A Phase 2a, Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-1942 Added to Stable Antidepressant Therapy in Participants With Treatment-Resistant Depression
Phase: PHASE2
Conditions: Treatment Resistant Depression
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04663321 
Document Date: 
28-JUL-2022
A Phase 2a, Randomized, Placebo-Controlled Clinical Study to 
Evaluate the Efficacy and Safety of MK-1942 Added to Stable 
Antidepressant Therapy in Participants With Treatment-Resistant 
Depression

PRODUCT: MK-1942  
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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, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2a, Randomized, Placebo-Controlled Clinical Study to Evaluate the 
Efficacy and Safety of MK-1942 Added to Stable Antidepressant Therapy in Participants 
With Treatment-Resistant Depression
Protocol Number: 006-03
Compound Number: MK-1942
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
152126
EudraCT
Not applicable
Approval Date: 28 July 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 3
28-JUL-2022
This amendment was primarily created to extend the study population by 
including WOCBP.
Amendment 2
27-MAY-2022
This amendment was primarily created to add safety laboratory assessments to 
the 14-day postdose visit (Week 6) and to change this visit to either a site visit
or TC visit.
Amendment 1
07-MAR-2022
This amendment was primarily created to update the inclusion and exclusion 
criteria, which expands the TRD population and increases enrollment.
Original Protocol
19-OCT-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
This amendment was primarily created to extend the study population by including WOCBP.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
2.2.2 Preclinical and Clinical 
Studies
2.3 Benefit/Risk Assessment
5.1 Inclusion Criteria
5.2 Exclusion Criteria
7.1 Discontinuation of Study 
Intervention
8.1.7.2 Concomitant 
Medications
8.1.12 Study Intervention 
Administration
8.3.6.1 Confirmation of 
Postmenopausal State
8.3.6.2 Pregnancy Testing
Women of childbearing potential were 
added to this study. Inclusion criteria, 
contraception requirements, and pregnancy 
testing were updated to reflect this 
additional population. Exclusion criterion
excluding women with <12 months of 
amenorrhea receiving HRT or estrogen-
based contraceptives was removed. 
Study population is being extended to WOCBP as they
represent a significant portion of the TRD population. 
Mitigation strategies have been implemented to minimize 
the risk of undesired pregnancies. 
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Section # and Name
Description of Change 
Brief Rationale 
8.3.8 Contraceptive Use 
Confirmation
8.11.1 Screening
10.2 Appendix 2: Clinical 
Laboratory Test
10.5 Appendix 5: 
Contraceptive Guidance
11 References
2.2.2 Preclinical and Clinical 
Studies
2.3 Benefit/Risk Assessment
Phase 1 data were updated to reflect 
recently completed studies.
Section 2.2.3 Ongoing Clinical Studies 
was removed
To align with recent IB update.
4.3.2 Maximum 
Dose/Exposure for This 
Study
Safety text previously included in Section 
2.2.3 was added and data from completed
studies was added.
Statement on safety margins was updated 
to align with recent IB update.
Updated safety text for consistency across the protocol 
and to align with IB. 
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Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
10.2 Appendix 2: Clinical 
Laboratory Tests
-eGFR exclusion criterion was revised to 
<30 mL/min/1.73m2.
-Liver disease exclusion criterion was 
updated to clarify hepatitis exclusion.
Clarification to align with other studies in the MK-1942 
program. MK-1942 is not renally excreted. eGFR 
exclusionary threshold was updated to be consistent with 
severe renal impairment definition and to align with other 
studies in the MK-1942 program. While chronic viral 
hepatitis and non-viral hepatitis pose an increased risk for 
DILI, the evaluation of liver enzymes is not sufficient to 
establish clinical stability or remission. Therefore, there 
is a need to exclude participants with chronic viral 
hepatitis and non-viral hepatitis regardless of the liver 
enzyme stability in the previous 6 months.
5.2 Exclusion Criteria
7.1 Discontinuation of Study 
Intervention
8.1.7.2 Concomitant 
Medications
8.11.1 Screening
10.2.1 Drug Screening 
(Local and Central)
Intermittent cannabis use is not prohibited
if abuse or substance use disorder has been 
ruled out by investigator.
Cannabis and its derivatives are widely used for medical 
purposes. 
This exclusion was relaxed given that intermittent use of 
cannabis is not expected to pose a risk to participant 
safety or interpretation of study results if drug abuse or 
substance use disorder is ruled out.
8.1.6 MGH-ATRQ
Clarified instructions to sites and focused
pharmacy verification on current failed 
therapy. Broadened documentation options 
for earlier treatment(s).
To allow for more flexibility in documenting failed 
antidepressants taken for the current MDD episode and 
focus pharmacy verification on most critical time 
interval.
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Section # and Name
Description of Change 
Brief Rationale 
8.1.7.2 Concomitant 
Medications
Moderate CYP2C19 inducers were 
removed from the list of prohibited 
medications. Sensitive CYP2C19 
substrates were updated.
Results from study MK-1942-007 showed that CYP2C19 
activity has a moderate impact on the PK of MK-1942. 
Therefore, only strong CYP2C19 inducers need to be 
excluded.
Throughout the document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the intent 
of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities...........................................................................................23
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................32
2.2
Background ..........................................................................................................32
2.2.1
Pharmaceutical and Therapeutic Background .............................................32
2.2.2
Preclinical and Clinical Studies ...................................................................33
2.2.3
Information on Other Study-related Therapy ..............................................35
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................39
4.2.1
Rationale for Endpoints ...............................................................................40
4.2.1.1
Efficacy Endpoints.............................................................................40
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Pharmacokinetic Endpoints ...............................................................41
4.2.1.4
Pharmacodynamic Endpoints.............................................................41
4.2.1.5
Planned Exploratory Biomarker Research.........................................42
4.2.1.5.1
Planned Genetic Analysis ........................................................42
4.2.1.6
Future Biomedical Research..............................................................42
4.2.2
Rationale for the Use of Placebo .................................................................42
4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring...........................43
4.3
Justification for Dose...........................................................................................43
4.3.1
Starting Dose for This Study........................................................................43
4.3.2
Maximum Dose/Exposure for This Study ...................................................43
4.3.3
Rationale for Dose Interval and Study Design ............................................44
4.4
Beginning and End of Study Definition .............................................................44
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................45
5.1
Inclusion Criteria.................................................................................................45
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5.2
Exclusion Criteria................................................................................................48
5.3
Lifestyle Considerations......................................................................................51
5.3.1
Meals and Dietary Restrictions....................................................................51
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................52
5.3.3
Activity Restrictions ....................................................................................52
5.4
Screen Failures.....................................................................................................53
5.5
Participant Replacement Strategy......................................................................53
6
STUDY INTERVENTION............................................................................................53
6.1
Study Intervention(s) Administered...................................................................53
6.1.1
Medical Devices...........................................................................................55
6.2
Preparation/Handling/Storage/Accountability .................................................55
6.2.1
Dose Preparation..........................................................................................55
6.2.2
Handling, Storage, and Accountability........................................................55
6.3
Measures to Minimize Bias: Randomization and Blinding..............................56
6.3.1
Intervention Assignment..............................................................................56
6.3.2
Stratification.................................................................................................56
6.3.3
Blinding........................................................................................................56
6.4
Study Intervention Compliance..........................................................................56
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Rescue Medications and Supportive Care ...................................................57
6.6
Dose Modification (Escalation/Titration/Other)...............................................57
6.7
Intervention After the End of the Study............................................................59
6.8
Clinical Supplies Disclosure................................................................................59
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................59
7.1
Discontinuation of Study Intervention...............................................................59
7.2
Participant Withdrawal From the Study...........................................................61
7.3
Lost to Follow-up .................................................................................................61
8
STUDY ASSESSMENTS AND PROCEDURES........................................................62
8.1
Administrative and General Procedures ...........................................................62
8.1.1
Informed Consent.........................................................................................62
8.1.1.1
General Informed Consent.................................................................63
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................63
8.1.2
Inclusion/Exclusion Criteria ........................................................................63
8.1.3
Participant Identification Card.....................................................................63
8.1.4
Medical History ...........................................................................................64
8.1.5
Psychiatric History and MINI......................................................................64
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8.1.6
MGH-ATRQ................................................................................................64
8.1.7
Prior and Concomitant Medications Review...............................................65
8.1.7.1
Prior Medications...............................................................................65
8.1.7.2
Concomitant Medications..................................................................65
8.1.8
External Verification of Diagnosis ..............................................................67
8.1.9
Assignment of Screening Number...............................................................68
8.1.10
Assignment of Treatment/Randomization Number.....................................68
8.1.11
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing....................................................................................................68
8.1.12
Study Intervention Administration ..............................................................68
8.1.12.1
Timing of Dose Administration.........................................................69
8.1.13
