
For baseline, the category will be deemed as present if observed in any replicates from all 
time points that constitute baseline.  
9.4.1.6
Categorical Analysis of QTc
Counts will be provided by treatment and time point for QTc values falling in the following 
ranges:  ≤ 450, > 450, > 480 and > 500 msec.  Counts will also be provided by treatment and 
time point for QTc change from baseline values falling in the following ranges:  < 30, ≥ 30 
and ≥ 60 msec.
9.4.2
Statistical Methods for Pharmacokinetics and Safety Analyses
Pharmacokinetics
Individual values will be listed for AUC0-24, AUC0-last, Cmax, C24, and Tmax of MK-
8189, and the following (non-model-based) descriptive statistics will be provided: N (number 
of subjects with non-missing data), arithmetic mean, standard deviation, arithmetic  percent 
CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as  100 x sqrt( exp(s2) - 1), where s2 
is the observed variance on the natural log-scale). 
Safety
Clinical and laboratory adverse experiences will be tabulated. Additionally, laboratory tests, 
12-lead ECG parameters, and vital signs may be summarized for each treatment, as deemed 
appropriate.
Summary statistics and plots will be generated for BARS, AIMS, and SAS, as well as for 
change from baseline. Responses to the C-SSRS will be listed.
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9.5
Interim Analyses
No interim analysis is scheduled.
9.6
Multiplicity
No multiplicity adjustment is needed, since the primary hypothesis needs to be supported at 
each time point. Hochberg’s step-up method is applied to preserve the overall alpha level at 
0.05 for the secondary hypothesis testing.
9.7
Sample Size and Power Calculations
Primary Hypothesis:
The following power calculation is based on assumed true standard deviation for QTcF 
change from baseline of 12 msec obtained from participants in schizophrenia.
With 60 completing subjects, and true mean differences (MK- 8189 - placebo) in QTcF 
change from baseline no worse than 3 msec at all nine time points, there is at least 89% 
probability of observing 90% confidence intervals for the true difference to fall completely 
below 10.0 msec at all nine time points. 
With 60 completing subjects, and true mean differences (MK- 8189 - placebo) in QTcF 
change from baseline no worse than 2 msec at all nine time points, there is at least 99% 
probability of observing 90% confidence intervals for the true difference to fall completely 
below 10.0 msec at all nine time points. 
Secondary Hypothesis:
With 60 completing subjects, and true difference in QTcF change from baseline 
(moxifloxacin – placebo) of 7.9 msec, 10.3 msec, 12 msec, and 11.2 msec at 1, 2, 3, and 4 
hours postdose, there is at least 99% probability that the secondary hypothesis will be 
supported; that is, that the true mean difference (moxifloxacin – placebo) in QTcF change 
from baseline is greater than 5 msec for at least one time point.
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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)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in 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 
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.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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.
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.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 
Regulation 536/2014 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 Regulation 536/2014, 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.
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10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 4 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 4
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
fasting
Calcium
Alkaline 
phosphatase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick

Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing

Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
Other Screening Tests

FSH (as needed in PONCBP only)

Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; <HBsAg=hepatitis B surface antigen>; hCG=human chorionic gonadotropin; <HIV=human 
immunodeficiency virus>; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; ULN=upper limit of normal; WBC=white blood cell; POCBP=participant of childbearing potential; 
PONCBP=participant of nonchildbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention 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.
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•
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.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the 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.
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•
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?
◦
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.
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•
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.
•
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.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure 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
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant 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.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth who are 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.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen- only contraceptive implantb,c
IUSb,d
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Penile/external or vaginal/internal condom with or without spermicidee
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
If hormonal contraception efficacy for a participant assigned female sex at birth is potentially decreased due to 
interaction(s) with study intervention(s) (eg, CYP3A4 inducers), penile/external condoms must be used in addition 
to the POCBP’s hormonal contraception
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
IUS is a progestin releasing IUD
e
Vaginal/internal condom used for contraceptive purposes
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condom should not be used together (due to risk of failure with friction)e
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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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. 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 
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Blood Volume Table
Periods 1, 2, and 3
Prestudy
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/
Test
Laboratory Safety Test
including serum βhCG 
(POCBP) or serum FSH 
(PONCBP) and BDS
1
4
(1 sample in 
Periods 1 & 2, 2 
samples in 
Period 3)
1
6
12
72
HIV/Hepatitis Screen 
(at the discretion of the 
investigator)
1
1
4.5
4.5
Blood for Planned 
Genetic Analysis
1
sample in 
Period 1
1
8.5
8.5
Blood for MK-8189 
and/or Metabolites 
Assay (Treatments A & 
C)
48
(24 samples in 2 
of the 3 
Periods)
48
4
192
Blood for Moxifloxacin 
(Treatment B - Day 2 
only)
14
samples in 1 of 
the 3 Periods
14
4
56
Total Blood Volume per Participant for Periods 1, 2, and 3a
333 mL
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (no more than 
50 mL in total) may be obtained.
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10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
RHYTHM
Sinus Tachycardia
>110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
>1 beat
≥3 beats
Ventricular Premature Complex
All
≥3 beats
Ectopic Atrial Rhythm
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; or 
PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intraventricular Conduction 
Delay
QRS ≥130 ms
QRS ≥130 ms + Increase of ≥10 ms
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
QTc (B or F)
Male
QTc ≥450 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
Female
QTc ≥450 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P. Mitrale or 
P. Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus Strain 
Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Nonspecific ST-T Changes (In 
2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; mm=millimeter; 
ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using Fridericia 
formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1.
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol-specified laboratory value is outside the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
a.
The participant may be excluded from the study.
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
c.
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
a.
The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter the 
study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: General and Targeted Neurological Examinations
The General and Targeted Neurological Examination will be performed at the time points
specified in the SoA (Section 1.3).
Note to the investigator: If at any time abnormalities are observed in the General or Targeted 
Neurological Exams, the investigator should do additional examinations as needed based on 
medical judgment.
10.11.1
The General Neurological Examination
The General Neurological Examination includes all of the modules listed below and is 
intended to be a general screening examination.
10.11.1.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention).
B. Thought Processes and Language (generally assess logic, relevance, organization, and 
coherence of participant’s use of language throughout the interview).
C. Orientation (time, place, person).
D. Attention/Concentration.
Ask the participant to count backwards from 100 by 7’s (“Serial 7’s”) or ask to recite 
months backwards or spell a 5 unique letter word (eg, “WORLD”) backwards.
Note: To avoid learning effects, switch between tests throughout the study.
E. Memory (test registration of 3 objects; then test immediate recall 5 minutes later).
Grade: NORMAL or IMPAIRED and describe abnormality (for each, A to E, above). 
Normal performance on Serial 7’s is getting to 65 with no more than 1 error.
10.11.1.2
Module 2 – Cranial Nerve Assessment
A. II – Visual Fields and acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus).
Observe for nystagmus during eye movements, increased nystagmus at the end of gaze or 
other oculomotor changes (mild nystagmus at extremes of gaze is normal). Note direction 
of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test [eg, by rubbing fingers 
on each side of participant’s head or by whispering numbers])
G. IX – Gag reflex
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H. X – Swallow
I.
XI – Shoulder shrug
J.
Tongue Protrusion (midline)
Score: left and right (except for G, H, J)
Grade: NORMAL or IMPAIRED and describe abnormality
10.11.1.3
Module 3 – Motor System
A. Muscle Tone
1. Ask the participant to relax.
Flex and extend the participant’s elbows and knees (bilaterally).
There is a small, continuous resistance to passive movement.
Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score: left and right
Grade: NORMAL, INCREASED or DECREASED
