A Randomized, Double-Blind, Placebo-Controlled, Cross-over Evaluation of Evoked Responses as Pharmacodynamic Biomarkers in Healthy Adults and Schizophrenic Patients
Phase: PHASE1
Conditions: Cognitive Impairment Associated With Schizophrenia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
NCT05136690
Document Date:            21-Sep-2022
A Randomized, Double-Blind, Placebo-
Controlled, Cross-over Evaluation of Evoked 
Responses as Pharmacodynamic Biomarkers in 
Healthy Adults and Schizophrenic
Patients

PRODUCT: MK-4334  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, NJ, USA (MSD).
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Cross-over Evaluation of 
Evoked Responses as Pharmacodynamic Biomarkers in Healthy Adults and Schizophrenic 
Patients
Protocol Number: 007-04
Compound Number: MK-4334
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
157,663
Approval Date: 21 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
21-SEP-2022
Correct error to Hypotheses, Objectives, and Endpoints
Amendment 03
01-SEP-2022
To update the Sponsor entity name and address change
Amendment 02
15-MAR-2022
To add baseline EEGs to the study design
Amendment 01
01-DEC-2021
Corrections and clarifications
Original Protocol
03-SEP-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 007-04
Overall Rationale for the Amendments:
The text in the Endpoints were inadvertently changed
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
One of the secondary endpoints was changed to “Plasma 
nicotine levels at time of ERP recording” from “ITC 
magnitude derived from the 40 Hz-ASSR”.
This was inadvertently changed in 
Amendment 007-03 and this restores the 
original text. 
1.1 Synopsis
One of the endpoints in the first tertiary/exploratory 
endpoint was changed to “P3A, MMN magnitude derived 
from the DD-MMN” from “ITC magnitude derived from 
the 40 Hz-ASSR”.
This was inadvertently changed in 
Amendment 007-03 and this restores the 
original text.
3 Hypotheses, 
Objectives, and 
Endpoints
One of the endpoints in the first tertiary/exploratory 
endpoint was changed to “P3A, MMN magnitude derived 
from the DD-MMN” from “ITC magnitude derived from 
the 40 Hz-ASSR”.
This was inadvertently changed in 
Amendment 007-03 and this restores the 
original text.
3 Hypotheses, 
Objectives, and 
Endpoints
One of the endpoints in the second tertiary/exploratory 
endpoint was changed to “MMN, P3A magnitudes 
derived from the DD-MMN” from “MMN and P3A 
magnitudes derived from the DD-MMN”.
This makes the endpoint consistent between 
Section 1 and Section 3 of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................20
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................27
2.2
Background ..........................................................................................................28
2.2.1
Pharmaceutical and Therapeutic Background .............................................29
2.2.2
Preclinical and Clinical Studies ...................................................................29
2.2.3
Ongoing Clinical Studies.............................................................................29
2.2.4
A Randomized, Double-Blind, Placebo-Controlled, Cross-over 
Evaluation of Evoked Responses as Pharmacodynamic Biomarkers in 
Healthy Adults and Schizophrenic Patients.................................................30
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................30
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Efficacy Endpoints.............................................................................35
4.2.1.2
Safety Endpoints................................................................................35
4.2.1.3
Pharmacokinetic Endpoints ...............................................................35
4.2.1.4
Pharmacodynamic Endpoints/Biomarkers.........................................36
4.2.1.4.1
Passive, Duration-Deviant, Mismatch Negativity ERP...........36
4.2.1.4.2
20, 40 Hz-Auditory Steady State Responses ...........................36
4.2.1.4.3
Resting EEG.............................................................................37
4.2.1.5
Planned Exploratory Biomarker Research.........................................37
4.2.1.5.1
Planned Genetic Analysis ........................................................37
4.2.1.6
Future Biomedical Research..............................................................37
4.2.2
Rationale for the Use of Comparator/Placebo .............................................38
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................38
4.3
Justification for Dose...........................................................................................38
4.4
Beginning and End-of-Study Definition ............................................................39
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4.4.1
Clinical Criteria for Early Study Termination .............................................39
5
STUDY POPULATION ................................................................................................40
5.1
Inclusion Criteria.................................................................................................40
5.2
Exclusion Criteria................................................................................................42
5.3
Lifestyle Considerations......................................................................................46
5.3.1
Meals and Dietary Restrictions....................................................................46
5.3.1.1
Diet Restrictions.................................................................................46
5.3.1.2
Fruit Juice Restrictions ......................................................................46
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................46
5.3.2.1
Caffeine Restrictions..........................................................................46
5.3.2.2
Alcohol Restrictions...........................................................................47
5.3.2.3
Tobacco Restrictions..........................................................................47
5.3.3
Activity Restrictions ....................................................................................47
5.4
Screen Failures.....................................................................................................47
5.5
Participant Replacement Strategy......................................................................47
6
STUDY INTERVENTION............................................................................................47
6.1
Study Intervention(s) Administered...................................................................48
6.1.1
Medical Devices...........................................................................................50
6.2
Preparation/Handling/Storage/Accountability .................................................50
6.2.1
Dose Preparation..........................................................................................50
6.2.2
Handling, Storage, and Accountability........................................................50
6.3
Measures to Minimize Bias: Randomization and Blinding..............................51
6.3.1
Intervention Assignment..............................................................................51
6.3.2
Stratification.................................................................................................51
6.3.3
Blinding........................................................................................................51
6.4
Study Intervention Compliance..........................................................................52
6.5
Concomitant Therapy..........................................................................................52
6.5.1
Rescue Medications and Supportive Care ...................................................57
6.6
Dose Modification (Escalation/Titration/Other)...............................................57
6.6.1
Stopping Rules.............................................................................................57
6.7
Intervention After the End of the Study............................................................57
6.8
Clinical Supplies Disclosure................................................................................57
6.9
Standard Policies..................................................................................................58
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................58
7.1
Discontinuation of Study Intervention...............................................................58
7.2
Participant Withdrawal From the Study...........................................................58
7.3
Lost to Follow-up .................................................................................................59
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STUDY ASSESSMENTS AND PROCEDURES........................................................59
8.1
Administrative and General Procedures ...........................................................60
8.1.1
Informed Consent.........................................................................................60
8.1.1.1
General Informed Consent.................................................................60
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................61
8.1.2
Inclusion/Exclusion Criteria ........................................................................61
8.1.3
Participant Identification Card.....................................................................62
8.1.4
Medical History ...........................................................................................63
8.1.5
Prior and Concomitant Medications Review...............................................63
8.1.5.1
Prior Medications...............................................................................63
8.1.5.2
Concomitant Medications..................................................................63
8.1.6
Assignment of Screening Number...............................................................63
8.1.7
Assignment of Randomization Number.......................................................63
8.1.8
Study Intervention Administration ..............................................................64
8.1.8.1
Timing of Dose Administration.........................................................64
8.1.9
Discontinuation and Withdrawal .................................................................64
8.1.9.1
Withdrawal From Future Biomedical Research ................................65
8.1.10
Participant Blinding/Unblinding..................................................................65
8.1.11
Domiciling ...................................................................................................66
8.1.12
Calibration of Equipment.............................................................................66
8.2
Efficacy Assessments ...........................................................................................66
8.3
Safety Assessments...............................................................................................66
8.3.1
Complete Physical Examinations ................................................................67
8.3.2
Symptom Driven Physical Examinations ....................................................67
8.3.3
BMI..............................................................................................................67
8.3.4
Vital Signs....................................................................................................67
8.3.4.1
Resting Vital Signs ............................................................................68
8.3.4.2
Orthostatic Vital Signs.......................................................................68
8.3.4.3
Electrocardiograms ............................................................................68
8.3.5
Clinical Safety Laboratory Assessments .....................................................70
8.3.6
Pregnancy Testing........................................................................................70
8.3.7
Suicidal Ideation and Behavior Monitoring.................................................70
8.3.7.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................70
8.3.8
Photograph of Rash......................................................................................71
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................71
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................72
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......74
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...74
8.4.4
Regulatory Reporting Requirements for SAE .............................................74
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................75
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................75
8.4.7
Events of Clinical Interest............................................................................75
8.4.8
Medical Device and Drug-device Combination Products -
PQCs/Malfunctions......................................................................................76
8.5
Treatment of Overdose........................................................................................76
8.6
Pharmacokinetics.................................................................................................76
8.6.1
Blood Collection for MK-4334 Determinations..........................................76
8.6.2
Blood Collection for Plasma Nicotine Determinations ...............................76
8.7
Pharmacodynamics..............................................................................................76
8.8
Biomarkers ...........................................................................................................76
8.8.1
Planned Genetic Analysis Sample Collection..............................................77
8.9
Future Biomedical Research Sample Collection...............................................77
8.10
Visit Requirements...............................................................................................77
8.10.1
Screening......................................................................................................77
8.10.2
Treatment Period Visit.................................................................................77
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........78
8.10.4
Poststudy......................................................................................................78
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......78
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................79
9
STATISTICAL ANALYSIS PLAN .............................................................................80
9.1
Statistical Analysis Plan Summary.....................................................................80
9.2
Responsibility for Analyses.................................................................................80
9.3
Hypotheses/Estimation ........................................................................................81
9.4
Analysis Endpoints...............................................................................................82
9.5
Analysis Populations............................................................................................82
9.6
Statistical Methods...............................................................................................83
9.7
Interim Analyses ..................................................................................................85
9.8
Multiplicity ...........................................................................................................85
9.9
Sample Size and Power Calculations .................................................................85
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................86
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10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........86
10.1.1
Code of Conduct for Clinical Trials.............................................................86
10.1.2
Financial Disclosure.....................................................................................88
10.1.3
Data Protection.............................................................................................89
10.1.3.1
Confidentiality of Data ......................................................................89
10.1.3.2
Confidentiality of Participant Records...............................................89
10.1.3.3
Confidentiality of IRB/IEC Information............................................89
10.1.4
Committees Structure...................................................................................90
10.1.5
Publication Policy........................................................................................90
10.1.6
Compliance with Study Registration and Results Posting Requirements ...90
10.1.7
Compliance with Law, Audit, and Debarment ............................................90
10.1.8
Data Quality Assurance ...............................................................................91
10.1.9
Source Documents .......................................................................................92
10.1.10
Study and Site Closure.................................................................................92
10.2
Appendix 2: Clinical Laboratory Tests..............................................................93
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................94
10.3.1
Definition of AE ..........................................................................................94
10.3.2
Definition of SAE ........................................................................................95
10.3.3
Additional Events Reported.........................................................................96
10.3.4
Recording AE and SAE ...............................................................................96
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................97
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................99
10.4.1
Definitions....................................................................................................99
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ..100
10.5
Appendix 5: Contraceptive Guidance..............................................................101
10.5.1
Definitions..................................................................................................101
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................103
10.7
Appendix 7: Country-specific Requirements..................................................108
10.8
Appendix 8: Blood Volume Table ....................................................................109
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................110
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...112
10.11 Appendix 11: Mapping Between Suicidal Ideation and Behavior 
Categories and the C-SSRS...............................................................................113
10.12 Appendix 11: Abbreviations .............................................................................114
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REFERENCES.............................................................................................................118
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LIST OF TABLES
Table 1
Study Treatments .............................................................................................18
Table 2
Study Interventions..........................................................................................49
Table 3
Treatment Allocation. ......................................................................................51
Table 4
List of Restricted Medications.........................................................................53
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................73
Table 6
Pharmacokinetic (Blood) Collection Windows ...............................................78
Table 7
Sample Size Calculations.................................................................................85
Table 8
Protocol-required Safety Laboratory Assessments..........................................93
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LIST OF FIGURES
Figure 1
Schedule of Monitoring and Interventions ......................................................19
Figure 2
Relative Timing of Procedures During Each Treatment Session (Period). .....19
Figure 3
GBO are Generated by Networks of Pyramidal Neurons and Interneurons 
in the Cerebral Cortex......................................................................................25
Figure 4
ASSR are Derived from the GBO and are Altered in SZ Patients...................26
Figure 5
ITC Time/Frequency Analyses of the 40 Hz-ASSR........................................27
Figure 6
Correlation Between the ITC Values Averaged over 200-500 msec 
Latency Blocks: SZ vs HV Responses.............................................................28
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Cross-over Evaluation of 
Evoked Responses as Pharmacodynamic Biomarkers in Healthy Adults and Schizophrenic 
Patients
Short Title: Evoked Responses as Pharmacodynamic Biomarkers
Acronym: ASSR
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study population consists of healthy adult males and females (WONCBP) and male and 
female (WONCBP) patients with mild-to-moderate SZ, 18-55 years of age.
Objectives
Endpoints
Primary
Objective: Record and measure the 40 Hz-
ASSR in HC and SZ patients at baseline and 
determine whether the mean ITC magnitude 
derived from the 40 Hz-ASSR at baseline is 
lower in SZ patient than in HC.
Hypothesis: The mean magnitude of the ITC 
recorded from SZ patients at baseline will be 
lower than those recorded from HC at 
baseline.
ITC magnitude derived from the 40 Hz-
ASSR 
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Objectives
Endpoints
Secondary
Objective: Record and measure the DD-
MMN in HC and SZ patients at baseline and 
determine whether the mean MMN 
magnitude derived from the DD-MMN at 
baseline is lower in SZ patient than in HC. 
Hypothesis: The mean magnitude of the 
MMN derived from the DD-MMN recorded 
from SZ patients at baseline will be lower 
than that recorded from HC at baseline.
Objective: Determine if pharmacologically 
relevant plasma concentrations of nicotine 
change the mean magnitude of the 40 Hz-
ASSR ITC recorded from HC or SZ patients 
relative to placebo treatment.
Hypothesis: Pharmacologically relevant 
plasma levels of nicotine change the mean 
magnitude of the ITC recorded from HC or 
SZ patients relative to placebo treatment, 
with each subject group tested separately.
MMN magnitude derived from the DD-
MMN
ITC magnitude derived from the 40 Hz-
ASSR
Plasma nicotine levels at time of ERP 
recording
Tertiary/Exploratory
Exploratory Objective: Determine if 
pharmacologically relevant plasma 
concentrations of nicotine change the mean 
magnitude of the P3A, MMN or GBO 
recorded from HC or SZ patients relative to 
placebo treatment.
Estimation: Estimate difference between the 
treatment groups (nicotine vs. placebo) in the 
mean change from baseline in the magnitude 
of the P3A, MMN or GBO recorded from HC 
or SZ patients, with the difference for the two 
groups (HC and SZ) estimated separately.
P3A, MMN magnitude derived from the 
DD-MMN
Plasma nicotine levels at time of ERP 
recording
Resting GBO magnitude
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Objectives
Endpoints
Exploratory Objective: Determine if 
pharmacologically relevant plasma 
concentrations of MK-4334 change the mean 
magnitude of the 40 Hz-ASSR ITC, the 
MMN, P3A, or GBO recorded from HC or 
SZ patients relative to placebo treatment.
Estimation: Estimate difference between the 
treatment groups (MK-4334 vs. placebo) in 
the mean change from baseline in the 
magnitude of the 40 Hz-ASSR ITC, MMN, 
P3A or GBO recorded from HC or SZ 
patients, with the difference for the two 
groups (HC and SZ) estimated separately.
Exploratory Objective: To determine intra-
subject variability of ITC measurements 
collected using the 40 Hz-ASSR in HC and 
SZ patients at baseline conditions (Days -1, 7, 
13).
Estimation: Estimate intra-subject variability 
of ITC measurements collected using the 40 
Hz-ASSR in HC and SZ patients at baseline 
conditions (Days -1, 7, 13). More 
specifically, mean ITC over time (Days -1, 7, 
13) will be summarized and graphically 
displayed. Pairwise (Day -1 vs. Day 7 or Day 
-1 vs. Day 13) ICC will be estimated.  Scatter 
plot with diagonal line and Bland-Altman 
plot will also be presented. 
ITC magnitude derived from the 40 Hz-
ASSR 
MMN, P3A magnitudes derived from the 
DD-MMN
Plasma MK-4334 levels at time of ERP 
recording
Resting GBO magnitude
Exploratory Objective: To explore the 
relationship between the genetic variation and 
response to the treatment(s) administered and 
mechanisms of disease. Variation in 
CYP2C19 and across the human genome may 
be analyzed for association with the clinical 
data in this study.
Germline genetic variation and association 
with clinical data collected from this study 
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Overall Design:
Study Phase
Early Phase 1
Primary Purpose
Basic Science
Indication
Cognitive Impairment Associated with Schizophrenia
Population
Healthy adults and schizophrenic patients
Study Type
Interventional
Intervention Model
Cross-over
This is a multi-site study.
Type of Control
Double dummy placebo with active control
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 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 45 participants will be screened such that 36 will be randomized as evaluable 
participants to complete the study as described in Section 9.9.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period/ 
Use
Healthy 
Controls 
(HC, Panel A)
Nicotine
21 mg
Single dose
Topical (patch)
Single 
application
Exp
Nicotine 
placebo
patch
N/A
Single dose
Topical (patch)
2 single 
applications, 
7 or 14 days 
apart
Exp
MK-4334
250 mg
Single dose
PO
Single dose, 
250 mg
Exp
MK-4334 
placebo
N/A
Single dose
PO
2 single 
doses, 7 
days apart
Exp
Schizophrenic 
Patients 
(SZ, Panel B)
Nicotine
21 mg
Single dose
Topical (patch)
Single 
application
Exp
Nicotine 
placebo
patch
N/A
Single dose
Topical (patch)
2 single 
applications, 
7 or 14 days 
apart
Exp
MK-4334
250 mg
Single dose
PO
Single dose, 
250 mg 
Exp
MK-4334 
placebo
N/A
Single dose
PO
2 single 
doses, 7 
days apart
Exp
Abbreviations: Exp, experimental; N/A, not applicable; PO, per os (oral) 
Current or former name(s) or alias(es) for study intervention(s) is NicoDerm
CQ
Placebo: Tegaderm (Nexcare) patch
Total 
Number of 
Intervention 
Groups/
Arms
2 Panels, 2 parts, 3 periods
Duration of 
Participation
Each individual will participate in the study for approximately 80 days from 
the time they provide documented informed consent through the final 
contact. After a screening phase of up to 35 days, each participant will 
undergo study related procedures over a period of approximately 17 days. 
After all treatments are completed, each participant will be followed for an 
additional 28 days.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
There are no study governance committees for this investigation.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations is in Appendix 12.
1.2
Schema
The study design is depicted in Table 1, Figure 1, and Figure 2.
Table 1
Study Treatments 
Part 1
Part 2
Panel
Period 1
Period 2
Period 3
A