Witnessed Dose............................................................................................69
8.1.14
Study Intervention Accountability...............................................................69
8.1.15
Telephone Contacts (Site to Participant) .....................................................69
8.1.16
Discontinuation and Withdrawal .................................................................70
8.1.16.1
Withdrawal From Future Biomedical Research ................................70
8.1.17
Participant Blinding/Unblinding..................................................................71
8.1.18
Calibration of Equipment.............................................................................71
8.2
Efficacy Assessments ...........................................................................................72
8.2.1
MADRS, HAM-D17, CGI-S, BAC SC .......................................................72
8.3
Safety Assessments...............................................................................................72
8.3.1
Physical and Neurological Examinations ....................................................73
8.3.2
Vital Signs....................................................................................................73
8.3.3
Height/Weight..............................................................................................74
8.3.4
ECGs............................................................................................................74
8.3.5
Alcohol Screen (Breathalyzer).....................................................................74
8.3.6
Clinical Safety Laboratory Assessments .....................................................74
8.3.6.1
Confirmation of Postmenopausal State..............................................75
8.3.6.2
Pregnancy Testing..............................................................................75
8.3.7
Suicidal Ideation and Behavior Monitoring.................................................76
8.3.7.1
Clinical Assessments for Suicidal Ideation and Behavior 
Monitoring .........................................................................................76
8.3.8
Contraceptive Use Confirmation .................................................................77
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................77
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................78
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......80
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...80
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8.4.4
Regulatory Reporting Requirements for SAE .............................................80
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................81
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................81
8.4.7
Events of Clinical Interest............................................................................81
8.5
Treatment of Overdose........................................................................................82
8.6
Pharmacokinetics.................................................................................................82
8.6.1
Blood Collection for Plasma MK-1942 .......................................................82
8.7
Pharmacodynamics..............................................................................................82
8.8
Biomarkers ...........................................................................................................82
8.8.1
Planned Genetic Analysis Sample Collection..............................................82
8.9
Future Biomedical Research Sample Collection...............................................83
8.10
Health Economics Medical Resource Utilization and Health Economics.......83
8.11
Visit Requirements...............................................................................................83
8.11.1
Screening......................................................................................................84
8.11.2
Lead-in Calls................................................................................................85
8.11.2.1
Central Vendor Rater Review of Participant Eligibility....................85
8.11.3
Treatment Period..........................................................................................86
8.11.4
Down-titration Visit.....................................................................................86
8.11.5
EOT/DC Visit ..............................................................................................86
8.11.6
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................87
8.11.7
Post-dose Follow-up Period.........................................................................87
8.11.8
Poststudy......................................................................................................87
9
STATISTICAL ANALYSIS PLAN .............................................................................87
9.1
Statistical Analysis Plan Summary.....................................................................88
9.2
Responsibility for Analyses/In-house Blinding .................................................89
9.3
Hypotheses/Estimation ........................................................................................90
9.3.1
Estimands.....................................................................................................90
9.4
Analysis Endpoints...............................................................................................92
9.4.1
Efficacy Endpoints.......................................................................................92
9.4.2
Safety Endpoints..........................................................................................94
9.4.3
Pharmacokinetic Endpoints .........................................................................94
9.4.4
Derivation of Efficacy Endpoints ................................................................94
9.5
Analysis Populations............................................................................................95
9.5.1
Efficacy Analysis Populations.....................................................................95
9.5.2
Safety Analysis Populations ........................................................................95
9.5.3
Pharmacokinetic Analysis Populations........................................................96
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9.6
Statistical Methods...............................................................................................96
9.6.1
Statistical Methods for Efficacy Analysis....................................................96
9.6.2
Statistical Methods for Safety Analysis.......................................................99
9.6.3
Statistical Methods for Pharmacokinetic Analysis ....................................102
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................102
9.7
Interim Analyses ................................................................................................102
9.8
Multiplicity .........................................................................................................105
9.9
Sample Size and Power Calculations ...............................................................106
9.9.1
Sample Size and Power for Efficacy Analyses..........................................106
9.9.2
Sample Size and Power for Safety Analyses .............................................107
9.10
Subgroup Analyses.............................................................................................109
9.11
Compliance (Medication Adherence)...............................................................110
9.12
Extent of Exposure.............................................................................................110
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................111
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......111
10.1.1
Code of Conduct for Clinical Trials...........................................................111
10.1.2
Financial Disclosure...................................................................................113
10.1.3
Data Protection...........................................................................................113
10.1.3.1
Confidentiality of Data ....................................................................114
10.1.3.2
Confidentiality of Participant Records.............................................114
10.1.3.3
Confidentiality of IRB/IEC Information..........................................114
10.1.4
Committees Structure.................................................................................115
10.1.4.1
Internal Data Monitoring Committee...............................................115
10.1.4.2
Scientific Advisory Committee (SAC)............................................115
10.1.5
Publication Policy......................................................................................115
10.1.6
Compliance with Study Registration and Results Posting Requirements .115
10.1.7
Compliance with Law, Audit, and Debarment ..........................................116
10.1.8
Data Quality Assurance .............................................................................116
10.1.9
Source Documents .....................................................................................117
10.1.10
Study and Site Closure...............................................................................118
10.2
Appendix 2: Clinical Laboratory Tests............................................................119
10.2.1
Drug Screening (Local and Central)..........................................................121
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................123
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................123
10.3.2
Definition of AE ........................................................................................123
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10.3.3
Definition of SAE ......................................................................................124
10.3.4
Additional Events Reported.......................................................................125
10.3.5
Recording AE and SAE .............................................................................126
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................129
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................131
10.5
Appendix 5: Contraceptive Guidance..............................................................132
10.5.1
Definitions..................................................................................................132
10.5.2
Contraception Requirements......................................................................133
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................134
10.7
Appendix 7: Country-specific Requirements..................................................139
10.8
Appendix 8: General Neurological Examination............................................140
10.9
Appendix 9: Abbreviations ...............................................................................144
11
REFERENCES.............................................................................................................147
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LIST OF TABLES
Table 1
Study Interventions....................................................................................54
Table 2
Prohibited Medications/Therapies/Products and Prohibited Dose 
Strengths for Allowed Medications ...........................................................66
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................79
Table 4
Efficacy Measures by Dosing Regimen and Timepoint ............................93
Table 5
Directionality of Improvement in Efficacy Measures ...............................94
Table 6
Analysis of Key Efficacy Variables...........................................................98
Table 7
Analysis Strategy for Safety Parameters..................................................101
Table 8
Summary of Interim Analysis Strategy....................................................102
Table 9
Operating Characteristics of the Interim Futility Analysis......................104
Table 10
Primary Assumptions, Marginal Power, and Probabilities for MADRS 
Total Score...............................................................................................107
Table 11
Differences (95% CIs) in Incidence in AEs Between MK-1942 Daily 
Dose and Placebo.....................................................................................108
Table 12
Differences (95% CIs) in Incidence in AEs Between MK-1942 
Intermittent Dose and Placebo.................................................................108
Table 13
Protocol-required Safety Laboratory Assessments..................................120