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
Test proximal limb strength by having the participant flex and extend the knees and 
elbows against your resistance.
Test bilaterally and compare one side to the other.
Score: left and right
Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
Test distal limb strength by having the participant conduct dorsiflexion and plantar 
flexion of the participant’s feet; finger abduction and handgrip strength against your 
resistance.
Test bilaterally, and compare one side to the other.
Score: left and right
Grade:
5/5: normal
4/5: movement against resistance impaired
3/5: movement against gravity but not against resistance
2/5: visible movement but not against gravity
1/5: visible contraction
0/5: no visible activity
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C. Pronator Drift
Ask the participant to hold both arms straight forward with, palms up and eyes closed for 
≈10 to 15 seconds as tolerated; watch for how well the arm position is maintained.
Instruct the participant to keep both arms still while you tap them briskly downward. The 
participant should normally be able to maintain extension and supination. Inability to 
maintain extension and supination (and drift into pronation) indicates an upper motor 
neuron deficit.
Score: left and right
Grade: NORMAL or IMPAIRED and describe abnormality
10.11.1.4
Module 4 – Reflexes
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at investigator's discretion (eg, elbow, 
wrist, or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED, or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
10.11.1.5
Module 5 – Coordination and Gait
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the participant to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the rapid alternate movements are disturbed, the participant will be 
asked to strike their hand on the thigh, raise the hand, turn it over and then strike the 
back of the hand down on the same place. (This test is impaired in cerebellar disease, 
extra pyramidal disease and upper motor neuron weakness.)
B. Point-to-Point Movements
1. Ask the participant to touch your index finger and their nose alternately several times. 
Move your finger about as the volunteer performs this task.
Score: left and right
Grade: NORMAL or IMPAIRED
Reminder: If the point-to-point testing is disturbed, the participant will be asked to 
place one heel on the opposite knee and then run it down the shin to the big toe. 
Repeat this for both sides. (Impaired tests indicate cerebellar disease.)
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C. Romberg
1. Ask the participant to stand with both feet together and eyes closed for 20 to 30 
seconds without support.
Be prepared to catch the participant if they are unstable.
Grade: NORMAL or IMPAIRED
D. Gait
1. Ask the participant to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs).
Grade: NORMAL or IMPAIRED and describe abnormality
Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.11.1.6
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
D. Vibration: tuning fork vibration detection in hands, feet bilaterally.
E. Position sense: perception of thumb and toe movement, bilaterally.
F. Stereognosis: (identify common objects placed in hand, [eg, coin, key, etc]).
Score: left and right
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F)
10.11.2
The Targeted Neurological Examination
The Targeted Neurological Examination, which is intended to focus on tests where drug 
effects can be seen, includes the following tests only:
10.11.2.1
Module 1 – Mental Status Examination
A. General Level of Arousal (generally assess general level of alertness, attentiveness, and 
concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example, difficulty remembering or following 
instructions or distractibility may be signs of inattention)
10.11.2.2
Module 2 – Cranial Nerve Assessment
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
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10.11.2.3
Module 3 – Motor System
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL or IMPAIRED and describe abnormality
10.11.2.4
Module 5 – Coordination and Gait
D. Gait
1. Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
10.11.2.5
Module 6 – Sensory
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
AAP
atypical antipsychotics
ADME
absorption, distribution, metabolism, and excretion
AME
Absorption, Metabolism, and Excretion
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
AUC0-24hr
area under the curve from 0 to 24 hours
AV
atrioventricular
BARS
Barnes Akathisia Rating Scale
BDS
blood drug screen
bid
twice daily
BMI
body mass index
bpm
beats per minute
BP
blood pressure
BRPS
Brief Psychiatric Rating Scale
cAMP
cyclic adenosine monohydrate
CCU
Cardiac care unit
CF
compact flash
cfb
change from baseline
CG
Cockcroft-Gault
cGMP
cyclic guanosine monohydrate
CI
confidence interval
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Abbreviation
Expanded Term
Cmax
maximum plasma concentration
CNS
central nervous system
CL
clearance
COVID-19
coronavirus disease 2019
CrCl
creatinine clearance
CR
controlled release
CRF
Case Report Form
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EPQT
extra precision QT
EPS
extrapyramidal symptoms
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Abbreviation
Expanded Term
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HSSB
Hepatic-specific Safety Board
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LLOQ
lower limit of quantitation
mRNA
messenger RNA
NCS
not clinically significant
NDA
New Drug Application
NOAEL
no observed adverse effect level
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Abbreviation
Expanded Term
NR
normal range
PCL
Protocol Clarification Letter
PD
pharmacodynamic
PK
pharmacokinetic
POCBP
participant of childbearing potential
PONCBP
participant of non-childbearing potential
PP
per-protocol
QD
once daily
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAS
Simpson Angus Scale
SD
standard deviation
SGA
second generation antipsychotics
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
SUSAR
suspected unexpected serious adverse reaction
Tmax
time to maximum plasma concentration
TdP
Torsades de Pointes
TD
Tardive dyskinesia
t½
half life
UDS
urine drug screen
ULN
upper limit of normal
UTN
Universal Trial Number
VS
vital signs
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Abbreviation
Expanded Term
WBC
white blood cell
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11
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[03RW0F]
[Seeger, T. F., et al 2003]
Seeger TF, Bartlett B, Coskran TM, Culp JS, 
James LC, Krull DL, et al. 
Immunohistochemical localization of PDE10A 
in the rat brain. Brain Res 2003;985:113-26.
[03RW0G]
08D3CJ
08RTSC


PRODUCT: MK-8189
142
PROTOCOL/AMENDMENT NO.: 019-02
MK-8189-019-02 FINAL PROTOCOL
16-AUG-2023
[U.S. Prescribing 
Information 2020]
U.S. Prescribing Information: 
MOXIFLOXACIN tablets for oral use: Oct 
2020.
[07VXSB]
08D3CJ
08RTSC