21 mg Nicotine patch + 
Capsule placebo; or

Capsule placebo+ Patch 
placebo

21 mg Nicotine patch 
+ Capsule placebo; or

Capsule placebo + 
Patch placebo

250 mg MK-4334 + 
Patch placebo; or 

Capsule placebo + 
Patch placebo
B

21 mg Nicotine patch + 
Capsule placebo; or

Capsule placebo+ Patch 
placebo

21 mg Nicotine patch 
+ Capsule placebo; or

Capsule placebo + 
Patch placebo

250 mg MK-4334 + 
Patch placebo; or 

Capsule placebo + 
Patch placebo
In Part 1, twelve (12) healthy controls (HC, Panel A) and 24 schizophrenic patients (SZ, 
Panel B) will receive either a nicotine patch (21 mg) and capsule placebo, or matching patch 
and capsule placebos in in a 1:1 active:placebo ratio within each panel in 2 periods (Periods 1 
and 2) in the cross-over design. 
In Part 2, Period 3, participants will be randomly assigned to receive either 250 mg MK-4334 
and patch placebo or patch and capsule placebos in a 3:1 active:placebo ratio within each 
panel.  Assignment of participants to their treatments will be determined according to a 
computer-generated allocation schedule. MK-4334/matching capsule placebo will be 
administered as a DFC formulation.
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Participants in both Panel A (HC, n = 12) and Panel B (SZ, n =24) will undergo the treatments outlined above. 
In Part 2, participants will be randomized to receive either MK-4334 (HC, n = 9; SZ, n = 18) or DD pbo (HC, n 
= 3; SZ, n = 6) treatment.
DD: Double dummy
Figure 1
Schedule of Monitoring and Interventions 
Representative example of the relative sequence of procedures to be conducted during each of the 3 treatment 
periods. The timing of the procedure, sequence, number and nature of the procedures may change as necessary.
ERP reflects recording of 20, 40 Hz ASSR and DD-MMN; EEG reflects recording of resting gamma EEG 
(GBO).
AE: adverse event, ASSR: auditory steady state response, DD-MMN: duration deviant mismatch negativity, 
ECG: electrocardiogram, EEG: electroencephalogram, GBO: gamma-band oscillation, PK: pharmacokinetics, 
VS: vital signs
Figure 2
Relative Timing of Procedures During Each Treatment Session (Period).
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1.3
Schedule of Activities
All Panels/Parts
Study Period:
Screening
Intervention (Days)
Post-Study
Notes
Scheduled Day
Up to day 
-35
-2
-1
1
6
7
8
13 14 15
43
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
X
Participant ID Card
X
Screening Procedures/Reviews
Medical History
X
Include substance usage: Drugs, alcohol, tobacco and caffeine; 
family history of systemic disease, mental illness
Prior/Concomitant 
Medication Review
X
X-------------------------------------------------------X
Height 
X
Weight (BMI)
X
Full physical examination
X
X
PE on Day 43 should be conducted within ≈4 hrs of the time of 
administration of the last dose of study intervention on Day 15.
Symptom driven physical 
examination
X
X
X
Neurological examination
X
X
NE on Day 43 should be conducted within ≈ 4 hrs of the time 
of administration of the last dose of study intervention on Day 
15.
Audiometry Test
X
To be administered to participants in both panels  
Tone Matching Test
X
To be administered to participants in both panels
MINI 7.0.2 Screen
X
To be administered to participants in both panels
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All Panels/Parts
Study Period:
Screening
Intervention (Days)
Post-Study
Notes
Scheduled Day
Up to day 
-35
-2
-1
1
6
7
8
13 14 15
43
PANSS (Complete 
Assessment)
X
X
X
X
X
SZ patients (Panel B). Inclusion criteria to be applied at 
screening and Day -2:
a. Delusions (item P1) score ≤ 4
b. Hallucinatory behavior (item P3) score ≤4
c. Unusual thought content (item G9) score ≤4
d. Conceptual disorganization (item P2) score ≤4 
e. Hostility (item P7) score ≤ 4.
f. Total score ≤80
WRAT-5
X
HC (Panel A) candidates and SZ patients (Panel B).
Only the Letter Reading and Word Reading portions are to be 
administered.
BACS
X
HC (Panel A) candidates and SZ patients (Panel B).
CDSS
X
SZ patients (Panel B). 
C-SSRS 
Screening/Baseline
version
X
C-SSRS SLA
X
X
X
X
HIV, hepatitis B and C 
screen
X
FSH screen (females only)
X
Drug Screen
X
X
X
X
X
Drug screen may be done upon arrival at the CRU for 
domiciling. Matrix taken for screening (blood, urine, saliva) to 
be determined by site and used through study
CYP2C19 Genotyping
X
Inclusion/Exclusion 
Criteria
X---------------X
Review I/E criteria prior to assigning randomization number
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All Panels/Parts
Study Period:
Screening
Intervention (Days)
Post-Study
Notes
Scheduled Day
Up to day 
-35
-2
-1
1
6
7
8
13 14 15
43
Domiciling
X
X
X
X
X
X
Participants should be instructed to arrive in the afternoon 2 
days before their intervention administration date to provide 
sufficient time for pre-intervention processing and are expected 
to spend two nights domiciled.
Assignment of 
Treatment/Randomization 
Number
X
X
Participants will each receive a randomization number for Part 
1 and will then be re-randomized (with a new randomization 
number) for continuation in Part 2. Randomization can occur 
on Day 1 predose if results are still pending on Day -1.
Meals
X------------------------------------X
In addition to providing meals during domiciling, a meal may 
be offered after completion of all safety measures post-
recording and prior to site exit for periods 1-3.
Intervention Administration
Nicotine or patch placebo 
Administration
X
X
X
MK-4334 or capsule 
placebo Administration
X
X
X
Safety Procedures
Vital Signs (HR, BP, RR, 
BT)
X
X-------------------------------------------------------X
Triplicate measures of supine HR and BP will be taken on Day 
-2 as baseline reference before taking single measures of BT, 
RR and any recordings. Single VS (HR, BP, BT, RR) measures 
will be taken on days 6 and 13 after admission to the study site
and on days 1, 8, and 15 at predose, ≈ 2 (nicotine/pbo) or 4 
(MK/pbo) hrs postdose (before recording session) and again at 
≈ 3 (nicotine/pbo), or 5 (MK/pbo) hrs (after recording session). 
VS measures out of normal range will be repeated up to 3 times 
in 15 minutes, or until measures return to normal.
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All Panels/Parts
Study Period:
Screening
Intervention (Days)
Post-Study
Notes
Scheduled Day
Up to day 
-35
-2
-1
1
6
7
8
13 14 15
43
Orthostatic VS (HR, BP)
X
X
X
X
X
X
X
X
Orthostatic HR and BP to be taken on Days -2, 6 and 13 after 
completion of the VS measures. Additional orthostatic VS 
measures will be taken after completing the VS measures on 
days 1, 8, and 15 at predose and again at ≈ 3 (nicotine/pbo), or 
5 (MK/pbo) hrs postdose, or ≈ 1 hr after completing the 
recording session. Participants should be supine for at least 
10 minutes and then stand upright.  Measures of orthostatic VS 
will be taken after 1 min and 3 min of standing.
12-lead ECG
X
X
X
X
X
X
X
X
Single ECGs will be recorded on Days -2, 6, and 13 after VS 
measures. Additional ECGs will be recorded on Days 1, 8, and 
15 predose at ≈ 3 (nicotine/pbo), or 5 (MK/pbo) hrs postdose (≈ 
1 hr after completing the recording session) and on Day 43 at 
approximately the same time as during the intervention period.  
Hematology
X
X
X
X
X
Blood samples will be taken at screening and on Days -1, 7, 14, 
and 43.
Chemistry
X
X
X
X
X
Blood samples will be taken at screening and on Days -1, 7, 14 
and 43.
Urinalysis
X
X
X
Sample will be taken at screening and on Days -1 and 43.
AE/SAE Review
       X-------------------------------------------------------------X
EEG/ERP Recording Session
Passive, duration-deviant 
mismatch negativity
X
X
X
X
X
X
DD-MMN will be recorded at baseline, predose and ≈2 hrs 
post-nicotine or 4 hrs post MK-4334 administration
20, 40 Hz-ASSR
X
X
X
X
X
X
40 Hz-ASSR will be recorded at baseline, pre-dose and ≈2 or 4 
hrs post-nicotine or MK-4334 dosing, respectively.  Similarly, 
20 Hz-ASSR will be recorded at ≈C2 or C4.
Resting EEG
X
X
X
X
X
X
Resting EEG/GBO will be recorded at baseline, predose and ≈
2 hrs post-nicotine or 4 hrs post MK-4334 administration
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All Panels/Parts
Study Period:
Screening
Intervention (Days)
Post-Study
Notes
Scheduled Day
Up to day 
-35
-2
-1
1
6
7
8
13 14 15
43
Blood Sampling
Blood for MK-4334 assay
X
Blood samples will be taken on Day 15 at predose and at ≈ 4 
hrs postdose, after VS, ECG measures and before recording.
Blood for nicotine assays
X
X
X
X
X
X
X
X
X
X
Blood samples for nicotine assessments will be taken at 
Screening and during all intervention days.  A single sample 
will be taken on the first day of domiciling (Days -2 6, 13).  On 
days when baseline recordings are being taken (Days -1, 7, 14), 
a sample will be taken just before recording.  On days when 
study treatment is being administered (Days 1, 8, 15), samples 
will be taken predose and at ≈2 hrs post administration of 
study intervention. In all cases, blood sampling will occur after 
taking VS, ECG measures.
Blood for cotinine assays
X
Blood samples will be taken at screening for measures of 
cotinine levels to validate chronic nicotine use. Sampling will 
occur after taking VS, ECG measures.
Biomarkers
Blood for Genetic 
Analysis 
X
Collect predose only from enrolled participants during period 1. 
(See section 8.8.1) Sample can also be collected on Day 1 
Predose.
     