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................22
Figure 2
Testing Strategy to Address Multiplicity.................................................106
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a, Randomized, Placebo-Controlled Clinical Study to Evaluate the 
Efficacy and Safety of MK-1942 Added to Stable Antidepressant Therapy in Participants 
With Treatment-Resistant Depression
Short Title: A Phase 2a Proof-of-Concept Study of MK-1942 in Participants With TRD
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
In men and women with TRD on a stable course of antidepressant therapy:
Primary Objectives
Primary Endpoints
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in MADRS total score 
at Week 3. 
Hypothesis (H1): Daily MK-1942 treatment 
is superior to placebo in reducing MADRS 
total score at Week 3.  
MADRS total score
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
MADRS total score at Week 1. 
Hypothesis (H2): Intermittent MK-1942 
treatment is superior to placebo in reducing 
MADRS total score at Week 1.  
MADRS total score
To evaluate the safety and tolerability of 
daily and intermittent MK-1942 treatment. 
AEs
Discontinuation of study intervention due 
to AEs
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Secondary Objectives
Secondary Endpoints
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in HAM-D17 total 
score at Week 3.
Hypothesis (H3): Daily MK-1942 treatment 
is superior to placebo in reducing HAM-D17 
total score at Week 3.
HAM-D17 total score
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
HAM-D17 total score at Week 1.
Hypothesis (H4): Intermittent MK-1942 
treatment is superior to placebo in reducing 
HAM-D17 total score at Week 1.
HAM-D17 total score
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in CGI-S score at 
Week 3. 
Hypothesis (H5): Daily MK-1942 treatment 
is superior to placebo in reducing CGI-S 
score at Week 3.
CGI-S score
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
CGI-S score at Week 1. 
Hypothesis (H6): Intermittent MK-1942 
treatment is superior to placebo in reducing 
CGI-S score at Week 1.
CGI-S score
To evaluate the PK of MK-1942 when 
administered daily or intermittently.
MK-1942 plasma concentration
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To compare the effect of daily and 
intermittent MK-1942 treatment with the 
effect of placebo on the change from baseline 
in BAC SC score at Week 3.
BAC SC score (number of correct matches 
on the BAC SC cognitive test after 90 
seconds) 
To compare the effect of daily and 
intermittent MK-1942 treatment with the 
effect of placebo on: 
- the change from baseline in MADRS total 
score, HAM-D17 total score, HAM-D6 total 
score, and CGI-S score at time points 
through Week 4 that are not specified for the 
primary or secondary endpoints.  
- MADRS remission rate at all time points 
through Week 4.
- the proportion of participants with a ≥50% 
reduction from baseline in MADRS total 
score at all time points through Week 4.
MADRS total score
HAM-D17 total score
HAM-D6 total score
CGI-S score
To explore the relationship between genetic 
variation and response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in the study.
Germline genetic variation and association 
to clinical data collected in this study.
To investigate the relationship between the 
genetic polymorphisms of CYP2C19 and the 
pharmacokinetics of MK-1942. Variation in 
CYP2C19 alleles may be analyzed for 
association with any laboratory or clinical 
data collected in this study.
Germline genetic variation in CYP2C19 
and association to clinical data collected in 
this study.
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of TRD
Population
Men and women with TRD on a stable course of 
antidepressant therapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo-controlled
Study Blinding
Double-blind
Blinding Roles
Sponsor
Investigator
Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 36 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 140 participants will be allocated/randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin-
istration
Treatment 
Period
Use
MK-1942 Daily 
Dose Group
MK-1942
5 mg, 
10 mg
bid
Oral
Weeks 1, 2, 
3, 4
Test Product
Placebo
0 mg
bid
Oral
Weeks 1, 2, 
3, 4
Placebo
MK-1942 
Intermittent 
Dose Group
MK-1942
10 mg
biw
Oral
Weeks 1, 2, 
3, 4
Test Product
Placebo
0 mg
bid
Oral
Weeks 1, 2, 
3, 4
Placebo
Placebo
Placebo
0 mg
bid
Oral
Weeks 1, 2, 
3, 4
Placebo
Abbreviations: bid=twice-daily, biw=twice-weekly
Note 1: The dose of MK-1942 for participants in the MK-1942 daily dose group will be uptitrated as follows: 5 
mg bid (Visit 4/Day 1 to Visit 5/Week 1), 10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 
6/Week 2 to Visit 8/Week 4).
Note 2: Dose modification to the intended regimen of MK-1942 may occur due to intolerance or non-adherence, 
as described in Section 6.6.
Note 3: MK-1942 and matching placebo will be packaged in blister cards and an equal number of capsules will 
be administered in the morning and evening regardless of treatment assignment.
Total 
Number of 
Intervention 
Groups/ 
Arms
3
Duration of 
Participation
Each participant will participate in the study for approximately 9 weeks
from the time the participant provides documented informed consent
through the final contact. After a pretreatment screening and lead-in period 
of approximately 3 weeks, each participant will receive assigned 
intervention for approximately 4 weeks. After the end of treatment, each 
participant will be followed for at least 2 weeks.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Administra-
tive 
Procedures
Screening period 
may be less than 3 
weeks (see Section 
8.11.1) Clinic visits 
and Lead-in Calls 
should occur at 
about the same time 
of day in the 
morning.
Informed 
Consent
X
Informed 
Consent for 
FBR
X
Participants remain 
eligible for the main 
study if they opt out 
of FBR.
Assignment 
of Screening 
Number
X
Inclusion/
Exclusion 
Criteria
X
X
X
X
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Participant 
Identification 
Card
X
X
The randomization 
number will be 
added to the 
identification card at 
Visit 4 (Day 1). 
Medical 
History
X
Psychiatric 
History and 
MINI
X
MINI will also be 
audio recorded.
MGH-ATRQ
X
MGH-ATRQ will 
also be audio 
recorded.
Prior/
Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
Contraceptive 
Use 
Confirmation
X
X
X
X
X
X
X
See Section 8.3.3
External 
Verification 
of Diagnosis
X
See Study 
Operations Manual
(see Section
8.11.2.1) for details.
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
IRT Visit 
Registration 
X
X
X
X
X
X
X
At Visit 8, IRT entry 
applies to DC visits 
only.
IRT 
Randomization
X
Study 
Intervention 
Dispensing
X
X
X
X
X
Except for Down-
titration Visit, 
WOCBP must have 
a negative urine 
pregnancy test
immediately before 
study intervention is 
administered or 
dispensed.
Study 
Medication 
Guidance 
Dispensing 
and Review
X
X
X
X
X
At Visit 4, dispense 
guide and train 
participants. At 
Visits 5-8, review 
guide and retrain 
participants, as 
needed (see Section 
8.1.12).
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Witnessed
Dose
X
X
X
X
X
The Day 1 AM dose 
must be 
administered on the
first day of each 
treatment week
irrespective of the
time of day (see 
Section 8.1.12.1). 
A witnessed dose 
may not be 
administered at the 
Down-titration Visit 
depending on when 
the participant’s last 
dose was taken (see 
Section 5.3.1). 
Study 
Intervention 
Accountability
X
X
X
X
X
Telephone 
Contacts 
After Visits
X
X
X
X
X
A telephone contact 
will be performed 
within the first 3
days after Visits 4, 
5, 6, 7 and the 
Down-titration 
Visit, if applicable
(see Section 8.1.15). 
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Efficacy 
Assessments
The efficacy 
assessments are 
listed in 
recommended order 
of administration 
(see Section 8.2).
BAC SC
X
X
X
MADRS
X
X
X
X
X
X
X
MADRS will be 
audio recorded.
HAM-D17
X
X
X
X
X
X
X
X
X
Administered by the 
site at Visit 1 and 
Visits 4 to 9. 
Administered by the 
central vendor rater 
at Visits 2 and 3 (see 
Section 8.11.2).
HAM-D17 will be 
audio recorded.
CGI-S
X
X
X
X
X
X
X
Safety 
Procedures
Full Physical 
Examination 
X
X
Neurological 
Examination
X
X
see Section 10.8
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Vital Signs 
(temperature, 
blood 
pressure, 
pulse rate, 
and 
respiratory 
rate)
X
X
X
X
X
X
X
Height
X
Weight
X
X
12-lead ECG
(centrally 
read)
X
X
X
X
Measured in 
triplicate at each
visit (see Section
8.3.4).
Alcohol 
Screen 
(breathalyzer)
X
X
Chemistry 
and 
Hematology
X
X
X
X
X
Visit 10 laboratory 
assessments may be 
performed at a local 
laboratory, as
needed 
Urinalysis
X
X
X
X
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Local Urine
Pregnancy 
Test,
(WOCBP)
X
X
X
X
X
X
X
Schedule for women 
of child-bearing 
potential
Local Urine 
Pregnancy 
Test 
(WONCBP)
X
X
X
Schedule for women 
of NON child-
bearing potential
Serum 
Pregnancy 
Test 
(WOCBP)*
X
X
X
X
X
*WONCBP will be 
tested if there is a 
positive urine test or 
ambiguous result
INR
X
TSH
X
FT4
X
Performed if 
participant has 
abnormal TSH 
value.
FSH
X
FSH may be 
measured to confirm 
postmenopausal 
state. (see Section 
8.3.6.1 and 
Appendix 5).
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
Genotyping 
for CYP2C19
X
Urine Drug 
Screen 
(central) 
X
X
X
X
Urine Drug 
Screen 
(local)
X
X
X
X
C-SSRS 
(Baseline/
Screening 
Version)
X
C-SSRS 
(Since Last 
Visit 
Version)
X
X
X
X
X
X
X
X
Visit 10 C-SSRS 
may be performed 
by TC, as needed.
AE 
Monitoring
X
X
X
X
X
X
X
X
X
Visit 10 AE 
monitoring may be 
performed by TC, as
needed.
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Study Period
Screening 
Lead-in 
Call 1
Lead-in
Call 2
Double-blind Treatment Period
Post-dose Follow-up 
Period
Down-
titration
Notes
Visit 
Number/Title
1
2
3
4
5
6
7
8
EOT/DC
9
10
(14 days 
Postdose)
Down-
titration 
Visit
Scheduled
Visit 
Week/Day
Wk -3/
Day
-21
Day
-8
Day
-1
Wk 0/
Day 
1
Wk 1/
Day
8
Wk 2/
Day 
15
Wk 3/
Day 
22
Wk 4/
Day
29
Wk 5/
Day 36
Wk 6/
Day
43
NA
Visit 
Windows 
(Days)
-3
-3
-3
0
-1
±2
+3
PK and 
Biomarkers
MK-1942 PK 
Blood 
Sample 
X
X
X
X
X
At Visit 4 (Day 1),
predose and 
approximately 1-
hour postdose PK 
samples will be 
collected. At all 
other visits, only 
predose PK samples 
will be collected. 
See Section 8.9 for 
FBR details.
Blood for 
Genetic 
Analysis
X
The blood sample 
will be collected
predose in 
randomized 
participants only
(see Section 8.8).
AE=adverse event, BAC SC=Brief Assessment of Cognition Symbol Coding, CGI-S=Clinical Global Impression-Severity, C-SSRS=Columbia-Suicide 
Severity Rating Scale, DC=discontinuation, ECG=electrocardiogram, EOT=end of treatment, FBR=future biomedical research, FSH=follicle-stimulating 
hormone; FT4=free T4 test, HAM-D17=17-item Hamilton Depression Rating Scale, INR=international normalized ratio, IRT=interactive response 
technology, MADRS=Montgomery-Asberg Depression Rating Scale, MGH-ATRQ=Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire, MINI=Mini International Neuropsychiatric Interview, NA=not applicable, PK=pharmacokinetic, TC=telephone call, TSH=thyroid-stimulating 
hormone, Wk=week, WOCBP=woman of childbearing potential, WONCBP=woman of non-childbearing potential.
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2
INTRODUCTION
2.1
Study Rationale
MDD is a common mental illness that can significantly affect quality of life (Section 2.2.1). 
A large proportion of those with MDD either fail to respond to antidepressant therapy or 
initially respond to antidepressant therapy but relapse within 3 months. Ketamine and 
esketamine, which appear to work by increasing glutamate signaling in the brain, have been 
shown to rapidly improve depressive symptoms in those with TRD, but are associated with 
important safety concerns and abuse potential. MK-1942, which also appears to work by 
increasing glutamate signaling in the brain, has been generally well-tolerated in healthy 
adults in 4 completed Phase 1 studies and in preclinical evaluations. The purpose of this 
Phase 2a PoC study is to evaluate the therapeutic effect of MK-1942 in participants with 
TRD on stable antidepressant therapy, and to characterize the safety and tolerability of 
MK-1942 in this population.
While patients failing 2 or more antidepressant therapies are often considered to have TRD
[Gaynes, B. N., et al 2020], this study will also enroll participants with 1 treatment failure for 
the current episode of moderate-to-severe MDD. This approach is considered appropriate 
given the high likelihood that participants with MDD who fail 1 antidepressant therapy will 
continue to fail additional courses of antidepressant therapy. However, the study will aim to
randomize approximately 30% of participants with more than1 treatment failure (for the 
current episode of moderate-to-severe MDD) to ensure adequate representation of this 
population.
Two different dosing regimens of MK-1942 will be evaluated in this study. In the daily dose 