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2
INTRODUCTION
SZ is a disabling neuropsychiatric disorder characterized by clinical symptom clusters 
(positive and negative) and cognitive deficits [Parciauskaite, V., et al 2019]. The range of 
cognitive deficits observed in SZ suggests the presence of substantial abnormalities in 
adapting thoughts or behaviors to achieve goals [Lesh, T. A., et al 2011], consistent with a 
loss of coordination in the neuronal activity of multiple brain regions [Light, G. A., et al 
2006]. Of several oscillation bands of neuronal activity implicated in brain function, the 
GBO (ranging from 30–80 Hz, centering around 40 Hz) arising from neural networks in the 
cortex and brainstem act as a key neural substrate for cognitive processes and the 
coordination of network activity across brain regions [Miller, E. K. 2001], [Howard, M. W., 
et al 2003]. GBO are generated by fast-spiking, parvalbumin-positive, GABAergic 
interneurons (PVI) residing in neural networks in the prefrontal cortex and superior temporal 
gyrus [Lewis, D. A., et al 2012] (Figure 3). Alterations in the synchronization of GBO may 
result from abnormalities in both pre- and post-synaptic function of these networks due to 
imbalances in glutamatergic and/or GABAergic neurotransmission.
Phasic, excitatory inputs to the PVI from cortical pyramidal neurons result in feedback inhibition of the 
pyramidal neurons, synchronizing their activity. Alterations in the synchronization of this oscillation may result 
from abnormalities in glutamatergic signaling due to decreased glutamate release from the pyramidal neurons, 
decreased density of glutamatergic receptors on PVI, or loss of PVI. Modified from [Lewis, D. A., et al 2012]
Figure 3
GBO are Generated by Networks of Pyramidal Neurons and Interneurons in the 
Cerebral Cortex.
The ability of the brain to generate GBO in response to stimuli can be monitored using the 
ASSR [Kwon, J. S., et al 1999]. ASSRs are elicited by temporally modulated auditory 
stimuli, such as a train of 40 Hz clicks (Figure 4A). This stimulus train evokes synchronous 
neuronal oscillations in the γ frequency band that remain constant in amplitude and phase 
over time (Figure 3B) [O'Donnell, B. F., et al 2013], [Uhlhaas, P. J. 2010]. The evoked EEG 
signal is filtered (Figure 4B) and processed by FFT (Figure 4C), allowing the derivation and 
quantitation of event-related changes in GBO to be determined (eg, EP, ITC), (Figure 4D), 
(Figure 5).
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(A) The 40 Hz-ASSR is elicited using an auditory stimulus of 40 Hz click trains with a 500 msec inter-train interval. (B) 
These evoke a GBO waveform that is averaged and filtered (39-41 Hz). Note that the regularity (phase) and amplitude of the 
GBO recorded from the SZ patient is disorganized relative to that from HC. (C) A power spectrum is obtained by processing 
the GBO using a FFT. Note that the amplitude of the 40 Hz response from the HC group is reduced in the SZ group. (D) 
Heat map of the EP across the stimulus epoch. The average change from baseline in EP is centered at 40 Hz (Y axis), with 
the area of highest amplitude lasting ≈ 0.5 seconds (X axis). The colors represent the power amplitude, with red signifying 
the highest voltage. Modified from [O'Donnell, B. F., et al 2013].
Figure 4
ASSR are Derived from the GBO and are Altered in SZ Patients.
Abnormalities in the EP and ITC (Figure 4, Figure 5) are observed in SZ patients and are 
believed to reflect NMDA receptor/glutamatergic hypofunction [Kim, J. S., et al 1980], 
[Tamminga, C. A. 1998] [Coyle, J. T. 2006]. This is supported by the observation that 
inhibition of glutamatergic signaling using NMDA receptor antagonists such as ketamine 
induces a psychotomimetic state analogous to SZ [Lahti, A. C., et al 1995]. Together, these 
observations support the hypothesis that glutamatergic hypofunction is involved in GBO 
abnormalities which contribute to the pathophysiological manifestations of SZ, including 
cognitive impairment [Dauvermann, M. R., et al 2017].
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Heat maps show the correlation with on vs off stimuli between trials conducted in healthy controls (A) and SZ 
patients (B). Color indicates the magnitude of phase coherence (0 = no consistent phase locking across trials; 1 
= absolute phase consistency across trials). ITC increases in response to faster stimulation rates, with maximal 
EEG coherence at 40 Hz stimulation. SZ patients show significant deficits in ITC relative to healthy controls. 
Modified from [Light, G. A., et al 2006]. 
Figure 5
ITC Time/Frequency Analyses of the 40 Hz-ASSR. 
The glutamatergic hypofunction underlying these electrophysiological and cognitive 
impairments in SZ may be ameliorated by the administration of agents that activate 
glutamatergic pathways. While orthosteric agonists of glutamate receptors have not been 
successful in improving SZ symptomatology, it is commonly observed that SZ patients are 
frequent users of tobacco and nicotine containing products [Hughes, J. R., et al 1986],
[Leonard, S., et al 1996]. This may reflect the ability of nicotinic cholinergic receptor 
agonists to increase synaptic release of glutamate [Fedele, E., et al 1998], reversing the 
glutamatergic hypofunction and acutely alleviating some of the symptoms of SZ [Glynn, S. 
M. 1990]. Such an observation would support the use of selective nicotinic receptor 
activators such as the 
 MK-4334 as treatments for CIAS [Olincy, A. 2012]. 
2.1
Study Rationale
This study is designed to evaluate the suitability of the 40 Hz-ASSR as a PD biomarker that 
can be used to identify the range of potentially efficacious doses of treatments for CIAS. Of 
the 2 ASSR endpoints (EP, ITC), the timing of the ITC reflects the abnormality in spike 
timing in pyramidal neuron networks observed in SZ, is very stable and can be recorded with 
high reliability both between tests at a given site and between investigational sites (Figure 6). 
Therefore, the study will evaluate the difference in ITC magnitude between HC and SZ 
patients, measure the change in ITC magnitude in these populations in response to a positive 
control (nicotine) and explore ITC responses to administration of
, 
MK-4334. Successful achievement of these goals will support the use of the ASSR in future 
investigations as a PD biomarker.
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Rationale for Amendment 007-02
Baseline ERP measurements are being taken before each treatment session to help 
compensate for any changes in electrophysiology over the course of the investigation.  
However, the baseline measure of the resting gamma band EEG (GBO) was inadvertently 
left out from previous versions of the protocol.  For consistency with the overall 
experimental design, the baseline recording session for the GBO is now included in the SoA 
on days -1, 7 and 14.
A) The ITC parameters recorded from healthy volunteers (HV, blue circles) and schizophrenic patients (SZ, red 
circles) do not significantly differ between recording sessions conducted 1 week apart.  Mean difference 
between baseline vs retest: HC, -0.00544 ± 0.133; SZ, 0.0149 ± 0.101.  B) Between site variability.  Each point 
represents the average ITC from HV (red circles) and SZ patients (blue circles) recorded from 4 different study 
sites.  Overall intraclass correlation coefficient (ICC) = 0.7426 (Merck internal analysis of data obtained from 
ERP Biomarker Qualification Consortium protocol EBS-A V2).
Figure 6
Correlation Between the ITC Values Averaged over 200-500 msec Latency 
Blocks: SZ vs HV Responses.
2.2
Background
Refer to the IB for detailed background information on MK-4334.
While the magnitude of 40 Hz-ASSR parameters (EP, ITC) is reportedly reduced in SZ 
patients relative to healthy controls, this difference has not been consistently observed, due in 
part to the lack of uniformity in recording techniques. Moreover, the ability of either the ITC
or EP to be pharmacologically modulated has not been established. Given the hypothesis that 
GBO synchronization depends on glutamatergic transmission within the cortical neuron 
network, this pathophysiology may be ameliorated by activating glutamatergic pathways in 
SZ patients indirectly by the administration of nicotinic cholinergic receptor activators. 
Therefore, the agents used in this study include the non-selective, nicotinic cholinergic 
receptor orthosteric agonist nicotine, which reverses the deficits in evoked responses 
recorded from SZ patients [Domino, E. F. 2003], [Dulude, L., et al 2010] and in the ASSR 
recorded from preclinical models [Sivarao, D. V., et al 2016]. In addition, the 
 
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MK-4334 will be administered to evaluate the involvement of the α7 nicotinic 
cholinergic receptor subtype in modulating the 40 Hz-ASSR [Preskorn, S. H., et al 2014],
[Antonio-Tolentino, K. 2020]. The ability of either of these agents to reverse or normalize 
the deficits in the 40 Hz-ASSR ITC would support the use of the 40 Hz-ASSR as PD
biomarker for assessing the mechanism of action and effective dose range of novel 
antipsychotics/cognitive enhancers that act to increase glutamatergic activity. 
2.2.1
Pharmaceutical and Therapeutic Background
MK-4334 is 
 