group, MK-1942 will be uptitrated as follows: 5 mg bid (Visit 4/Day 1 to Visit 5/Week 1), 
10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 6/Week 2 to 
Visit 8/Week 4). This titration regimen was selected to help participants improve tolerance to 
higher doses of MK-1942 (safety data are summarized in Section 2.2.1). The primary time 
point to evaluate the effect of daily MK-1942 treatment on TRD is Week 3. 
The intermittent dose group is included in this study to evaluate if twice-weekly dosing with 
10 mg of MK-1942 can rapidly improve depressive symptoms (by Week 1) in participants 
with TRD, with continued evaluation of this regimen through the end of the study. Details on 
the scientific rationale and the dose regimens of MK-1942 in this study are in Sections 4.2 
and 4.3, respectively.
2.2
Background
Refer to the IB for detailed background information on MK-1942.
2.2.1
Pharmaceutical and Therapeutic Background
MDD is a major contributor to the disease burden worldwide with lifetime prevalence 
ranging from 20% to 25% in women and 7% to 12% in men. MDD is a significant 
determinant of quality of life and survival, accounting for approximately 50% of psychiatric 
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consultations and 12% of all hospital admissions [Wang, J., et al 2017]. Current 
antidepressant therapies do not exert their full effects immediately [Zanos, P., et al 2019], 
and even if adequately treated, approximately 50% of patients with MDD fail to respond at 
all [Gaynes, B. N., et al 2020]. Moreover, even patients with TRD who respond to their 
current antidepressant therapy have a high rate of relapse (65% within 3 months) [Rush, A. 
J., et al 2006]. Healthcare costs and the risk of mortality due to suicide is elevated in patients 
with TRD [Reutfors, J., et al 2019].
MK-1942 is a small molecule NAM of mGluR2 that is being studied for treatment of TRD. 
In humans, MK-1942 suppresses the inhibitory effect of presynaptic mGluR2 on the release 
of glutamate in the brain, which thereby increases the synaptic levels of glutamate [Higgins, 
G. A., et al 2004] [Dietrich, D., et al 2002]. This increase in glutamate levels elevates 
postsynaptic neuron excitability and plasticity in the brain and is predicted to improve 
depressive symptoms. Ketamine and the S(+) enantiomer esketamine are NMDA antagonists 
that also appear to work by increasing glutamate signaling in the brain, and have been 
hypothesized to exert their effects, at least indirectly, through interactions with mGluR2
[Zanos, P., et al 2019]. They have shown clinically meaningful antidepressive effects within 
the first 24 to 48 hours of use [Molero, P., et al 2018]. However, due to prominent concerns 
about safety and abuse potential, these products are only available through a restricted 
program and must be taken in the office of a healthcare provider. In addition, patients must 
have medical supervision for at least 2 hours following their administration of ketamine or 
esketamine because of the substantial risk of sedation and dissociation. Thus, there remains a 
significant, unmet medical need for antidepressants that offer a safer and more accessible 
alternative for the treatment of TRD.
2.2.2
Preclinical and Clinical Studies
MK-1942 has shown to be active in the non-human primate glutamate cycling paradigm. In a 
preclinical study, mGluR2 knockout mice failed to demonstrate a ketamine-induced 
reduction of time immobile, equivalent to an antidepressant effect, in a tail suspension test 
compared with wild type. This result is consistent with that of another study in mice [Zanos, 
P., et al 2019] and supports the hypothesis that mGluR2 signaling may mediate ketamine’s 
antidepressant effects. MK-1942 dose-dependently increases glutamate cycling as measured 
by MRS in rhesus monkeys. Maximal effect appears to be achieved at RO levels ≥40%. An 
increase in glutamate cycling, as measured by MRS, has also been observed in humans 
acutely after a ketamine infusion [Abdallah, C. G., et al 2018], and is postulated as a 
potential mechanism for the promotion of rapid antidepressant effects. Hence, for 
antidepressant efficacy, the target RO is at least 40%.
The preclinical safety profile of MK-1942 indicates that there are no adverse CNS or 
cardiovascular findings at an EM of approximately 64-times above the clinical target 
(~200 nM). No effects on cardiovascular parameters or vital signs were observed in rats or 
guinea pigs, and the changes observed at the higher doses in a cardiovascular and respiratory 
safety study in rhesus monkeys were reversible and/or not considered adverse. MK-1942 did 
not induce seizures or abnormal spike cluster activity in a 9-day electroencephalogram study 
in monkeys at plasma concentrations corresponding to 61-times the Cmax corresponding to 
RO levels of approximately 40%.
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In embryo-fetal toxicity studies in rats and rabbits, skeletal malformations were observed in 
rats, and increased incidences of extra gallbladder and short 13th rib occurred in rabbits. 
Mitigations to reduce risks for WOCBP are described in Section 2.3 Benefit /Risk. 
Six Phase 1 clinical studies of MK-1942 are complete. Results from a single ascending-dose 
study (P001) of MK-1942 (0.1 mg to 12 mg) showed that it is absorbed rapidly and that its 
plasma concentrations declined in a biphasic manner, with a t1/2α of approximately 3 hours 
and an apparent terminal t1/2 of approximately 10 to 15 hours. Exposures (AUC0-inf and Cmax) 
increase in an approximately dose-proportional fashion. Following administration of 
MK-1942 (4 mg) with a high-fat meal, absorption was decreased (Cmax decreased by 52%, 
AUC0-inf decreased by 15%). Results from a PET study (P003) of MK-1942 (4 mg to 12 mg) 
suggest that the target RO level of approximately 41%, associated with a Cmax of ~200 nM,
may be achieved following a single dose of 10 mg of MK-1942. Results from a multiple 
ascending-dose study (P002) of MK-1942 showed that a twice-daily titration regimen (up to 
20 mg bid) improved tolerance to MK-1942 while surpassing the target Cmax of 200 nM.
Results from a multiple ascending-dose study of MK-1942 (P004) showed that steady state 
Cmax, Ctrough, and AUC0-12 were similar, or up to 85% higher in elderly participants compared 
to non-elderly participants across the 5- to 50-mg twice daily dose range, with longer 
apparent terminal t1/2 in elderly participants. 
P005 was a Phase 1, double-blind, placebo-controlled, DDI study of the safety, tolerability, 
and PK of MK-1942 and donepezil conducted in participants with AD receiving donepezil as 
part of their treatment for cognitive impairment associated with AD. This study is clinically 
complete although the CSR is not final.
P007 was a Phase 1, double-blind, placebo-controlled, single- and multiple-dose clinical 
study to evaluate the safety, tolerability, and PK of MK-1942 in healthy Japanese adult 
participants. This study is clinically complete although the CSR is not final. 
In the completed Phase 1 studies, treatment with MK-1942 was generally well-tolerated. 
Single (4 mg to 12 mg) and repeated doses (5 mg to 50 mg) of MK-1942 were associated 
with episodes of dizziness (which may be associated with gait disturbance in a minority of 
participants), headache, and nausea. These AEs were of mild to moderate intensity and
resolved without intervention. They were alleviated by titration dosing regimens. No SAEs 
and no clinically significant abnormalities were observed in safety measures, including those 
of vital signs, laboratory chemistry, hematology, urinalysis, physical examinations, or ECGs 
with one exception. Nonserious AEs of increased liver transaminases were observed in 2 
participants after 4 weeks of study treatment during Part 2 of P007. These AEs did not meet 
criteria for DILI or an event of clinical interest as defined in the protocol. The liver function 
test abnormalities were observed only in the group exposed to MK-1942 50 mg bid and no 
abnormalities were observed in any of the participants exposed to lower dosages. A third 
subject in P005 who was on either placebo or 50 mg bid of MK-1942 had increased ALT and 
AST 2 weeks after completing the 4-week trial, which remains blinded (see IB for details).
There are currently no efficacy or safety data for MK-1942 in participants with TRD.
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2.2.3
Information on Other Study-related Therapy
This section is not applicable to the current study. 
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
While no efficacy data on treatment with MK-1942 in participants with TRD are available, 
agents that appear to work by increasing glutamate signaling, like MK-1942, have shown 
clinically meaningful antidepressant effects in participants with TRD (Section 2.2.1). 
Phase 1 clinical studies to date have shown that treatment with MK-1942 is generally 
well-tolerated. Participants may experience dizziness that is mild to moderate in intensity. In 
a minority of cases, the dizziness may be associated with gait disturbance. Participants may 
also experience headaches that are mild to moderate in intensity. Episodes of dizziness and 
headache may be accompanied by feelings of nausea with or without emesis. In addition, 
isolated cases of asymptomatic increased ALT (up to ~13x ULN) with increased AST (up to 
~6x ULN) and without increased total bilirubin or ALP have been observed after 4 weeks of 
treatment with MK-1942 up to 50 mg bid or placebo (see IB for details). Given that the AEs 
observed were reversible and monitorable, there are currently no safety issues from the 
completed or ongoing clinical studies that preclude continued clinical investigation.
Regarding the teratogenicity risk, WOCBP make up a major portion of women with 
depression, including TRD [Brody, D. J., et al 2018]. Given the limited number of treatment 
options, and given their risk of embryo-fetal toxicity (esketamine label), including WOCBP 
in trials of potentially new medication is warranted. To reduce fetal risk, use of birth control 
will be required and closely monitored. Pregnancy status will be assessed weekly. Given 
these safeguards, the risk of pregnancy and fetal exposure to MK-1942 is extremely low.
Given the limited treatment options for participants with TRD, the serious health risks 
associated with inadequately treated TRD, and the available preclinical and clinical data for 
MK-1942 summarized above and in the IB, the benefit-to-risk assessment for conducting the 
current study is considered favorable. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study are in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In men and women with TRD on a stable course of antidepressant therapy:
Objectives
Endpoints
Primary
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in MADRS total score 
at Week 3. 
Hypothesis (H1): Daily MK-1942 treatment
is superior to placebo in reducing MADRS 
total score at Week 3.  
MADRS total score
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
MADRS total score at Week 1. 
Hypothesis (H2): Intermittent MK-1942 
treatment is superior to placebo in reducing 
MADRS total score at Week 1.  
MADRS total score
To evaluate the safety and tolerability of 
daily and intermittent MK-1942 treatment. 
AEs
Discontinuation of study intervention due 
to AEs
Secondary
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in HAM-D17 total 
score at Week 3.
Hypothesis (H3): Daily MK-1942 treatment 
is superior to placebo in reducing HAM-D17
total score at Week 3.
HAM-D17 total score
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Objectives
Endpoints
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
HAM-D17 total score at Week 1.
Hypothesis (H4): Intermittent MK-1942 
treatment is superior to placebo in reducing 
HAM-D17 total score at Week 1.
HAM-D17 total score
To compare the effect of daily MK-1942 
treatment with the effect of placebo on the 
change from baseline in CGI-S score at Week 
3. 
Hypothesis (H5): Daily MK-1942 treatment 
is superior to placebo in reducing CGI-S 
score at Week 3.
CGI-S score
To compare the effect of intermittent 
MK-1942 treatment with the effect of 
placebo on the change from baseline in 
CGI-S score at Week 1. 
Hypothesis (H6): Intermittent MK-1942 
treatment is superior to placebo in reducing 
CGI-S score at Week 1.
CGI-S score
To evaluate the PK of MK-1942 when 
administered daily or intermittently.
MK-1942 plasma concentration
Tertiary/Exploratory
To compare the effect of daily and 
intermittent MK-1942 treatment with the 
effect of placebo on the change from baseline 
in BAC SC score at Week 3.
BAC SC score (number of correct matches 
on the BAC SC cognitive test after 90
seconds) 
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Objectives
Endpoints
To compare the effect of daily and 
intermittent MK-1942 treatment with the 
effect of placebo on: 