under development for treating cognitive impairment
 Evidence 
from preclinical investigations indicates that it may increase glutamatergic neurotransmission 
as part of its downstream mechanisms of action. Detailed information on the pharmacology, 
PK, safety, and toxicity of MK-4334 is provided in the IB. 
The nicotine patch administered during this study is approved for OTC use to aid in smoking 
cessation.
2.2.2
Preclinical and Clinical Studies
Extensive preclinical work characterizing the pharmacology of MK-4334 has been performed 
and is described in the IB. To date, 4 clinical studies of MK-4334 have been completed and 
their outcomes are described in the IB. 
2.2.3
Ongoing Clinical Studies
MK-4334-006 is a 2-part study evaluating the use of selPOCE-MRS for measuring in vivo 
the FE of glu and gln with 13C in vivo in the brain and the changes in glutamatergic signaling 
and neuroenergetics in response to administration of dl-ketamine or MK-4334.  Part 1 of the 
study will assess the intra-subject T/RT variability in baseline measures of the FE of 13C-glu 
and 13C-gln in the prefrontal cortex of healthy adult males between 2 scans separated by a 
minimum of 7 days. No pharmacologic interventions or placebo are administered during this 
part of the study. Part 2 will evaluate the effects of ketamine or the 
 MK-4334 on the 
turnover of glu and gln (FE of 13C-glu, gln), an additional measure of glu turnover (eg, the 
ratio of [3-13C] to [4-13C] glutamate), the rate of glu to gln cycling (Vcyc) and the rate of 
oxidative metabolism linked to glutamatergic neurotransmission (VTCA) will be compared 
to placebo treatment as exploratory objectives. Successful completion of this study will 
validate selPOCE-MRS as a technique suitable for monitoring changes in glutamatergic 
activity in response to pharmacologic interventions, serving as a biomarker of the PD 
modulation of glutamatergic neurotransmission.
As of 12 Aug 2021, 3 participants have been infused with 13C-glucose in Part 1. Two 
participants have received a single infusion, one has received 2 infusions spaced 1 week
apart. No other investigational treatments have been administered. There have been no SAEs, 
deaths, or ECIs. The only AEs reported were an abnormal ECG considered NCS and not 
related to treatment, and an inability to tolerate confinement in the MRI chamber for the 
duration of the scan (2 hours).
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2.2.4
A Randomized, Double-Blind, Placebo-Controlled, Cross-over Evaluation of 
Evoked Responses as Pharmacodynamic Biomarkers in Healthy Adults and 
Schizophrenic Patients
Nicotine is a non-selective orthosteric agonist of nicotinic cholinergic receptors. It will be 
administered by transdermal patch. Additional information about the nicotine patch is 
outlined in the product label (Operations Manual).
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.
It is not expected that the nicotine patch will cause any untoward responses from the 
participants due to their previous exposure to nicotine in tobacco products. Nonetheless, 
some participants may experience transient dizziness, headache, nausea and stomach upset
following patch application (see Operations Manual for nicotine patch label). To reduce the 
risk of experiencing these effects, all study participants will be fasted at least 2 hours before 
administration of study treatment. Treatment of nicotine induced nausea / vomiting is at the 
discretion of the investigator.
MK-4334 has undergone extensive acute safety testing, both in the clinic and preclinical 
models. A summary of potential risks can be found in the IB. These risks are expected to be 
minimal due to the acute (single dose) nature of administration. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study population consists of healthy adult males and females (WONCBP) and male and 
female (WONCBP) patients with mild-to-moderate SZ, 18-55 years of age.
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Objectives
Endpoints
Primary
Objective: Record and measure the 40 Hz-
ASSR in HC and SZ patients at baseline and 
determine whether the mean ITC magnitude 
derived from the 40 Hz-ASSR at baseline is 
lower in SZ patient than in HC.
Hypothesis: The mean magnitude of the ITC 
recorded from SZ patients at baseline will be 
lower than those recorded from HC at 
baseline.
ITC magnitude derived from the 40 Hz-
ASSR 
Secondary
Objective: Record and measure the DD-
MMN in HC and SZ patients at baseline and 
determine whether the mean MMN 
magnitude derived from the DD-MMN at 
baseline is lower in SZ patient than in HC. 
Hypothesis: The mean magnitude of the 
MMN derived from the DD-MMN recorded 
from SZ patients at baseline will be lower 
than that recorded from HC at baseline.
Objective: Determine if pharmacologically 
relevant plasma concentrations of nicotine 
change the mean magnitude of the 40 Hz-
ASSR ITC recorded from HC or SZ patients
relative to placebo treatment.
Hypothesis: Pharmacologically relevant 
plasma levels of nicotine change the mean 
magnitude of the ITC recorded from HC or 
SZ patients relative to placebo treatment, 
with each subject group tested separately.
MMN magnitude derived from the DD-
MMN
ITC magnitude derived from the 40 Hz-
ASSR
Plasma nicotine levels at time of ERP 
recording
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Objectives
Endpoints
Tertiary/Exploratory
Exploratory Objective: Determine if 
pharmacologically relevant plasma 
concentrations of nicotine change the mean 
magnitude of the P3A, MMN or GBO 
recorded from HC or SZ patients relative to 
placebo treatment.
Estimation: Estimate difference between the 
treatment groups (nicotine vs. placebo) in the 
mean change from baseline in the magnitude 
of the P3A, MMN or GBO recorded from HC 
or SZ patients, with the difference for the two 
groups (HC and SZ) estimated separately.
P3A, MMN magnitude derived from the 
DD-MMN
Plasma nicotine levels at time of ERP 
recording
Resting GBO magnitude
Exploratory Objective: Determine if 
pharmacologically relevant plasma 
concentrations of MK-4334 change the mean 
magnitude of the 40 Hz-ASSR ITC, the 
MMN, P3A, or GBO recorded from HC or 
SZ patients relative to placebo treatment.
Estimation: Estimate difference between the 
treatment groups (MK-4334 vs. placebo) in 
the mean change from baseline in the 
magnitude of the 40 Hz-ASSR ITC, MMN, 
P3A or GBO recorded from HC or SZ 
patients, with the difference for the two 
groups (HC and SZ) estimated separately.
Exploratory Objective: To determine intra-
subject variability of ITC measurements 
collected using the 40 Hz-ASSR in HC and 
SZ patients at baseline conditions (Days -1, 7, 
13).
Estimation: Estimate intra-subject variability 
of ITC measurements collected using the 40 
Hz-ASSR in HC and SZ patients at baseline 
conditions (Days -1, 7, 13). More 
specifically, mean ITC over time (Days -1, 7, 
13) will be summarized and graphically 
displayed. Pairwise (Day -1 vs. Day 7 or Day 
-1 vs. Day 13) ICC will be estimated.  Scatter 
plot with diagonal line and Bland-Altman 
plot will also be presented. 
ITC magnitude derived from the 40 Hz-
ASSR 
MMN, P3A magnitudes derived from the 
DD-MMN
Plasma MK-4334 levels at time of ERP 
recording
Resting GBO magnitude
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Objectives
Endpoints
Exploratory Objective: To explore the 
relationship between the genetic variation and 
response to the treatment(s) administered and 
mechanisms of disease. Variation in 
CYP2C19 and across the human genome may 
be analyzed for association with the clinical 
data in this study.
Germline genetic variation and association 
with clinical data collected from this study 
4
STUDY DESIGN
4.1
Overall Design
This study is a randomized, double-blind, placebo controlled, cross-over investigation with 2 
panels of participants, to be conducted in 2 parts. The 2 panels consist of male and female 
(WONCBP) HC (Panel A, n = 12) or SZ patients (Panel B, n = 24) who range in age from 18
to 55 years of age, are moderate users of tobacco (≈ 10-15 cigarettes/day) for at least 1 year
but are otherwise healthy. ERP/EEG will be recorded from participants in each panel to 
obtain time-matched baseline data as well as after administering study intervention during 
each of the 3 treatment periods. In addition, 20 Hz-ASSR will be recorded during all 
treatment periods to serve as a control for the specificity (eg, psychiatric status and drug 
effect) of the 40 Hz-ASSR. 
In Part 1, participants will be treated with either a nicotine patch + a capsule placebo, or a 
patch placebo + a capsule placebo in cross-over fashion (Figure 1, Table 1), with a 1 week 
washout between treatment periods. During Part 2, participants will be randomized for 
treatment with either MK-4334 + patch placebo, or capsule placebo + patch placebo in a 3:1
active:placebo ratio. Both the participants and PI will be blinded to treatment. The controls 
will consist of matched, double-dummy placebos for both the transdermal nicotine patch and 
the MK-4334 DFC. Nicotine is being included as an active control for the effect of nicotinic 
cholinergic activation on ERPs. Participants will be randomized to the order of treatment in 
the first part of the study, then randomized again for the receipt of either MK-4334 or 
placebo in the second part of the study. Each participant will be involved in the study for a 
total of ≈ 80 days, including screening, intervention, and follow-up phases. In addition to 
recording the evoked potentials, all participants will undergo safety and PK monitoring 
during each intervention period and at the post-treatment follow-up. Participant safety will be 
monitored by recording AEs, measuring VS, recording 12-lead ECGs, conducting lab safety 
tests, PE and NE.
This study will use the COGNISION® Systems EEG/ERP recording device to measure the 
EP and ITC components of the 20, 40 Hz-ASSR and the other EEG and ERPs being 
monitored. Baseline recording sessions (recording 20, 40 Hz-ASSR, DD-MMN, GBO/EEG) 
will be conducted the day before administration of study interventions and time matched to 
the recording sessions conducted on treatment days to avoid diurnal variation. During the 
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Screening Visit, SZ patients and HC will undergo informed consent procedures, a urine drug 
screen, alcohol breath test, family and medical history, concomitant medications review,
physical and neurological exams, and blood sampling for nicotine/cotinine levels. The SZ 
patient medical history review must confirm a duration of illness of at least 1 year, that they 
are clinically stable and in the non-acute phase of illness for at least 12 weeks. A review of 
concomitant medications must show that the SZ patients have been on stable medications for 
at least 8 weeks. There will be no washout of antipsychotic medications.
The precise timing of ERP recording, ECGs, blood sampling for PK, clinical and hematology 
labs and/or other procedures may be altered at any time during the study based on newly 
available data.  Similarly, the conditions (eg, electrode placement, auditory stimulus 
parameters, post dose-recording time) for conducting and recording the ERPs may be altered 
at any time during the study based on newly available data. Finally, the doses (not to exceed 
21 mg nicotine and 250 mg MK-4334) and administration times of either nicotine or 
MK-4334 may be altered in response to newly available information.
Because this is a Phase 1 assessment of MK-4334 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 PD biomarker of the action of antipsychotic therapeutics is currently not available. Such a 
biomarker would greatly aid in determining target engagement, and a safe and potentially 
effective dose range for an agent under development. Moreover, a PD biomarker may 
provide insight into the potential efficacy of an agent in a shorter period of time than a proof-
of-concept study. Because alterations in glutamatergic neurotransmission are believed to 
contribute to the pathogenesis of SZ [Coyle, J. T. 2006] and SZ patients commonly self-
medicate with nicotine [Glynn, S. M. 1990], [Hughes, J. R., et al 1986], possibly due to its 
ability to modulate glutamatergic pathways [Fedele, E., et al 1998], this study will evaluate 
the effects of 2 nicotinic receptor activators on ERP parameters in an exploratory fashion.
4.2.1
Rationale for Endpoints
The purpose of this study is to characterize the utility of the 40 Hz-ASSR as a 
pharmacodynamic biomarker. To this end, the primary objective of the study is to validate 
the ability of the COGNISIONERP recording system to differentiate between HC and SZ 
patients on the basis of the difference in magnitudes of the ITC of the 40 Hz-ASSR. 
Additional endpoints to be explored include monitoring the ability of two pharmacologic 
treatments known to enhance glutamatergic neurotransmission by activating specific 
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nicotinic cholinergic receptors in the brain to modulate ERP magnitude (P3A, MMN and 
ITC) and EEG parameters (resting γ-EEG). 
4.2.1.1
Efficacy Endpoints
Not Applicable
4.2.1.2
Safety Endpoints
The safety and tolerability of MK-4334 and nicotine when administered as single doses will 
be monitored throughout the study by collecting the following safety endpoints: direct 
assessment/reporting of AEs; physical exams; C-SSRS endpoints; supine and orthostatic VS 
measures (SBP, DBP, HR, RR, BT); 12-lead ECG parameters; and laboratory safety tests 
(serum chemistry, hematology, and urinalysis). 
ECG and VS monitoring (Section 8.0) will be scheduled prior to starting treatment on each 
intervention day, in proximity to the times when steady state plasma levels of nicotine 
(2 hours post application, C2) and MK-4334 (4 hours post administration, C4) have been 
achieved, but before ERP recording, and after completing all recording procedures (Figure 2). 
The C-SSRS prospective assessment of suicidal ideation and behavior will be included in this 
study in compliance with the 2012 FDA guidance requiring prospective assessment in 
clinical trials conducted under IND applications and trials that are intended for submission in 
a NDA to the Neurology or Psychiatry Divisions of the FDA or biologics license application, 
as well as assessment in trials 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). The Baseline/ 
Screening version of the C-SSRS will be administered at screening, while the Since Last 
Assessment version of the C-SSRS/SLA will be given at several points during and after 
intervention administration to all subjects enrolled, including at the Post-trial visit (see 
Section 8.0).
4.2.1.3
Pharmacokinetic Endpoints
Blood samples will be taken at approximately C2 for nicotine and prior to ERP recording for 
the determination of plasma concentrations of nicotine following the administration of 
nicotine/placebo. This reflects the approximately 2 hours it takes for nicotine levels to 
achieve steady state when using a topical patch [Rasmussen, S., et al 2018]. Plasma MK-
4334 levels will be determined in samples taken at approximately C4 after administration of 
MK-4334/placebo and prior to ERP recording. While the Tmax for MK-4334 ranges from 2 
to 24 hours, the 4 hour post-dose sampling time approximates the achievement of steady state 
plasma levels and is of reasonable time post-dose to accommodate study procedures within 
the treatment day (refer to MK-4334 IB for more information). Plasma concentrations of 
nicotine and MK-4334 will be correlated with the magnitude of the effect on ERP parameters 
to validate that any changes observed in the ERP are associated with pharmacologically 
significant plasma levels of the agents. Any plasma remaining from the MK-4334 samples 
will be retained for future use. 
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Samples taken at screening and prior to intervention administration for measures of plasma 
nicotine and cotinine levels will be used for monitoring nicotine consumption outside of the 
study parameters over the previous 2 and 30 hours [Hill, P., et al 1983].
4.2.1.4
Pharmacodynamic Endpoints/Biomarkers
All EEG/ERP assessments will be performed using the COGNISION® System. The 
COGNISION® System has been approved by the FDA for clinical use, 510(k): K141316. 
The system is a general-purpose EEG/ERP system composed of an electrode cap, which 
records from 7 active electrode channels, a battery powered headset control unit (HCU) with 
integrated response capture buttons, and medical grade insert earphones. The active 
electrodes are electrically coupled to the scalp using pre-gelled HydroDot® Biosensors. All 
study-related information is stored on the system’s online database hosted in the Microsoft 
Azure environment.
During the EEG/ERP testing session, the participant will be seated comfortably in a chair 
facing a table on which a computer monitor is placed. The COGNISION® Headset is applied 
and a disposable chinstrap is secured to hold the Headset in place. The Biosensors are then 
inserted in each of 10 electrode pod locations. The Biosensors will not be used during the 
audiometry and tone-matching tests conducted at the Screening Visit (See Section 8.3.6 for a 
description of these screening tests). The participant is then asked to hold the handset and 
place the thumb on their dominant hand on one of the action buttons on the handset. Upon 
completion of the instructions, insert earphones with disposable tips are placed in their ears. 
The participant is now ready to begin the testing session. The COGNISION® system will be 
used to conduct and record the ERPs described below. Additional information on the 
stimulus/recording parameters can be found in the Operations Manual.
4.2.1.4.1
Passive, Duration-Deviant, Mismatch Negativity ERP
In this paradigm, 2 tones of the same frequency and sound intensity, one of short duration 
(Standard) and one of either shorter or longer duration than the standard (Deviant) are 
sequentially presented to the participant through insert earphones. The Standard stimuli are 
presented more often than Deviant stimuli. While the auditory stimuli are being presented to 
the participant, they are instructed to watch a short cartoon video on a computer monitor 
positioned in front of them. The sound on the video is turned off. The participant is asked to 
abstain from performing any tasks while watching the video. The testing session lasts 
approximately 12 minutes (Figure 2).  Characteristics of the stimulus are provided in the 
Operations Manual. 
4.2.1.4.2
20, 40 Hz-Auditory Steady State Responses
In this paradigm, a short stream of clicks is repeatedly presented to the participant through 
insert earphones (see Operations Manual). While the clickstreams are being presented, the 
participant is instructed to fix their gaze on a white cross displayed on a computer monitor 
positioned in front of them. The participant is asked not to perform any task while watching 
the video. 
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As a control for the specificity of the ASSR responses to the disease state, two sets of tone 
stimuli will be administered, the standard, 40 Hz tone and an additional 20 Hz tone [Light, G. 
A., et al 2006]. The magnitude of the ITC in response to the 40 Hz tone should be reduced in 
SZ patients relative to HC, while the magnitude of the ITC in response to the 20 Hz tone 
should be the same in both HC and SZ participants.
Each testing session will last approximately 4 minutes.
4.2.1.4.3
Resting EEG
In this paradigm, the subject is asked to close their eyes and relax while γ-band EEGs are 
recorded. This testing session lasts approximately 6 minutes.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
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, polymorphisms of CYP2C19 will 
be specifically investigated. MK-4334 is oxidized by CYP2C19. Participants with certain 
allelic variants of the CYP2C19 gene have been shown to have alterations in MK-4334 
metabolism, resulting in changes in systemic exposures. Therefore, the relationship between 
CYP2C19 polymorphisms identified in participants tested at screening and the plasma levels 
of MK-4334 and other clinical endpoints will be explored.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebos for both nicotine and MK-4334 will be used to maintain study blinding and reduce 
bias. A crossover design will be used for nicotine/pbo interventions in Periods 1 and 2, 
allowing each participant to serve as their own control. A randomized allocation of 
participants to either MK-4334 or pbo (3:1) will be used in Period 3, allowing within-period 
comparison of the mean active intervention group response to that of pbo. Because of the 
different routes of administration of nicotine (topical) and MK-4334 (oral), this study is 
designed to use placebos for both the active comparator (nicotine patch) and the active 
intervention (MK-4334 capsule). To maintain participant blinding, both placebos will be 
administered throughout all periods of the study
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or BLA, as well as assessment in studies that fall within the 
guidance for other reasons (eg, CNS active/penetrant compounds, and known mechanisms or 
indications for which suicidal ideation/behavior has been previously identified as a potential 
concern).
4.3
Justification for Dose
All participants in this study will be treated with a nicotine patch of 21 mg dose strength 
(NicoDerm CQ, GSK) [U.S. User's Guide 2006]. This formulation releases the nicotine 
equivalent of approximately 15 cigarettes per day and is known to be safe and well-tolerated. 
Moreover, this dose strength has been shown to alter evoked potentials, including the 
mismatch negativity, while lower dose strengths do not have as consistent an effect on 
evoked potentials [Knott, V., et al 1999], [Inami, R., et al 2005]. 
MK-4334 will be administered to a subset of participants as a single dose of 250-mg. A 
preclinical model of cognitive impairment (rhesus object retrieval) indicates that a plasma 
level of MK-4334 =
 was minimally efficacious in improving cognitive function. 
Because efficacious dose levels of MK-4334 have not been determined in humans, and the 
plasma PK is highly variable, a 100-fold multiple beyond this plasma level 
 has 
been targeted as a potentially efficacious exposure level (C24). This plasma concentration 
CCI
CCI
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has been obtained in several clinical studies at the 250 mg dose level. This dose is associated 
with exposures 
 approximately ≈ 
 below the rat NOAEL 
exposure cap (37.5 μM·hr) established in preclinical toxicology studies (See the IB for 
additional information on preclinical safety and PK). 
The MK-4334 dose chosen for this trial is supported by favorable tolerability. Previous 
studies of single oral doses of MK-4334 up to 300 mg administered to healthy adults 
(MK-4334-002) indicated that the 250 mg dose is well-tolerated. There were no dose-
limiting tolerability issues and no pattern of drug-related AEs other than headache, diarrhea 
and/or abdominal pain of mild-to-moderate intensity observed with doses up to 300 mg. 
There were no SAEs and no participants discontinued from study MK-4334-002 due to an 
AE. MK-4334 will be administered as an adjunct to the antipsychotic therapy that the SZ 
participants are already receiving. Based on clinical and non-clinical experiences, its 
mechanism of action 
 its metabolism (primarily via CYP2C19), and 
the duration of treatment (single dose), no impact of MK-4334 on the PK, PD, safety or 
tolerability of any antipsychotics approved for administration in this investigation are 
expected.  Please refer to the MK-4334 IB for additional information on clinical studies of 
MK-4334. 
As this is a Phase 1 assessment of MK-4334 in humans, and the PK, PD 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.
4.4
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 (ie, the 
participant is unable to be contacted by the investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
CCI
CCI
CCI
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procedure-related problems or the number of discontinuations for administrative reasons is 
too high. Otherwise, there are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy control male and female (WONCBP) participants between the ages of 18 to 55 years 
(inclusive) will be enrolled in this study.
Male and female (WONCBP) patients with SZ of mild to moderate severity who are 
otherwise healthy, between the ages of 18 to 55 years (inclusive) will also be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
Healthy Control (HC) Participants
1. Be judged to be in good health based on medical history, physical examination, VS 
measures and ECG performed prior to randomization. Section 10.8, Appendix 8 provides 
a table of 12-Lead ECG Abnormality Criteria.
2. Be judged to be in good health based on laboratory safety tests (Section 8.3.5) obtained at 
the screening visit. 

Participants with chronic medical conditions, including but not limited to 
hypertension, hyperlipidemia, diabetes (Type 1 or 2) or hypothyroidism, which have 
been well-controlled on a stable dose of medication for the past two months and who 
are not receiving any proscribed medications for intervention may be enrolled if 
clinically acceptable to the investigator and Sponsor. 

Appendix 9 provides an algorithm for the assessment of out-of-range laboratory 
values
3. Has no history or evidence of clinically relevant neuropsychiatric illness.
4. Is fluent in English, even if English is not their primary language.
5. Has a BMI ≥ 18 and ≤38 kg/m2, inclusive for HC and SZ participants. See Section 8.3.3
for criteria on rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
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6. Is a mild-to-moderate tobacco user of at least 1-year duration, smoking the equivalent of 
approximately 10-15 cigarettes/day, as reflected in plasma cotinine levels > 100 ng/mL 
[Patterson, F., et al 2003], [Hill, P., et al 1983].
SZ Patients
7. Have a current diagnosis of schizophrenia. Enrolled patients should have the following 
PANSS scores: Delusions (item P1) score ≤ 4; Hallucinations (item P3) score ≤4; 
Unusual thought content (item G9) score ≤4; Conceptual disorganization (item P2) score 
≤4. Total PANSS scores should be ≤80, consistent with a diagnosis of “mild to 
moderate” illness [Leucht, S., et al 2005]. Patients should be judged competent to 
complete all study procedures in the estimation of the investigator.
8. Duration of schizophrenia illness ≥ 1 years.
9. Clinically stable and in the residual (non-acute) phase of their illness for at least 12 weeks 
prior to the study.
10. Stably maintained on a regimen of up to 2 first or second-generation antipsychotics with 
no dose changes over 50% in combination with concomitant medications commonly 
prescribed to this patient population for at least 8 weeks prior to screening and during the 
study may be included (see Allowed Medications List and Table 4).
11. Fluent in English, even if English is not the primary language.
12. Is currently a mild-to-moderate tobacco user of at least 1 year duration, smoking the 
equivalent of approximately 10-15 cigarettes/day, as reflected in plasma cotinine levels > 
100 ng/mL [Patterson, F., et al 2003], [Hill, P., et al 1983].
Demographics
13. Is male or female (WONCBP) from 18 years to 55 years of age inclusive, at the time of 
signing the informed consent.
Male Participants
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days/weeks after the last dose of study intervention:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agree to remain abstinent
OR
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Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
A female participant is eligible to participate if: 
-
She is a WONCBP, as defined in Appendix 5.
Informed Consent
14. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
15. Is a smoker and is willing to comply with restrictions on the use of nicotine or nicotine-
containing products (eg, nicotine patch, gum, e-cigarettes or any form of tobacco) during 
the study.
16. Understands study procedures and is willing to comply with the study restrictions (see 
Section 5.3 for a complete summary of study restrictions).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
Healthy Control Candidates
1. Known (identifiable) biological family history of psychotic disorder in a first or second 
degree relative.
SZ Candidates
2. If there is a failure to confirm a diagnosis of schizophrenia by the Investigator based on 
the MINI Screen or pharmaceutical treatment history.
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3. They have more than a moderate severity rating on delusions as evidenced by a PANSS 
item P1 score > 4
4. They have more than a moderate severity rating on hallucinations and delusions as
evidenced by a PANSS score on item P3 > 4
5. They have more than a moderate severity rating on positive formal thought disorder as 
evidenced by a PANSS item G9 > 4 or item P2 > 4.
6. They have a total PANSS score > 80.
7. They have a minimal level of depressive symptoms as evidenced by a CDSS score ≥11.
All Candidates
8. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
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. SZ patients must be 
excluded if they report suicidal ideation or behavior with intent, with or without a plan or 
method (eg, positive response to items 4 or 5 in the assessment of suicidal ideation of the 
C-SSRS) in the past 1 year prior to the Screening Visit. For HC, there should be no 
positive responses to items 3, 4, or 5 in the past 2 years. 
10. Had major surgery, donated, or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit.
11. Evidence of cognitive impairment as determined by performing ≥ 1.5 standard deviations 
lower compared to the age corrected mean on either the BACS Symbol Coding and/or 
Verbal Memory.
12. Significant intellectual disability as evidenced by a standardized WRAT-5 Reading Test 
standardized score ≥ 1.5 standard deviations lower compared to the age corrected mean.
13. Unable to tolerate the electrode cap for the duration of the recording session (≈30 min).
14. 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.
15. Has a history of clinically significant endocrine, GI, cardiovascular, hematological, 
hepatic, immunological, renal, respiratory, genitourinary, or major neurological 
(including stroke and chronic seizures) abnormalities or diseases. Participants with a 
remote history of uncomplicated medical events (eg, uncomplicated kidney stones, as 
defined as spontaneous passage and no recurrence in the last 5 years, or childhood 
asthma) may be enrolled in the study at the discretion of the investigator.
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16. Has a history of cancer (malignancy). Exceptions: Adequately treated non-melanomatous 
skin carcinoma or carcinoma in situ of the cervix or other malignancies that have been 
successfully treated with appropriate follow up and therefore unlikely to recur for the 
duration of the study, in the opinion of the investigator and with agreement of the 
Sponsor (eg, malignancies that have been successfully treated ≥10 years prior to the pre-
study [screening] visit).
17. Participant has an estimated [eGFR ≤60 mL/min/1.73 m2] at the screening visit, with one 
recheck if requested by the Investigator. The eGFR may be calculated based on the CG 
Equation.
Cockcroft-Gault Equation: 
CrCl = (140-age[yr]) (body wt [kg])
(72) (serum creatinine [mg/dL])
[When creatinine is measured in µmol/L, use this formula]
CrCl = (140-age[yr]) (body wt[kg])
(72) (serum creatinine [µmol/L] x 0.0113)
For females, multiply the result by 0.85.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the CrCl.
Participants who have a measured CrCl of up to 10% below 80 mL/min may be enrolled in 
the study at the discretion of the investigator.
Prior/Concomitant Therapy
18. Is unable to refrain from or anticipates the use of any non-prescription drugs or herbal 
remedies beginning approximately 2 weeks (or 5 half-lives, whichever is longer) prior to 
administration of the initial dose of study intervention, and throughout the study 
(including washout intervals between treatment periods) until the poststudy visit. 
Sedative medications prescribed while participants are inpatients are allowed so long as 
they have not been administered within 12 hours of any EEG recording periods (see 
Section 6.5, Table 4). All medications being taken by candidates for enrollment in the 
study should be reviewed by the PI and the Sponsor to determine their propensity for 
altering MK-4334 exposure, or for MK-4334 to interfere with the metabolism of the 
medication. Medications prescribed for the candidate that are stably treating a condition 
should not be interrupted. Candidates should not be enrolled if they are taking clopidogrel 
(which requires CYP2C19 for activation),  fluoxetine (> 40 mg qd), , 
citalopram/escitalopram or proton pump inhibitors which may inhibit CYP2C19.
Enrollment of candidates taking prescription drugs that can alter QTi for an underlying 
condition (including anti-arrhythmics [quinidine, procainamide, disopromide, dofetilide, 
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sotalol] and antimicrobials) should be avoided. See Table 4 and Section 8.1.5 for more 
examples of excluded agents.
19. Use of any first generation, sedating H1 antihistamines within 12 hours of an EEG 
recording period. (see Medication Approval List)
20. Use of any sedative-hypnotic medications within 1 week prior to Screening or during the 
study. (see Medication Approval List)
21. Use of any other psychoactive medication known to interfere with ERP assessments 
within 1 week prior to Screening or during the study. (see Medication Approval List)
Prior/Concurrent Clinical Study Experience
22. Has participated in another investigational study within 6 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
23. Has a CYP2C19 genotype consistent with a poor metabolizer phenotype.
24. Has a QTc interval ≥470 msec (for males) or ≥480 msec (for females).
25. Any candidate unable to detect a 1000 and 2000 Hz tone at 40 dB in both ears is not 
eligible for enrollment.
Other Exclusions
26. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
27. 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.
28. Is a regular user of any illicit drugs or has a history of substance (including alcohol) use 
disorder per the DSM-5 (confirmed with MINI) within approximately 2 years. Cannabis 
use is not permitted within 4 weeks of randomization. Participants must have a negative 
DS prior to randomization and on Days -2, 6, and 13.
29. 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.
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30. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, including but not limited to laboratory safety 
evaluations, are specified below.
Participants will fast from all food and drinks, except water, for at least 2 hours after 
administration of study intervention. After the post-dose procedures have been completed, 
subsequent meals and snacks will be unrestricted in caloric content, composition, and timing. 
Participants will fast from all food and drinks except water between meals and snacks. The 
caloric content and composition of meals will be the same on each treatment day in each 
panel.
Study interventions will be administered approximately 1-2 hours after breakfast. Water will 
be provided during study drug administration, with the restrictions noted above. Additional 
water will be restricted up to 1 hour after study drug administration.
Each study drug administration will need to be taken with at least 240 mL (not to exceed 500 
mL) of water.
Labs will be collected nonfasting.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of study 
drug, throughout the study including the washout interval between treatment periods and 
until the post-study visit.
On treatment days, participants will refrain from the consumption of all fruit juices 8 hours 
prior to study drug administration and 2 hours following the morning dose.
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 8 hours prior to the pre-study (screening) and post-study (exit) visits. 
Participants may have 1 caffeine/xanthine containing beverage no later than 1 hour before the 
recording of VS/ECG prior to the baseline recording session. No caffeine/xanthine 
containing beverages are allowed until completion of the recording sessions. Outside of these 
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restricted periods, caffeinated beverages or xanthine-containing products will be limited to no 
more than 6 units per day (>6 units: 1 unit = 120-mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the pre-study and 
post-study visits and while domiciled at the CRU.
At all other times during the study (screening to post-study visit), alcohol consumption is 
limited to no more than approximately 3 alcoholic beverages or equivalent (1 glass is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) is not permitted within 4
hours of study treatment dosing and for the duration of recording on treatment days (Days 1, 
8, and 15), and within 4 hours of baseline recording (Days -1, 7, 14).
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, throughout the study (including washout intervals between treatment 
periods) and until the poststudy visit.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently 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 OR withdraws from the study, a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number.
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.
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Clinical supplies including study intervention(s) provided by the Sponsor will be packaged to 
support enrollment and replacement participants as required. When a replacement participant 
is required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP
or 
NIMP/
AxMP
Sourcing
A, B 
(HC, SZ)
Experimental 
Comparator
Nicotine
Drug
Patch
21 mg
21 mg
Dermal 
Patch
Single Dose
Test 
Product
NIMP/
AxMP
Provided 
locally by 
site
A, B 
(HC, SZ)
Experimental 
Comparator
MK-4334
Drug
Capsule
250 mg
250 mg
Oral
Single dose
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
A, B
(HC, SZ)
Placebo 
Comparator
Placebo to 
nicotine patch
Placebo
Patch
N/A
0 mg
Dermal 
Patch
Single dose
Placebo
NIMP/
AxMP
Provided 
locally by 
site
A, B
(HC, SZ)
Placebo 
Comparator
Placebo to 
MK-4334
Placebo
Capsule
N/A
0 mg
Oral
Single dose
Placebo
IMP
Provided 
centrally 
by 
sponsor
EEA=European Economic Area; 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 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Other medical device(s) (not manufactured by or for the Sponsor or licensed by the Sponsor) 
provided for use in this study are: COGNISION® Systems. Refer to Appendix 4 for 
reporting of events associated with these devices.
Instructions for medical device use are provided in the Operations Manual.
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.
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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.
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. Treatment groups are outlined in Table 3.
Table 3
Treatment Allocation.
Part 1
Part 2
N
Period 1
Period 2
Period 3
n = 6 HC
n = 12 SZ
21-mg nicotine patch
MK-4334 capsule placebo
Nicotine patch placebo
MK-4334 capsule placebo
n = 6 HC
n = 12 SZ
Nicotine patch placebo
MK-4334 capsule placebo
21-mg nicotine patch
MK-4334 capsule placebo
n = 9 HC
n = 18 SZ
250-mg MK-4334 
Nicotine patch placebo
n = 3 HC
n = 6 SZ
MK-4334 capsule 
placebo
Nicotine patch placebo
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-4334, nicotine 
comparator and patch and capsule placebos will be packaged so that the blind is maintained
(see dosing instructions in Operations Manual). 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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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.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of study intervention, they may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination,
during the ongoing study (ie, after randomization or intervention allocation) must first be 
discussed between the investigator and Sponsor before administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult. The participant will be allowed to continue in the study if both the 
Sponsor and the investigator agree.
Exceptions include medications prescribed while participants are inpatients are allowed so 
long as they have not been initiated within 12 hours of any EEG recording period.
CYP2C19 contributes to the oxidative metabolism of MK-4334, which may be impacted by 
the presence of inducers, inhibitors, or high levels of substrates for CYP2C19. Therefore, any 
agents known to induce, inhibit or be metabolized by CYP2C19 should be avoided as prior or 
concomitant medications for any study participants due to their potential for altering systemic 
exposure to MK-4334. In addition, many other drugs can elicit changes in the ERP endpoints 
regardless of any underlying pathology. Therefore, any prescribed medications used to stably 
treat a screening candidate or enrollee should be evaluated by the investigator in cooperation 
with the Sponsor to determine its propensity to interact with MK-4334 in any way, or to non-
specifically alter the ERP before either altering the treatment or enrolling the candidate. A 
representative list of concomitant medications to be avoided is found in Table 4.
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Table 4
List of Restricted Medications
Use by Panel
HC
SZ
Medication
Illicit Drugs (from DS)
Amphetamines
Not allowed
Not Allowed
Cocaine
Opioids (including 
Buprenorphine)
PCP
Benzodiazepines
Barbiturates
Cannabis
No use within 4 weeks of screening 
or study visits
No use within 4 weeks of 
screening or study visits
First- or second-generation antipsychotics or other 
medications commonly prescribed for SZ
Risperidone
Not allowed
Up to 2 with no dose changes 
over 50% during course of study
Clozapine not allowed 
(CYP2C19 substrate) 
Clozapine
Quetiapine
Olanzapine
Aripiprazole
Paliperidone
Ziprasidone
Lurasidone
Haloperidol
Chlorpromazine
Loxapine
Fluphenazine
Perphenazine
First-generation, sedating H1 antihistamines
Diphenhydramine
No use within 12 hours of EEG 
recording periods 
No use within 12 hours of EEG 
recording periods
Carbinoxamine
Clemastine
Chlorpheniramine
Brompheniramine
Sedative-hypnotics and anxiolytics
Secobarbital
No use within 1 week of screening 
or study visits
No use within 1 week of 
screening or study visits. The 
short duration benzodiazepine 
Lorazepam 1 mg prn is allowed 
for inpatient use if prescription is 
not initiated within 12 hours of 
EEG recording session.
Pentobarbital
Triazolam
Eszoplicone
Zaleplon
Diazepam
Chlordiazepoxide
Lorazepam
Alprazolam
Bromazepam
Clorazepate
Flurazepam
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Use by Panel
HC
SZ
Medication
Other Psychoactives
Glutamatergics:
Not allowed
Not allowed
    Ketamine
    Amantadine
    Dextromethorphan
    Memantine
    Methadone
    Dextropropoxyphene
    Ketobemidone
    Glycine
    N-Acetylcysteine
    Riluzole
Anticholinergics
Not allowed
Not allowed
    Benzhexol
    Benztropine
    Biperiden
    Orphenadrine
    Procyclidine
    Scopolamine
    Trihexylphenidyl
Antidepressants
Not allowed
Not allowed
    Sertraline
    Fluoxetine
    Citalopram
    Escitalopram
    Paroxetine
    Fluvoxamine
    Doxepin
    Clomipramine
    Bupropion
    Amoxapine
    Nortriptyline
    Duloxetine
Anticonvulsants
Not allowed
Not allowed
    Acetazolamide
    Clobazam
    Clonazepam
    Ethosuximide
Mood stabilizers
Not allowed
Not allowed
    Lithium
    Valproate
    Topiramate
    Oxcarbazepine
    Lamotrigine
    Carbamazepine
    Gabapentin
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Use by Panel
HC
SZ
Medication
Neuropathic Pain Analgesics
Not allowed
Not allowed
    Pregabalin
Psychostimulants
Not allowed
Not allowed
    Methylphenidate
    Dexmethylphenidate
    Lisdexamfetamine
    Dextroamphetamine
Agents Interacting with CYP2C19
Inhibitors
Not allowed
Not allowed
    Clopidogrel
    