the change from baseline in MADRS 
total score, HAM-D17 total score, 
HAM-D6 total score, and CGI-S 
score at time points through Week 4 
that are not specified for the primary 
or secondary endpoints. 

MADRS remission rate at all time 
points through Week 4.

the proportion of participants with a 
≥50% reduction from baseline in 
MADRS total score at all time points 
through Week 4.
MADRS total score
HAM-D17 total score
HAM-D6 total score
CGI-S score
To explore the relationship between genetic 
variation and response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in the study.
Germline genetic variation and association 
to clinical data collected in this study.
To investigate the relationship between the 
genetic polymorphisms of CYP2C19 and the 
pharmacokinetics of MK-1942. Variation in 
CYP2C19 alleles may be analyzed for 
association with any laboratory or clinical 
data collected in this study.
Germline genetic variation in CYP2C19 
and association to clinical data collected in 
this study.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2a, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety MK-1942 in adult participants with TRD on stable antidepressant 
therapy. The study population will consist of male and female participants aged 18 to 65
years with a primary diagnosis of moderate-to-severe MDD (MADRS total score ≥25) who 
are currently experiencing a depressive episode and who have not adequately responded to 1
to 4 courses of approved antidepressant therapy (including the current course of 
antidepressant therapy) despite sufficient dose and duration (referred to in this document as 
treatment failure [for the current episode of moderate-to-severe MDD]). Prior to 
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randomization, participants’ psychiatric history will be evaluated by the investigational site, 
and the primary diagnosis of moderate-to-severe MDD will be assessed centrally to confirm 
eligibility. Participant’s depressive symptoms (based on HAM-D17) will also be assessed 
centrally to confirm eligibility prior to randomization. Participants will continue taking their
stable background antidepressant therapy during the study.
Approximately 140 participants will be randomized in a 2:1:2 ratio to either (1) daily 
treatment with MK-1942 administered as 5 mg bid (Visit 4/Day 1 to Visit 5/Week 1), 
10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 6/Week 2 to 
Visit 8/Week 4), (2) intermittent treatment with MK-1942 administered twice-weekly (10 mg 
biw), or (3) placebo, respectively (Section 1.2). MK-1942 or matching placebo will be 
administered as oral capsules. Randomization will be stratified by the number of treatment 
failures for the current episode of moderate-to-severe MDD to antidepressant therapy (1 vs
>1) at Visit 1 (Screening). The study will aim to randomize approximately 30% of 
participants with more than 1 treatment failure (for the current episode of moderate-to-severe
MDD) to ensure adequate representation of this population.
Details on the selection of the 2:1:2 randomization ratio are in Section 9.9.1.
For the daily dose group, the primary time point for efficacy assessments is Week 3 after 
participants in this group complete 3 weekly titrations with MK-1942. An additional week of 
treatment is included in this study to evaluate the effects of continued treatment with the 
20 mg bid dose of MK-1942. For the intermittent dose group, the primary time point for 
efficacy assessments is Week 1. The effects of intermittent treatment with MK-1942 will also 
be examined through Week 4 (EOT/DC Visit). A post-dose follow-up visit (Visit 9) will 
occur approximately 1 week after the last dose of study intervention to evaluate the durability 
of MK-1942 effects on depression. 
Safety will be monitored at scheduled visits and by a phone contact after each visit where 
study intervention is dispensed (including the Down-titration Visit, if applicable). A final 
post-dose follow-up visit (Visit 10) (site visit or TC) will be performed to assess laboratory 
safety tests, suicidality, AEs, SAEs, and other reportable safety events approximately 14 days 
after the last dose of study intervention or at Visit 10, whichever is later. An siDMC will 
evaluate the accruing unblinded safety data on a regular basis. Additionally, the siDMC will 
evaluate the results of an interim futility analysis performed after the first approximately 60%
of randomized participants either complete Week 3 or discontinue before Week 3. The 
interim futility analysis will include a review of efficacy, safety, and tolerability data.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The goals of this Phase 2a PoC study are to test the hypothesis that MK-1942 reduces
depressive symptoms in participants with TRD on stable antidepressant therapy, and to 
evaluate its safety and tolerability. The study will use a double-blind, parallel-group design in 
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the assessment of MK-1942 versus placebo, a standard design for studies of major depression 
(details on the rationale for use of placebo are in Section 4.2.2).
Two different dosing regimens of MK-1942 will be evaluated. In the daily dose group, 
MK-1942 will be uptitrated as follows: 5 mg bid (Visit 4/Day 1 to Visit 5/Week 1),
10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 6/Week 2 to 
Visit 8/Week 4). This dosing regimen was selected to achieve maximum RO levels and to 
reduce the incidence and severity of AEs reported in the Phase 1 program. Titrated daily 
dosing in the Phase 1 program enabled testing of higher doses and improved tolerability with 
MK-1942. The primary time point for efficacy analyses comparing the MK-1942 daily dose
group with placebo is Week 3, which will allow participants in the MK-1942 daily dose 
group to complete 3 weekly titrations. An additional week of treatment is included in this 
study to evaluate the effects of continued treatment with the 20 mg bid dose of MK-1942. 
The intermittent dose group will receive MK-1942 10 mg biw to evaluate whether transient 
exposure followed by a period of recovery promotes rapid effects (at Week 1) on depressive 
symptoms. This dosing regimen is similar to the administration of ketamine for treatment of 
depression. Although the exact mechanism remains unclear, some data suggest that the rapid
antidepressant effects of medications such as ketamine may be induced by brief surges in 
glutamate cycling [Abdallah, C. G., et al 2018]. The 10 mg dose was selected based on 
available Phase 1 safety data while expected to achieve RO levels of approximately 40%. 
The effects of MK-1942 treatment in this group will also be examined through Week 4
(EOT/DC).
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The efficacy of MK-1942 treatment will be measured using scales that will assess changes in 
participants’ depressive symptoms and severity of illness. Each scale will be administered by 
a qualified and trained rater. Participants will also complete a validated cognitive test to 
measure improvements in cognitive function. Details about the efficacy endpoints are 
provided below. 
MADRS: 
The MADRS (primary endpoint) is a well-established, validated scale for evaluating severity 
of depressive symptoms [Montgomery, S. A. and Asberg, M. 1979]. It has been widely used 
in pharmacotherapy studies of major depression. The 10 items comprising the MADRS 
evaluate the core symptoms of depression. Each item is rated on a scale from 0 to 6, with 
total scores ranging from 0 to 60, and higher scores corresponding to greater symptom 
severity [Williams, J. B. W. 2008].
HAM-D17
The HAM-D17 is a 17-item scale developed to evaluate depressive symptoms experienced 
by patients over the past week. Each item is rated on a scale from 0 to 2 or 0 to 4, with total 
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scores ranging from 0 to 52 and higher scores corresponding to greater symptom severity 
[Hamilton, M. 1960] [Hamilton, M. 1967] [Williams, J. B. W. 2013].
Results from 6 of the 17 items in the HAM-D17 that represent the core symptoms of MDD 
according to DSM-5TM criteria (depressed mood, feeling of guilt, work and activities, motor 
retardation, psychic anxiety, and somatic symptoms [general]) [Lin, H. S. 2019] will also be 
evaluated to derive the HAM-D6 scores.
CGI-S:
The CGI-S is a single-item scale for assessing global illness severity. In this study, the CGI-S 
is intended to measure the severity of a participant’s depression. The CGI-S is rated on a 
7-point scale using a range of responses from 1 (normal, not at all ill) to 7 (among the most 
extremely ill patients) [Guy, W. 1976].
BAC SC
In addition to antidepressant effects, preclinical data suggest that treatment with MK-1942 
may enhance cognitive function by increasing glutamate signaling in the brain. There is also
evidence suggesting that cognitive function in those with MDD may be improved through 
amelioration of depressive symptoms [Russo, M., et al 2015]. The BAC SC will be used in 
this study to assess potential changes in cognitive function. The BAC SC is a cognitive test 
that requires participants to assign numbers to non-meaningful symbols according to a key. 
The number of correct matches within the allowed time (90 seconds) constitutes the score
[Atkins, A. S., et al 2017].
4.2.1.2
Safety Endpoints
Safety and tolerability will be assessed throughout the study by monitoring participants for 
AEs. Neurological and physical examinations, vital signs, 12-lead ECGs, and laboratory 
safety tests will be performed to detect any clinically meaningful effects. The C-SSRS will 
be administered to screen for the presence, and assess the severity, of possible suicidal 
ideation and behavior in all study participants (Section 4.2.3).
4.2.1.3
Pharmacokinetic Endpoints
Plasma samples will be drawn to evaluate the concentrations of MK-1942 at the time of the 
assessment of the efficacy endpoints to enable evaluation of potential PK/PD and PK/AE 
relationships. These data may be used in PK model development and analysis. Additional 
metabolites based on ongoing metabolites in safety testing analyses may also be evaluated.  
The final decision as to which plasma samples will be assayed will be made by the Sponsor's 
Department of Quantitative Pharmacology and Pharmacometrics and the Clinical Monitor.
4.2.1.4
Pharmacodynamic Endpoints
Pharmacodynamic endpoints are not applicable.