    Felbamate
    Proton pump inhibitors
    Probenecid
    
     
     Phenylbutazone
     Ticlopidine
     
     Efavirenz
     Isoniazid
     Ketoconazole
     Voriconazole
     Eslicarbazepine
     Oxcarbazepine
     Topiramate
     Methimazole
    Modafanil
Inducers
Not allowed
Not allowed
    Carbamazepine
    Norethisterone
    Prednisone
     
    Rifampin
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Use by Panel
HC
SZ
Medication
Substrates
Not allowed
Not allowed
     Labetalol
     Verapamil
     Nelfinavir
     Quinine
     Terbinafine
     Voriconazole
     Amitriptyline
     Citalopram, escitalopram
     Clomipramine
     Diazepam
     Imipramine
     Milnacipram
     Trimipramine
     Carisoprodol
     Tofacitinib
     Clobazam
     
     Trazodone
    Propranolol
    Progesterone
    Tolbutamide
Homeopathics, OTC compounds
St John’s wort
No use within 1 week of screening 
or study visits
No use within 1 week of 
screening or study visits
Artemisinin
Ginseng
Cassia
Licorice (glycyrrhizin)
Ginkgo
Epimedium
DHA/EPA (Omega-3 dietary 
supplements)
Alcohol
Use limited per protocol
Use limited per protocol
Nicotine
No use 4 hrs before baseline 
recording
No use 4 hrs before baseline 
recording
Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol for that medication. If there is a clinical indication for any 
medications specifically prohibited, discontinuation from study intervention may be required. 
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant’s primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
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Any medication or vaccine (including OTC 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
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
Rescue medications/supportive care may be administered by the investigator as necessary, in 
consultation with the Sponsor.
6.6
Dose Modification (Escalation/Titration/Other)
Not applicable. Only single, fixed doses of either study treatment are being administered in 
the study.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
If any of the below stopping rules are met, the study will be paused and no further dosing 
will occur until the Sponsor has reviewed the totality of safety data available. The study may 
continue with joint agreement of the Sponsor and investigator.  
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator.
2. Two (2) or more participants within a Panel (at the same dose level) report Severe 
Nonserious AEs considered related to the study intervention by the investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study. If a participant feels 
abnormal after conclusion of their participation in the study/completion of the study follow 
up exam, the PI should advise the participant to see their primary physician.
6.8
Clinical Supplies Disclosure
This study is blinded, but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
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identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are [not]provided.
The emergency unblinding call center will use the intervention allocation 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.
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
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, a 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. The participant has a 
positive UDS at any time during the study. The drug screen can be confirmed by a recheck at 
the discretion of the investigator after discussion with the Sponsor. For participants who are 
discontinued from study intervention all applicable discontinuation activities will be 
performed according to Section 8.1.9, or if available, a protocol clarification letter.
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.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. Delegation of study-site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
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 
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provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 500 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
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.
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If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
Inclusion and exclusion criteria are listed in sections 5.1 and 5.2. The following are screening 
measures that are being used for this study.
All HC and SZ candidates will undergo audiometric testing to establish their ability to hear 
the 20 Hz and 40 Hz auditory stimuli
Audiometry: In this test, a series of short-duration tones will be played in each ear through 
insert earphones at increasing sound intensity and then decreasing sound intensity. The 
participant is instructed to press a button on the handset whenever they hear a tone in either 
ear.
Tone-Matching: In this test, pairs of short-duration tones will be presented to the participant
through insert earphones. The participant is instructed to press a button on the handset 
whenever they think the tones are the same frequency.
Psychometric assessments to be used at screening include the following:
WRAT-5: Parts 1 and 2 (Word Reading and Letter Reading) of the WRAT-5 Reading Test 
are quick measures of fundamental academic skills, helpful in evaluating learning 
disabilities. This test is performed to ensure that all study subjects are not intellectually 
impaired which could inadvertently bias the EEG/ERP test results. Evidence of 
intellectual impairment in HC, as indicated by scoring ≥ 1.5 standard deviations lower 
compared to the age corrected mean standard score is exclusionary.
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MINI Screen 7.0.2: The MINI is a short, structured clinical interview that enables researchers 
to confirm a diagnosis of schizophrenia in SZ subjects. This test meets the criteria of the 
5th edition of the DSM-5
BACS: The BACS is an instrument that assesses the aspects of cognition found to be most 
impaired and most strongly correlated with outcome in patients with schizophrenia: 
verbal memory, working memory, motor speed, attention, executive functions, and verbal 
fluency. The BACS will be administered to HC participants and SZ patients. Potential 
cognitive impairments in HC participants will be assessed with the Symbol Coding and 
Verbal Memory domains of the BACS. The BACS requires less than 35 min to complete 
in patients with schizophrenia, yields a high completion rate in these patients, and has 
high reliability.
In addition to the above to be administered to both SZ and HC candidates, SZ patients will 
undergo the following confirmatory tests:
CDSS: The CDSS is a rating scale used to assess the level of depression in schizophrenia. It 
is the only depression scale designed for the assessment of depression in schizophrenia 
and it differentiates between depression and the negative and positive symptoms of 
schizophrenia. 
The PANSS will be administered to SZ candidates at screening, and to SZ patients enrolled 
in the study during the intervention period to monitor the status of their condition:
PANSS: The PANSS is a medical scale used for measuring symptom severity of patients with 
schizophrenia and is widely used in the study of antipsychotic therapy. Positive 
symptoms refer to an excess or distortion of normal functions (eg, hallucinations and 
delusions), and negative symptoms represent a diminution or loss of normal functions. 
The PANSS is a relatively brief interview, requiring 45 to 50 minutes to administer and 
will be performed to correlate with the EEG/ERP test results.
CYP2C19 Genotyping: Evidence from human hepatocytes in vitro indicates that CYP2C19 is 
responsible for approximately 50% of the metabolism of MK-4334 (see MK-4334 IB). 
Therefore, systemic exposures to MK-4334 may increase by as much as 2- fold in 
participants with a CYP2C19 poor metabolizer phenotype. To avoid excessive exposure 
to MK-4334 and any attendant safety issues, participants will be screened for CYP2C19 
genotypes consistent with the poor metabolizer phenotype. Any participant expressing a 
CYP2C19 poor metabolizer genotype will be excluded from 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. 
Participants will be administered 2 cards during the study. The initial card will be provided at 
the time of informed consent and will be updated with the Part 1 randomization number. 
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Participants will return the original card and be issued a new card at the start of Part 2 which 
will include the new randomization number for Part 2. 
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 4 weeks or 5 half-lives before the screening visit. Any medications necessary for 
keeping a candidate stably treated for an underlying condition should be reviewed by the PI 
for potential interference with/by the study medication (eg, CYP2C19 inhibitors) and brought 
to the attention of the Sponsor for mutual agreement on whether to enroll the candidate in the 
study (Section 6.5).
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 allocation/randomization. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.10.1.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
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Participants will each receive a randomization number for Part 1 and will be re-randomized 
with a new randomization number for continuation in Part 2.     
8.1.8
Study Intervention Administration
Study intervention should begin on the day of treatment allocation/randomization or as close 
as possible to the date on which the participant is allocated/assigned.
The nicotine patch/matching placebo patch should be applied at approximately the same time 
for Periods 1 and 2, after completion of all pre-dosing procedures (eg, AE report, ECG, VS, 
blood sampling, (Figure 1). Approximately 2 hours after patch application, post dosing 
procedures may commence, followed by ERP/EEG recordings. After all recordings are 
obtained, post-recording safety monitoring will be conducted. Upon completion of all the 
safety monitoring procedures are completed, the patches will be removed, and the participant 
allowed to exit the facility (approximately 3-4 hours after patch application).  Patch disposal 
procedures are outlined in the Operations Manual. 
Study treatment will be provided with matching placebos: Nicotine patch/matching placebo 
patch; MK-4334/matching capsule placebo. MK-4334/placebo capsules will be administered 
orally with at least 240 mL (not to exceed 500 mL) of water upon completion of all pre-dose 
procedures for that day, with administration of study medication witnessed by the 
investigator and/or study staff. Participants will not be allowed access to food for 2 hours 
after dosing. The nicotine patch/matching placebo patch should be applied prior to oral 
administration of MK-4334/matching placebo capsules.
8.1.8.1
Timing of Dose Administration
In Periods 1 and 2, the nicotine or placebo patch will be applied in the morning at 
approximately the same time every day after completion of all pre-dose procedures. 
Similarly, MK-4334 or placebo will be administered in the morning at approximately the 
same time and upon completion of all pre-dose procedures (Section 8.1.8). The time of 
administration of study treatment will constitute Time “0” for initiation of subsequent study 
events. All capsules will be distributed and consumed with water within 10 minutes of the 
recorded administration time. Participants will remain resting in bed in a semi-recumbent 
position for approximately 1 hour after dosing. Ancillary procedures (AE reports) may occur 
during this period. Blood samples for PK measures should be taken close to steady state (C2
or C4 hrs post-nicotine or MK-4334 dosing, respectively). ERP recording and related 
activities will commence after the last ancillary procedure is completed, either 2 
(nicotine/pbo) or 4 (MK-4334/pbo) hours after dosing. During the intervening period, the 
participant is free to ambulate. Refer to Figure 2 for relative timing of events during 
treatment periods and the Operations manual for further guidance.
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 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 
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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 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
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.
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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 will report to the CRU on Days -2, 6, and 13 for domiciling (2 overnights per 
study part, for a total of 6 overnight stays). Participants will remain in the unit until all 
recordings and post-dose procedures have been completed on the day of treatment. At the 
discretion of the investigator, participants may be requested to remain in the CRU longer. 
Decisions on how to monitor the participant during any post-treatment stays 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; surrogate markers of efficacy are 
outlined in Section 8.7.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood/tissue volumes drawn 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.
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8.3.1
Complete Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at screening and at 
poststudy. Height and weight will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Symptom Driven Physical Examinations
A symptom driven physical examination will be conducted upon domiciling only if 
participant symptoms warrant an exam or at the investigator’s discretion. The symptom 
driven physical should be conducted by an investigator or medically qualified designee 
(consistent with local requirements) as per institutional standard, specifically targeting any 
areas for which there are symptoms of concern.
8.3.3
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.4
Vital Signs
Oral or temporal artery temperature will be assessed. Whatever method for measuring BT is 
settled on by the site should be used throughout the study.
PR, RR, and BP will be assessed.
BP and HR measurements will be assessed in the supine and/or standing position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
BP and HR measurements should be preceded by at least 10 minutes of rest for the 
participant in a quiet setting without distractions.
VS to be taken before blood collection for laboratory tests will be measured in a supine
position after 10 minutes rest and will include temperature, systolic and diastolic BP, HR, 
and RR.
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8.3.4.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a supine position for at 
least 10 minutes before having VS measurements obtained. Supine VS will include HR, 
systolic and diastolic BP, RR, and BT at timepoints indicated in the SoA. The correct size of 
the BP cuff and the correct positioning on the participants' arm is essential to increase the 
accuracy of BP measurements.
The HR and BP measurements will be taken in triplicate before recording on Day -2 only. 
These measures will be obtained at least 1-2 minutes apart. The mean of these measurements 
will be used as the baseline to calculate the change from baseline for safety evaluations and 
rechecks, if needed. On all other days indicated in the SoA (See Section 1.3), pre-dose HR 
and BP will be single measurements. Post-dose VS measurements will be single 
measurements unless there is an out-of-range reading. In this case, at least three measures of 
VS (either resting or orthostatic HR, BP) will be taken within a 15-minute period, or until 
readings fall into normal range.
Participants will continue to rest in a semi-recumbent position from dosing until 1 hour post-
dose except to stand for the measurement of orthostatic VS (if needed) or other study-related 
procedures.
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.
8.3.4.2
Orthostatic Vital Signs
Orthostatic VS (HR, SBP, DBP) will be obtained. Participants should be supine for at least 
10 minutes and then stand upright.  Measures of orthostatic VS will be taken after 1 min and 
3 min of standing.
8.3.4.3
Electrocardiograms
Twelve-lead ECGs will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (see Appendix 9) using 
an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QTc 
intervals. Refer to Appendix 9 for evaluation and withdrawal criteria and additional QTc 
readings that may be necessary.
When triplicate ECGs are requested, 3 individual ECG tracings should be obtained at least 1 
to 2 minutes apart, but no more than 2 minutes apart. The full set of triplicates should be 
completed in no more than 6 minutes.
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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 position for at least 10 minutes before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
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 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 
post-dose 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 
considered for transfer to a location where closer monitoring and definitive care (eg, a CCU 
or ICU) is available.
If the QRS duration from any post-dose ECG is 20% greater than the mean baseline QRS 
duration and is >120 msec (and change is not considered rate related or pacing induced) or 
there appears to be new onset intermittent bundle branch block, then the ECG will be 
immediately repeated twice within 5 minutes. The mean value of the QRS interval from the 
3 ECGs will represent the value at that time point. If the mean QRS interval increase from 
baseline for any post-dose time point is >20%, the participant will continue to be monitored 
by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until the QRS is within 20% 
of baseline. If a >20% prolongation of the QRS interval persists, a consultation with a 
cardiologist may be appropriate and the Sponsor should be notified.
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.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6
Pregnancy Testing
Pregnancy testing is not required as only WONCBP will be enrolled in this study.
8.3.7
Suicidal Ideation and Behavior Monitoring
8.3.7.1
Clinical Assessments for Suicidal Ideation and Behavior Monitoring
Suicidal ideation and behavior will be prospectively assessed during this study using the C-
SSRS. The C-SSRS should be administered by trained raters at the time points indicated in 
the SoA. In addition, C-SSRS will be administered at any unscheduled visit where safety 
assessments are performed. The C-SSRS will not be routinely administered at visits with a 
sole purpose of PK sampling and/or witnessed study intervention administration. Site staff 
should review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, before their assessment of the participant 
and to further inform their evaluation. 
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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 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. 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.
8.3.8
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption or rash occurrence in determining etiology and drug relationship.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator under any of the following circumstances:

if the participant is receiving placebo run-in or other run-in treatment,

if the event causes the participant to be excluded from the study, 

if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation/randomization through 28 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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
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 Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 24 hours 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are WONCBP or males and 
partner pregnancy/lactation information is not required.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Disease related events and or disease related outcomes not qualifying as AEs or SAEs are not 
applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
3. Suicidal ideation and/or suicidal behavior. A supplemental document will be provided 
that contains guidance for additional information to be collected and reported for these 
events (Appendix 11).
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8.4.8
Medical Device and Drug-device Combination Products - PQCs/Malfunctions
The method of documenting and reporting of such events [Complaints associated with 
medical devices including PQCs/malfunctions] will occur as below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions including those that involve a participant or any user/associated person 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
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.
8.6
Pharmacokinetics
8.6.1
Blood Collection for MK-4334 Determinations
Sample collection, storage, and shipment instructions for samples will be provided in the 
Operations/Laboratory Manual.
8.6.2
Blood Collection for Plasma Nicotine Determinations
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations/Laboratory Manual.
8.7
Pharmacodynamics
N/A.  See Section 8.8.
8.8
Biomarkers
The PD parameters to be collected in this study are surrogate biomarkers of pharmacological 
activity. They are electrophysiological in nature and are derived from the ERP tests 
conducted at a specified time after treatment (see Section 4.2.1). No active responses are 
required by the participant to these auditory stimuli. Collection of samples for other 
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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 CYP2C19 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CYP2C19. Leftover extracted DNA will be stored for FBR if the 
participant provides documented informed consent for FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
Leftover main study plasma from MK-4334 assay will be stored for future research
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 5 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 be 
conducted if more than 35 days have elapsed between the participant’s initial screening and 
planned randomization. Rescreening should include all screening procedures listed in the 
SoA, including consent review. However, repeating the CYP2C19 genotyping is not required 
if the previous results remain in the participant’s record. Rescreen procedures cannot be 
conducted the day prior to intervention allocation/randomization if there are Day -1 
procedures planned per protocol. All results of screening 2 should be entered in Inform.
8.10.2
Treatment Period Visit
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
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8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all 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 28 days after the last dose of 
study intervention for the poststudy visit.
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
The relative timing of procedures can be found in Figure 2 and the Operations Manual. For 
this study, the time of administration of study treatment is the critical procedure. The time of 
administration will be T0 on the day of treatment. All other procedures will be conducted in 
relation to T0. 
Pre-dose blood samples for either nicotine or MK-4334 can be taken within 1 hour of dosing. 
The post-dose blood sample for MK-4334 needs to be collected as close to the C4 (4 hours 
post-dose) as possible, but before recording. Similarly, the post-dose blood sample for 
nicotine needs to be collected as close to the C2 as possible, but before recording. Post-
recording blood samples should be collected within 30 minutes of finishing all recording 
procedures, ECGs, and VS measures. 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, within the windows outlined below.
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.
Screening 2 procedures: up to additional 4 hours of scheduled time
PK Collection as outlined in Table 6.
Table 6
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
1 to 6 h (postdose)
30 min
The baseline ERP recording will commence after breakfast and all pre-recording procedures
are completed. Study-treatment related ERP recordings will commence approximately 2 or 4 
hours after administration of nicotine/pbo or MK-4334/pbo, respectively, with a window of ± 
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30 min. The timing of recordings should follow the sequence laid out in Figure 2, Relative 
Timing of Procedures During Each Treatment Session (Period).
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical exam
-
Prior to 24-hours postdose may be obtained within 30 minutes of the theoretical 
sampling time
-
From 48-hours to 168-hours postdose may be obtained within 2 hours of the 
theoretical sampling time
Note: Visit windows defined by +/- X day(s) refers to calendar days.
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MK-4334 in humans, and the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.  These may include:

Repeat of or decrease in the dose of the study intervention administered in any given 
period/panel

Modify the ratio of active:placebo treated subjects in part 2.

Entire period(s) or panel(s) may be omitted

Changes in the relative timing/duration of psychometric testing, blood sampling, VS, 
ECG, and ERP recordings.

Changes in the timing of the tobacco and caffeine washouts.

Lengthening of the washout period 

Instructions to take study intervention with or without food or drink may be modified 
based on newly available data

Modification of the PK sample processing and shipping details based on newly available 
data