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4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on 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.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
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 Placebo
Despite the seriousness of the indication, a placebo group is necessary to evaluate the 
efficacy and safety of the addition of MK-1942 treatment in participants with TRD on stable 
antidepressant therapy. Without the use of placebo, false assumptions regarding the true 
efficacy of new drugs may be made. In the absence of a placebo control, it is nearly 
impossible to distinguish true drug effects from placebo effects in this study population. In 
addition, all participants will continue to take their stable background antidepressant 
treatment.
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4.2.3
Rationale for Suicidal Ideation and Behavior Monitoring
Prospective assessment of suicidal ideation and behavior will be performed in this study 
using the C-SSRS. This assessment is being conducted in compliance with the 2012 FDA 
guidance requiring prospective assessment in clinical studies conducted under IND 
applications and studies that are intended for submission in a NDA to the Neurology or 
Psychiatry Divisions of the FDA or biologics license application, as well as assessment in 
studies that fall within the guidance for other reasons (eg, CNS active/penetrant compounds, 
and known mechanisms or indications for which suicidal ideation/behavior has been 
previously identified as a potential concern).
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The starting dose for the MK-1942 daily dose group is 5 mg bid. The completed multiple
ascending-dose study (P002) in healthy adults showed that a titration regimen with a starting
dose of 5 mg bid is well-tolerated. No participants in Study P002 discontinued study 
intervention due to an AE and all reported AEs were either mild or moderate in intensity and 
resolved. The most common AEs were dizziness, headache, and nausea. The completed
multiple ascending-dose study (P004) in healthy adults (non-elderly and elderly) had starting 
doses of either 5 mg bid or 8 mg bid, with extended dosing regimens that were generally 
well-tolerated. The starting and maximum dose for the MK-1942 intermittent dose group is
10 mg biw. The completed single ascending dose study (P001) in healthy adults showed that 
treatment with MK-1942 up to 12 mg is well-tolerated. No participants receiving MK-1942 
discontinued study intervention due to an AE and all reported AEs were either mild or 
moderate in intensity and resolved. The most common intervention-related AEs were 
dizziness (associated with gait disturbance in a minority of participants), headache, and 
nausea. The incidence and intensity of the AEs of dizziness were strongly correlated with 
increasing exposure. 
Based on the plasma concentration-RO relationship determined from the completed PET RO 
study (P003), single doses of 10 mg are anticipated to achieve a peak RO of 41%. Further, a
preclinical MRS study in rhesus monkeys demonstrated that ROs ≥40% are associated with 
maximal increase in glutamate metabolism. Therefore, a 10-mg dose given intermittently is 
anticipated to precipitate a glutamate surge similar to that hypothesized to induce rapid 
antidepressant effects with ketamine and esketamine treatment. As a transient surge in 
glutamate release followed by a period of recovery may be important for promoting rapid-
acting and durable antidepressant effects, intermittent administration of 10 mg biw will be 
evaluated in this study.
4.3.2
Maximum Dose/Exposure for This Study
In the MK-1942 daily dose group, MK-1942 will be uptitrated weekly (5 mg bid, 10 mg bid, 
and 20 mg bid) to assess efficacy at the primary time point (Week 3). The dose will be 
maintained at 20 mg bid for the last week of the study (Week 4) to obtain additional safety 
and tolerability data and evaluate the efficacy of longer exposure to inform the design of
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future studies. The selection of this titration regimen is informed by the highest well-tolerated 
dosing regimens tested in both healthy adults and healthy elderly in Phase 1 studies where a 
gradual stepwise uptitration approach improved tolerability for AEs such as dizziness (and 
associated gait disturbance) and headache (but not nausea), allowing for evaluation of higher 
ROs. Doses up to 20 mg bid were well-tolerated in healthy adults in the completed multiple 
ascending-dose study (P002) (see Section 2.2.2). Safety data in healthy elderly in the Phase 1 
study (P004) at doses up to 20 mg bid demonstrated similar tolerability with MK-1942 as 
observed in healthy adults. Doses up to 50 mg bid were also observed to be well-tolerated, 
but 3 out of 8 healthy non-elderly adults in the accelerated titration panel (Panel B) declined 
dose escalation to 30 mg bid. The most commonly reported AEs were dizziness, headache, 
abnormal dreams, and nystagmus (see IB for details). Studies investigating higher doses of 
MK-1942 reported non-serious AEs of asymptomatic increases in ALT and/or AST in 3 
participants (Section 2.2.2). Laboratory values returned to normal baseline values or near
normal with clear downward trends after discontinuation of study treatment in 2 participants, 
while 1 participant refused further testing. To ensure safety of participants, liver enzymes 
will be checked every 2 weeks during treatment and additional laboratory monitoring has 
been implemented at 2 weeks posttreatment (see SoA, Section 1.3). The dose titration for this 
Phase 2 PoC study will follow the gradual titration of 5 mg bid, 10 mg bid, and 20 mg bid.
To minimize discontinuation of study intervention in this study, participants unable to 
tolerate or adhere to treatment with study intervention at or after Visit 6 (Week 2) may 
undergo a dose modification to the intended regimen of MK-1942 (see Section 6.6).
Because translation of RO targets to the clinical endpoint of antidepressant efficacy remains 
unclear and other clinical biomarkers are unavailable, doses up to 20 mg bid will be 
evaluated to support a well-tolerated dose approach in this study. Based on the PK-RO 
relationship, a mean steady state peak RO of 65% and trough RO of 49% are projected for 
the 20 mg bid dose of MK-1942. As the minimum RO for antidepressant efficacy is uncertain 
and the RO target of 40% represents the threshold for MRS and cognition activity, daily 
dosing with gradual titration enables exploration of maximum RO to test the mechanism and
tolerability of MK-1942. The maximum dose of 20-mg bid maintains an adequate safety 
margin (16X) for the study population relative to the NOAEL (see IB for details).
4.3.3
Rationale for Dose Interval and Study Design
By inclusion of 2 MK-1942 treatment regimens, this study aims to investigate the therapeutic 
effects of higher ROs and sustained glutamate activity associated with daily treatment and 
the pulsatile glutamate surge potentially induced by intermittent treatment. This study will 
also evaluate the relationship of each regimen on the onset and time course of antidepressant 
effects.
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).
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For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
This study may be terminated early by the siDMC for safety concerns or futility based on the 
results of an interim analysis (see details in Section 9.7). 
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1), our studies include people
of varying age, race, ethnicity, and sex. The collection and use of these demographic data are 
to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
All psychiatric diagnoses specified for eligibility will be made according to DSM-5TM criteria 
by a qualified psychiatrist (MD) or psychologist (PhD) (or equivalent qualification). All 
assessments of psychiatric symptoms which require an interview with the participant must be 
done in a language in which both the assessor and the participant are fluent. An interpreter is 
not permitted.
Male and female participants with TRD aged 18 to 65 years will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1.
Meets the diagnostic criteria for moderate-to-severe MDD without psychotic features 
according to DSM-5TM criteria (assessed via MINI) at Visit 1 (Screening).
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2.
Is currently experiencing an episode of moderate-to-severe MDD based on a MADRS 
total score ≥25 at Visit 1 (Screening).
3.
Had an inadequate response, based on the investigator’s or qualified delegate’s clinical 
judgment, to 1 to 4 different courses of approved antidepressant therapy (including the
current course of antidepressant therapy) of sufficient dose and duration (assessed using 
MGH-ATRQ) for the current episode of moderate-to-severe MDD.
4.
Has HAM-D17 total scores at Visit 1 (Screening) as assessed by the site and at Visit 2 
(Lead-in Call 1) and Visit 3 (Lead-in Call 2) as assessed by the central vendor rater that 
meet the requirements for study inclusion, as defined by the Sponsor. Note: Site 
personnel and participants will be blinded to the specific HAM-D17 eligibility criteria. 
The central vendor rater will communicate eligibility status to the site.
5.
Has been on a stable course of antidepressant therapy for ≥4 weeks before Visit 1
(Screening). 
Note: Participants are to remain on their stable course of background antidepressant 
therapy through Visit 9 (Post-dose Follow-up Visit). See Section 8.1.7.2.  
Note: Inclusion criteria 1 to 5 will be independently verified by the central vendor rater 
before randomization (see Section 8.1.8).
6.
Has not initiated psychotherapy (based on participant report) for depressive symptoms 
in the last 3 months before Visit 1 (Screening) and agrees not to initiate a new 
psychotherapy for depressive symptoms or to modify their current regimen of 
psychotherapy for depressive symptoms from Visit 1 (Screening) to Visit 9 (Post-dose 
Follow-up Visit).
Demographics
7.
Is male or female, from 18 years to 65 years of age inclusive, at the time of providing 
documented informed consent.
Male Participants
8.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days 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, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview) 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
9.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and
at least 3 months postpartum, and at least one of the following conditions:

Not a WOCBP
OR

A WOCBP and:

Uses a contraceptive method that is highly effective (with failure rate of 
<1% per year), or be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long-term and persistent basis), 
as described in Appendix 5 during the intervention period and for at least 7 
days after the last dose of study intervention. Contraceptive methods with
user dependency (eg, oral hormonal contraception) must be combined with a 
supplementary barrier method, such as male condom. The investigator 
should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local 
regulations regarding the methods of contraception for those participating in 
clinical studies.

Has a negative highly sensitive pregnancy test (urine or serum) as required 
by local regulations) both within the screening period and immediately
before the first dose of study intervention. (If a urine test cannot be 
confirmed as negative [eg, an ambiguous result], a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation 
if the serum pregnancy result is positive.) Additional requirements for 
pregnancy testing during and after study intervention are in Section 8.3.6.2.

Abstains from breastfeeding during the study intervention period and for at 
least 7 days after last study intervention.
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
Medical history, menstrual history, and recent sexual activity has been 
reviewed by the investigator to decrease the risk for inclusion of a woman 
with an early undetected pregnancy.
Informed Consent
10.
Provides documented informed consent for the study. The participant may also provide 
consent for FBR. However, the participant may participate in the main study without 
participating in FBR.
Additional Categories
11.
Is willing and considered able by the investigator to participate in protocol assessments, 
including recordings of interviews, adherence to treatment and visit schedules, and 
adherence with study procedures and restrictions.
12.
Has a reliable contact person (eg, family member, social worker, case worker, case 
manager, or nurse) identified for emergent situations.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1.
Has an ongoing episode of MDD that started more than 2 years before Visit 1 
(Screening).
2.
Has a current or prior history of any personality disorder that may interfere with 
compliance or increase suicidal risk based on the investigator’s judgment.
3.
Has a current or prior history of one or more of the following:
a) diagnosis of a psychotic disorder, bipolar and related disorders, MDD with 
psychosis, MDD with mixed features, posttraumatic stress disorder (if not in 
remission for at least 5 years before Screening), obsessive-compulsive disorder, or 
autism spectrum disorder. 
b) chronic convulsive disorder (eg, epilepsy or seizure disorder), except febrile 
seizures during childhood.
c) neurodegenerative disorder (eg, Parkinson’s, Alzheimer’s, or Huntington’s disease), 
traumatic brain injury causing ongoing cognitive difficulties, or any chronic organic 
disease of the central nervous system (eg, multiple sclerosis).
d) intellectual disability of a severity that would affect the ability of the participant to 
participate in the study.
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4.
Meets criteria for substance abuse or dependence disorder (excluding caffeine and 
tobacco use) currently or within the 12 months before Visit 1 (Screening).
5.
Has a known allergy or intolerance to the active or inert ingredients in MK-1942. 
6.
Has a history of malignancy ≤3 years before Visit 1 (Screening) except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer.
7.
Has a BMI >40 kg/m2 (BMI = weight in kg/height in meters2); details are provided in 
the Study Operations Manual.
8.
Has a risk factor for QTc prolongation as defined by: 

a known history or current evidence of QTc interval >470 msec (men) or >480 
msec (women), OR

a known history of risk factors for Torsades de Pointes (eg, heart 
failure/cardiomyopathy or family history of long QT syndrome) 
Note: ECGs will be performed in triplicate. At Visit 1 (Screening), the average of the 3 
QTcF intervals based on the central vendor overread will be used to assess eligibility. 
At Visit 4 (Day 1), the average of the 3 QTcF intervals based on the local ECG printout
will be used to assess eligibility (additional details on ECG assessments are in Section 
8.3.4).
9.
Has HIV or nonstable hypothyroidism, diabetes, cardiovascular disease, or respiratory 
disease or has another chronic medical condition that is not considered to be adequately 
treated in the opinion of the investigator.
Note: The prescribed doses and regimens of prior medications should be stable for ≥3 
months before Visit 1 (Screening) and there should not be expected changes for these 
medications before and during the study. Treatment with a medication is considered 
stable if dose adjustments reflect optimizing treatment rather than reacting to significant 
changes in the treated conditions. Timing for substitution of prohibited medications is 
presented in Table 2.
10.
Has a severe, acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
administration of study intervention or may interfere with the interpretation of study 
results and, in the opinion of the investigator or Sponsor, would make the participant 
inappropriate for entry into this study.
11.
Is at imminent risk of self-harm, based on clinical interview and responses on the 
C-SSRS, or of harm to others in the opinion of the investigator. Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method 
(eg, positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) 
in the past 2 months or suicidal behavior in the past 6 months.
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Prior/Concomitant Therapy
12.
Does not meet the requirements defined in Section 8.1.7.2 (Concomitant Medications, 
Table 2) that specify when prohibited medications/products or prohibited doses for 
allowed medications must be stopped relative to Visit 1 (Screening). 
13.
Failed to adequately respond in the investigator’s or qualified delegate’s clinical 
judgment to treatment with ketamine or esketamine for the current or a prior episode of 
MDD.
14.
Previously received electroconvulsive therapy (within the past 10 years), deep brain 
stimulation, or vagal nerve stimulation for treatment of depression. TMS is not 
exclusionary unless received within 6 weeks before Visit 1 (Screening).
Prior/Concurrent Clinical Study Experience
15.
Is currently participating in or has previously participated in an interventional clinical 
study within the 2 months before Visit 1 (Screening), or has participated in >4
interventional clinical studies within the 2 years before Visit 1 (Screening).
Diagnostic Assessments
16.
This exclusion criterion has been removed.
17.
Has known renal disease or is experiencing renal insufficiency as defined by eGFR 
<30 mL/min/1.73 m2 (MDRD) at Visit 1 (Screening).
18.
Has laboratory or clinical evidence of clinically significant hepatic conditions such as 
one or more of the following: 

ALT ≥1.5x ULN or AST ≥2x ULN at Visit 1 (Screening)*
*Note: Participants may be retested 1 time at least 1 day after Visit 1 (Screening).