Changes to the time intervals between dosing and ERP recording.
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If it is determined that incomplete or aberrant data has been captured during the ERP 
recordings at any post-randomization study visit, the participant may be asked to repeat the 
treatment period. The evaluation to determine whether the treatment period is to be repeated 
will be performed on an individual basis per participant, and the decision will be reached by 
mutual agreement of the Sponsor and investigator. Up to 2 treatment periods per participant 
may be repeated. Repeating treatment periods may result in an increase in the total blood 
volume sampled, with 50 mL per repeated period. The resulting exposure and blood volume 
increases will be deemed acceptable by the Sponsor and investigator for that participant. The 
total blood volume should remain <500 mL. If there are >2 failed treatment periods for a 
certain participant, the participant may be discontinued from the study intervention and 
replaced.
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.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a summary of the statistical analyses for this trial. Full details can be 
found in the subsequent sections.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department.
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.
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Primary Objective: Record and measure the 40 Hz-ASSR in HC and SC patients at 
baseline.
Hypothesis: The mean magnitude of the ITC recorded from SZ patients at baseline is 
lower than those recorded from HC at baseline and determine whether the mean ITC 
magnitude derived from the 40 Hz-ASSR at baseline is lower in SZ patient than in 
HC.
Secondary Objectives: 
Objective: Record and measure the DD-MMN in HC and SZ patients at baseline and 
determine whether the mean MMN magnitude derived from the DD-MMN at baseline is 
lower in SZ patient than in HC. 
Hypothesis: The mean magnitude of the MMN derived from the DD-MMN recorded from 
SZ patients at baseline will be lower than that recorded from HC at baseline.
Objective: Determine if pharmacologically relevant plasma concentrations of nicotine 
change the mean magnitude of the 40 Hz-ASSR ITC recorded from HC or SZ patients 
relative to placebo treatment.
Hypothesis: Pharmacologically relevant plasma levels of nicotine change the mean 
magnitude of the ITC recorded from HC or SZ patients relative to placebo treatment, with 
each subject group tested separately.
Exploratory/Tertiary Objectives:
1. Exploratory Objective: Determine if pharmacologically relevant plasma concentrations 
of nicotine change the mean magnitude of the P3A, MMN or GBO recorded from HC or 
SZ patients relative to placebo treatment
Estimation: Estimate difference between the treatment groups (nicotine vs. placebo) 
in the mean change from baseline in the magnitude of the P3A, MMN or GBO 
recorded from HC or SZ patients, with the difference for the two groups (HC and SZ) 
estimated separately
2. Exploratory Objective: Determine if pharmacologically relevant plasma concentrations 
of MK-4334 change the mean magnitude of the 40 Hz-ASSR ITC, MMN, P3A or GBO 
recorded from HC or SZ patients relative to placebo treatment
Estimation: Estimate difference between the treatment groups (MK-4334 vs. 
placebo) in the mean change from baseline in the magnitude of the 40 Hz-ASSR ITC, 
MMN, P3A or GBO recorded from HC or SZ patients, with the difference for the two 
groups (HC and SZ) estimated separately
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3. Exploratory Objective: To determine intra-subject variability of ITC measurements 
collected using the 40 Hz-ASSR in HC and SZ patients at baseline conditions (Days -1, 
7, 13)
Estimation: Estimate intra-subject variability of ITC measurements collected using 
the 40 Hz-ASSR in HC and SZ patients at baseline conditions (Days -1, 7, 13). More 
specifically, mean ITC over time (Days -1, 7, 13) will be summarized and 
graphically displayed. Pairwise (Day -1 vs. Day 7 or Day -1 vs. Day 13) ICC   will 
be estimated.  Scatter plot with diagonal line and Bland-Altman plot will also be 
presented
9.4
Analysis Endpoints
Primary Endpoint
The primary endpoint is the ITC derived from the 40 Hz-ASSR recorded from HC and SZ 
patients at baseline.  
Secondary Endpoints
The secondary endpoints are the ITC derived from the 40 Hz-ASSR in the presence of 
nicotine and the MMN derived from the DD-MMN in the presence of nicotine recorded from 
HC and SZ patients.
Exploratory Endpoints
The exploratory endpoints are the ITC, P3A, MMN and resting GBO recorded from HC and 
SZ patients in the presence of MK-4334/placebo, and the MMN and resting GBO recorded 
from HC and SZ patients in the presence of nicotine/placebo.
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data.  All subjects 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated: The All Subjects as Treated Population consists of all subjects who 
received at least one dose of treatment.  This population will be used for assessments of 
safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of subjects who comply with the protocol sufficiently to ensure that these data will be 
likely to exhibit the effects of treatment 
, MK-4334), 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 subjects or data values excluded from analysis will be identified, along with their reason 
for exclusion, in the CSR. At the end of the study, all subjects who are compliant with the 
CCI
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study procedure as aforementioned and have available data from at least one treatment will 
be included in the Per-Protocol dataset. This population will be used for all primary and 
exploratory/tertiary analyses.
9.6
Statistical Methods
Safety 
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or 
VS as well as for change from baseline, as deemed clinically appropriate.  Depending on the 
safety parameter, the difference from baseline will either be computed on the original scale 
(raw change from baseline) or on the log scale and back transformed for reporting (percent 
change from baseline).
To conduct initial data exploration, summary statistics and plots will be generated as deemed 
clinically appropriate. For the primary endpoint, ITC, and secondary endpoint, MMN, 
descriptive summaries (mean, standard deviation, median, min, max) will be provided.
Pharmacokinetics/Pharmacodynamics
Descriptive summary will be provided for plasma concentrations (C2 [nicotine], 4
[MK-4334]) following the administration of study treatment. To assess the association 
between plasma concentration and the magnitude of ERP, appropriate display such as scatter 
plot will be provided, and correlation coefficient will be reported.
Primary Hypothesis: Comparison of SZ Patients to HC Participants
To determine whether, at baseline, the mean ITC recorded from SZ patients is lower than HC
participants, a Bayesian approach will be used. Utilizing a non-informative flat prior, the 
posterior probability that the difference in observed means of ITC measurements of SZ and 
HC participants is greater than zero will be calculated, and the criteria for success will be met 
if the following condition is satisfied. 
Posterior-probability (PP) (µHC - µSZ > 0) ≥ 0.60
Where 
µHC = mean of the ITC measurements for HC participants
µSZ = mean of the ITC measurements for SZ patients
Secondary Hypothesis:  
Comparison of SZ patients to HC Participants
To determine whether, at baseline, the mean MMN amplitude recorded from SZ patients is
lower than in HC participants, a Bayesian approach will be used. Utilizing a non-informative 
flat prior, the posterior probability that the difference in observed means of MMN
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measurements of SZ patients and HC participants is greater than zero will be calculated, and 
the criteria for success will be met if the following condition is satisfied. 
Posterior-probability (PP) (µHC - µSZ > 0) ≥ 0.60
Where 
µHC = mean of the MMN amplitudes for HC participants
µSZ = mean of the MMN amplitudes for SZ patients  
Comparison of SZ patients and HC Participants for the effect of nicotine relative to the 
placebo group
To determine if pharmacologically relevant plasma concentrations of nicotine change the 
mean magnitude of the 40 Hz-ASSR ITC recorded from HC or SZ patients relative to 
placebo treatment, we undertake a similar Bayesian approach as described above. In this 
case, the criterial for success will be met if the following condition is satisfied
Posterior-probability (PP) (abs(µnicotine - µplacebo)> 0) ≥ 0.60
Where 
µnicotine = mean of the ITC measurements from HC and SZ subjects treated with nicotine
µplacebo = mean of the ITC measurements from HC and SZ subjects treated with placebo
abs() = absolute value of the difference
Exploratory/Tertiary Hypothesis/Estimation:
For the tertiary hypotheses outlined above, we estimate the magnitude of MMN or GBO 
recorded from HC and SZ subjects with nicotine and placebo, respectively, to characterize 
the effect of nicotine. The sample sizes are too small for testing hypotheses given the 
variability.
Similarly, the magnitude of the ITC, MMN and P3A or GBO measurements in the SZ with 
MK-4334 versus the placebo will be estimated as the sample sizes are too small for testing 
hypothesis given the variability. 
With respect to the objective of estimating intra-subject variability of ITC measurements 
collected using the 40 Hz-ASSR in HC and SZ patients at baseline conditions (Days -1, 7, 
13), descriptive statistics such as arithmetic mean, standard deviation, arithmetic percent CV 
(calculated as 100 x standard deviation/arithmetic mean), median, minimum, and maximum
will be provided. Graphical results using (including but not limited to) Box plots will also be 
displayed. Other measures of reproducibility including the PCC, ICC, and CCC will be 
calculated to assess the agreement of ITC at various baseline measurement (Day -1 vs. Day 7 
or Day -1 vs. Day 13). The PCC measures the linear correlation between two sets of 
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measurements; the ICC measures the replication reliability; and the CCC measures the 
degree to which pairs of measurements coincide with a 45-degree line.
9.7
Interim Analyses
Not applicable
9.8
Multiplicity
Because there is only one primary hypothesis, no adjustments for multiplicity are needed.
9.9
Sample Size and Power Calculations
Approximately 45 subjects (30 SZ patients and 15 HC participants) are planned to be 
screened for this study in order to enroll 36 subjects in total (24 SZ patients and 12 HC 
participants). The success criterion is that the posterior probability (PP) of the delta, the 
detectable difference in mean ITC of the placebo treated SZ and HC subjects, greater than 
zero, is at least 60%. Assuming the mean difference from 0.06 to 0.08, PP is calculated based 
on 10,000 simulations and results are presented in the table below for sample size of n=36 
(24 in SZ vs 12 in HC). These assumptions are based on available data on test-retest ITC 
measurements from Event-Related Potential (ERP) Biomarkers Qualification Consortium 
(CT.Gov ID: NCT04025502).
Table 7
Sample Size Calculations
Param
Type
Mean 
HC
Mean 
SZ
Delta
Std HC
Std SZ
Num 
HC
Num 
SZ
Prob. Of 
Success 
(%)
ITC‡
BaseLn
0.3794
0.3185
0.0609
0.1787
0.1577
12
24
77.38
ITC‡
Retest
0.3851
0.3015
0.0837
0.1561
0.1443
12
24
90.04
ITC‡
Avg.
0.3799
0.3089
0.0709
0.1541
0.1409
12
24
86.00
‡ITC here refers to ITC 200/500
As displayed in the table above, the probability of success that PP(delta>0)>60% is 86% 
assuming mean ITC of 0.3799 in HC and 0.3089 in SZ subjects based on average of ITC 
measurements at baseline and retest from available data from ERP Biomarkers Qualification 
Consortium (CT.Gov ID: NCT04025502).
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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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.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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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.
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 
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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
Committees Structure
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
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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.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 8 will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 8.1.2. 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 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose, non-
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)
Other Screening 
Tests
FSH (as needed in WONCBP only)
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
PCP, cannabinoids, and benzodiazepines) if applicable. Breath test for alcohol 
acceptable
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]; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; 
WBC=white blood cell; WONCBP=women of nonchildbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
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
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol, that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product - A product comprised of two or more regulated components (ie, a 
drug and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint - Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part - A drug, device, or biological product that is part of a combination 
product.
Customer Feedback - A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark which may suggest an improvement in the 
functionality or quality of a medical device or device-like features of a drug delivery system).
Malfunction - The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device - Any instrument, apparatus, appliance, material or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 

diagnosis, prevention, monitoring, treatment or alleviation of disease, 

diagnosis, monitoring, treatment, alleviation of or compensation for an injury or
handicap, 

investigation, replacement or modification of the anatomy or of a physiological process,

control of conception, 
and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
function by such means.
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PQC - Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury - An injury or illness that: 
1. Is life-threatening, 
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or 
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording

When a Complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostic reports) related to the event.

Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 
8.4.1 via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.

The investigator will use clinical judgement to determine the relationship.

Alternative causes such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration should be considered and investigated.
Follow-up

The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP) Nonparticipant Only
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):

Women in the following categories are not considered WOCBP:
-
Premenarchal
-
Premenopausal female with 1 of the following:
-
Hysterectomy
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-
Bilateral salpingectomy
-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Mullerian agenesis, androgen insensitivity.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
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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.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a 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 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Blood Volume Table
Panels A and B
Prestudy
Intervention
Days (All 
Periods)
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests
2
4
1
7
12.5
87.5
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
1
5
5
Blood for Planned Genetic 
Analysis 
1
1
8.5
8.5
Blood for Nicotine/cotinine 
screen
1
5
5
Blood for Nicotine PK
12
12
4
48
Blood for MK-4334 PK
2
2
4
8
Total Blood Volume per Participanta
162 mL
a If additional pharmacokinetic or safety analyses are necessary, additional blood (no more than 50 mL in total) may be 
obtained. Note: never to exceed 500 mL total volume withdrawn.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant Post-
Randomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase 
of ≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease 
of ≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR 
<40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms + Increase of 15 
ms; or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB 
as Defined Above
New Onset RBBB (Not 
Including Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 
ms
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Screen Failure Criteria
Potentially Significant Post-
Randomization Findings 
(clarification on action to take)
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 
ms From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 
ms From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P Mitrale 
or P Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; LAHB=left 
anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; mm=millimeter; 
ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using Fredericia 
formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
a.
The participant may be excluded from the study;
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
c.
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
d. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the participant may enter the 
study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: Mapping Between Suicidal Ideation and Behavior Categories and 
the C-SSRS
Mapping Between the 11 Categories
of Suicidal Ideation and Behavior and the C-SSRS
Category
C-SSRS Question (from eCRF)†
Suicidal ideation
1. Passive
1. Wish to be dead
2. Active: Nonspecific (no method, intent, 
or plan)
2. Non-specific active suicidal thoughts
3. Active: Method, but no intent or plan
3. Active suicidal ideation with any methods 
(not plan) without intent to act
4. Active: Method and intent, but no plan
4. Active suicidal ideation with some intent 
to act, without specific plan
5. Active: Method, intent and plan
5. Active suicidal ideation with specific plan 
and intent
Suicidal behavior
6. Preparatory actions toward imminent 
suicidal behaviors
Preparatory acts or behavior
7. Aborted attempt
Aborted attempt
8. Interrupted attempt
Interrupted attempt
9. Suicide attempt
Actual attempt
10. Completed suicide
Completed suicide
Self-injurious behavior, no suicidal intent
Has participant engaged in nonsuicidal self-
injurious behavior?
C-SSRS=Columbia-Suicide Severity Rating Scale; eCRF=Electronic Case Report Form
†Data are "yes" or "no"
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10.12 Appendix 11: Abbreviations
Abbreviation
Expanded Term
AD
Alzheimer disease
AE
adverse event 
AP
alkaline phosphatase
ALT
alanine aminotransferase
AR
adverse reaction
ASSR
auditory steady-state response
AST
aspartate aminotransferase
AUC
area under the curve
BDS
blood drug screen
bid
twice daily
BLA
biologics license application
BMI
body mass index
BP
blood pressure
BT
body temperature
C2, C4
plasma concentration at 2 hours post-dose (nicotine) or 4 hours post-
dose (MK-4334)
CCU
coronary care unit
CDSS
Calgary Depression Scale for Schizophrenia
CG
Cockcroft-Gault
CI
confidence interval
CIAS
cognitive impairment associated with schizophrenia
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
Cmax
maximum plasma concentration
CNS
central nervous system 
CrCl
creatinine clearance
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
clinical study report
CZ
center, midline electrode
CYP
cytochrome P450
DBP
diastolic blood pressure
DD
double-dummy
DFC
dry-filled capsule
DILI
drug-induced liver injury
CCI
088KBB

PRODUCT: MK-4334  
115
PROTOCOL/AMENDMENT NO.: 007-04
MK-4334-007-04 FINAL PROTOCOL
21-SEP-2022
Abbreviation
Expanded Term
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
eCTA
exploratory clinical trial application
EDC
electronic data collection 
EEG
electroencephalogram
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EP
evoked power
ERP
event related potential
FBR
Future biological research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FE
fractional enrichment
FFT
fast Fourier transform
FZ
frontal, midline electrode
GABAergic
gamma-amino butyric acid-ergic
GBO
gamma-band oscillation (EEG)
GCP
Good Clinical Practice 
GI
gastrointestinal
gln
Glutamine
glu
Glutamate
H1
histamine receptor type 1
HBsAg
hepatitis B surface antigen
HC
healthy control
HCU
headset control unit
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
Hz
Hertz (cycles per second)
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICC
intraclass correlation coefficient
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
088KBB

PRODUCT: MK-4334  
116
PROTOCOL/AMENDMENT NO.: 007-04
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21-SEP-2022
Abbreviation
Expanded Term
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
ITC
inter-trial coherence
IV
intravenous
mg
milligram
min
minute
MINI
Mini-Mental Status Exam
mL
Milliliter
MRS
magnetic resonance spectroscopy
msec
milliseconds
MTD
maximum tolerated dose 
NCS
not clinically significant
NDA
new drug application
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level 
OTC
over-the-counter
PANSS
Positive and Negative Symptom Scale for Schizophrenia
pbo
placebo
PCL
protocol clarification letter
PD
Pharmacodynamic
PE
physical exam
PK
pharmacokinetic
po
per os, orally
PP
per-protocol
PVI
parvalbumin-positive interneuron
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
selPOCE
selective, proton observed, carbon-edited
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
088KBB

PRODUCT: MK-4334  
117
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21-SEP-2022
Abbreviation
Expanded Term
SOP
standard operating procedures
SUSAR
suspected unexpected serious adverse reaction
SZ
schizophrenia
t1/2
half life
Tmax
time to maximum plasma concentration
T/RT
test/retest
UDS
urine drug screen
ULN
upper limit of normal
Vcycle
rate of glutamate to glutamine conversion
VS
vital signs
VTCA
turnover rate of tricarboxylic acid cycle
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
WRAT-5
Wide-Range Achievement Test 5
088KBB

PRODUCT: MK-4334  
118
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21-SEP-2022
11
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