Liver disease, including but not limited to chronic viral hepatitis, non-viral 
hepatitis, cirrhosis, malignancies, autoimmune liver diseases (ie, autoimmune 
hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis).
19.
Has an abnormal TSH value at Visit 1 (Screening). Exception: A participant with an 
abnormal TSH value and a normal FT4 value may be eligible if clinically stable and 
without signs of hypo- or hyperthyroidism, in the investigator’s judgment. Any thyroid 
treatment must be stable for ≥3 months before Visit 1 (Screening).
20.
Routinely consumes >3 alcoholic drinks per day. One standard drink is defined as any 
beverage containing 14 g of pure alcohol (ie, 12 oz of beer, 8 to 9 oz of malt liquor, 5 
oz of wine, 1.5 oz of distilled spirits).
21.
Has a positive breath test for alcohol at Visit 1 (Screening) or Visit 4 (Day 1). 
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22.
Has a local or central positive test result for drugs of abuse at Visit 1 (Screening) or a 
local positive test result for drugs of abuse at Visit 4 (Day 1). Drugs of abuse include
opiates, barbiturates, amphetamine/methamphetamine, cannabis, methadone, cocaine, 
and phencyclidine. 
Note 1: Participants who have a positive test result at Visit 1 (Screening) due to 
prescribed opiates (excluding methadone), barbiturates, or amphetamines may continue 
in the pretreatment period if the prohibited medication is discontinued at least 1 week 
or 5 half-lives (whichever is longer) before the first dose of investigational intervention. 
The participant may be enrolled if the Visit 4 (Day 1) test for drugs of abuse is 
negative. A retest is not permitted for those who test positive at Visit 1 (Screening) due 
to non-prescription of drugs of abuse.
Note 2: Participants who have a positive test result for cannabis at Visit 1 (Screening) 
must be evaluated by the investigator for substance use disorder and may be enrolled if
abuse is ruled out.
Other Exclusions
23.
Requires use of a language interpreter to participate in the study. 
24.
Had major surgery or donated or lost >1 unit of blood (approximately 500 mL) within
the 4 weeks before Visit 1 (Screening).
25.
Has a positive pregnancy test at Visit 1 (Screening) or Visit 4 (Day 1) (see Section 
8.3.6.2) or is currently breastfeeding or plans to breastfeed during the course of the 
study.
26.
This exclusion has been removed.
27.
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants will refrain from consuming grapefruit juice, grapefruits, and grapefruit products 
from Visit 1 (Screening) through Visit 8 (EOT/DC Visit). Other types of fruit juice, fruits, 
and fruit products are permitted during the study. Sites should instruct participants to take 
study intervention with water. 
MK-1942 should NOT be taken with food. Participants should fast (ie, no food or drink, 
except water, black coffee, black tea, or juice [except grapefruit juice]) according to the 
guidance below. In situations where the fasting guidance cannot be followed, the participant 
should fast for at least 1 hour before and 1 hour after dosing. Non-study medications can be 
taken with water during fasting periods.
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
Evening Dosing: Participants should take their evening dose of study intervention close 
to bedtime, at least 1 hour after the evening meal, and should continue to fast for at least 
1 hour after dosing.

Morning Dosing (days with no clinic visit): Participants should take their morning dose 
of study intervention either:
o
before their morning meal with at least 1 hour fast after dosing or
o
at least 1 hour after a light breakfast with at least 1 hour fast after dosing.

Morning Dosing (days with scheduled clinic visits): From Visit 4 (Day 1) to 
Visit 7 (Week 3), participants should attend clinic visits after their overnight fast. They
must NOT take a morning dose of study intervention from the blister cards dispensed at 
the previous visit. Participants should NOT eat a meal until at least 1 hour after taking 
study intervention from the new blister cards dispensed in the clinic. A low fat, low 
caloric snack (eg, a slice of toast with jelly, a cup of skim or 1% milk, a cup of nonfat 
yogurt, a packet of oatmeal made with water, or a piece of fruit [except grapefruit]) can 
be eaten at least 1 hour before dosing at these visits to minimize hunger. 

Down-titration Visit Dosing (if applicable): The first dose of study intervention from the 
blister cards dispensed at the Down-titration Visit depends on when the last dose was 
taken from the previously dispensed blister cards. For example, if the last dose from the 
previously dispensed blister cards was taken in the morning on the third day after Visit 6 
(Week 2), then the evening dose corresponding to the third day after Visit 6 (Week 2) 
will be the first dose taken from the blister cards dispensed at the Down-titration Visit. 
Participants should fast for 1 hour before and 1 hour after dosing. Additional information 
will be provided in the Study Operations Manual. 
The last dose of study intervention will be taken the evening before Visit 8 (EOT/DC Visit). 
There are no fasting requirements for Visit 8 (EOT/DC Visit) or Visit 9 (Post-dose Follow-up 
Visit). 
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants will be counseled to limit alcohol use to moderate amounts while participating in 
the study (ie, ≤3 drinks per day and not more than 21 drinks per week). One standard drink is 
defined as any beverage containing 14 g of pure alcohol (ie, 12 oz of beer, 8 to 9 oz of malt 
liquor, 5 oz of wine, 1.5 oz of distilled spirits). There are no caffeine or tobacco/nicotine
restrictions. 
5.3.3
Activity Restrictions
Participants will be informed about the risk of dizziness with MK-1942 treatment and will be 
instructed not to drive or operate heavy machinery until they determine that study 
intervention, taken as directed, does not affect their ability to engage in these activities.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Information on rescreening is provided in Section 8.11.1.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws consent will not be 
replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
MK-1942 and matching placebo to be used in this study will be packaged in blister cards and 
an equal number of capsules will be administered in the morning and evening regardless of 
treatment assignment. Study interventions are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Inter-
vention
Name
Inter-
vention
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
MK-1942 
Daily 
Dose 
Group
Experi-
mental
MK-
1942
Drug
Capsule
5 mg, 
10mg 
5 mg bid, 10 
mg bid, 20 mg 
bid
Oral
Weeks 1, 2, 3, 4
Test Product
IMP
Central
MK-1942 
Daily 
Dose 
Group
Experi-
mental
Placebo
Drug
Capsule
0 mg
0 mg bid
Oral
Weeks 1, 2, 3, 4
Placebo
IMP
Central
Placebo
Placebo 
Comparator
Placebo
Drug
Capsule
0 mg
0 mg bid
Oral
Weeks 1, 2, 3, 4
Placebo
IMP
Central
MK-1942
Inter-
mittent 
Dose 
Group
Experi-
mental
MK-
1942
Drug
Capsule
10 mg
10 mg biw
Oral
Weeks 1, 2, 3, 4
Test Product
IMP
Central
MK-1942 
Inter-
mittent 
Dose 
Group
Experi-
mental
Placebo
Drug
Capsule
0 mg
0 mg bid
Oral
Weeks 1, 2, 3, 4
Placebo
IMP
Central
Abbreviations: bid=twice-daily, biw=twice-weekly, 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 European Economic Area (EEA). 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note 1: The dose of MK-1942 for participants in the MK-1942 daily dose group will be uptitrated weekly as follows: 5 mg bid (Visit 4/Day 1 to Visit 5/Week 1), 10 mg bid (Visit 
5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 6/Week 2 to Visit 8/Week 4).
Note 2: Dose modification to the intended regimen of MK-1942 may occur due to intolerance or non-adherence, as described in Section 6.6.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.12 for details regarding administration of the study intervention.
6.1.1
Medical Devices
No medical devices are used in this study. 
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an IRT system. There are 3
study intervention arms. Participants will be assigned randomly in a 2:1:2 ratio to either (1) 
daily treatment with MK-1942 administered as 5 mg bid (Visit 4/Day 1 to Visit 5/Week 1), 
10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 20 mg bid (Visit 6/Week 2 to 
Visit 8/Week 4), (2) intermittent treatment with MK-1942 administered twice-weekly (10 mg 
biw), or (3) placebo, respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factor(s):
1. Number of treatment failures (1 vs >1) for the current episode of moderate-to-severe 
MDD
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-1942 and placebo will 
be packaged identically so that the blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for ≥2 days within a weekly 
treatment interval will lead to the participant being retrained on compliance by site personnel. 
Any additional interruptions from the protocol-specified treatment plan for ≥2 days within a 
weekly treatment interval will require consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
Participants in the daily dose and intermittent dose groups who have substantial 
non-adherence with study intervention may undergo a dose modification to the intended 
regimen of MK-1942 (in a blinded manner), as described in Section 6.6. Dose modification
for non-adherence is not applicable to the placebo group. 
Compliance with study intervention will be analyzed to assess the percentage of days when 
participants take the prescribed capsules of study intervention (Section 9.11). Adherence with 
study intervention will be assessed to facilitate clinical decision making on appropriate 
dosing (additional details on adherence are provided in the Study Operations Manual). 
Participants will be directed to bring all dispensed blister cards to each visit. Participants’ 
compliance with study intervention will be monitored using technology that collects data on 
when capsules are removed from blister cards and through participant interview by site 
personnel. If a participant’s report is inconsistent with electronically captured compliance 
data, then site personnel will reconcile the differences and determine the most accurate 
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representation of study intervention administration. The electronically captured dispensing 
data can be annotated after reconciliation occurs.
6.5
Concomitant Therapy
Medications, therapies, or products specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study. If there is a clinical indication for any medications or 
treatments specifically prohibited, discontinuation from study intervention may be required. 
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director. The final decision on any supportive therapy rests with the investigator and/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.
Prohibited medications, therapies, and products and prohibited dose strengths for allowed 
medications are listed in Table 2. Any medication or vaccine (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) that the participant receives 
concomitantly during the study (from Visit 1 [Screening] through Visit 10 [14-day Post-dose 
Follow-up Visit]) should be recorded in the study database.
Any licensed COVID-19 vaccine (including for emergency use) in a particular country is 
permitted in the study as long as they are mRNA vaccines, adenoviral vaccines, or 
inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. 
Investigational vaccines (ie, those not licensed or approved for emergency use) are not 
permitted.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
As described in Section 4.1 (Overall Design) and shown in Section 1.2 (Schema), the dose of 
MK-1942 for participants in the daily dose group will be uptitrated as follows: 5 mg bid 
(Visit 4/Day 1 to Visit 5/Week 1), 10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 
20 mg bid (Visit 6/Week 2 to Visit 8/Week 4). The dose of MK-1942 (10 mg biw) for 
participants in the intermittent dose group will remain stable throughout the study (unless 
down-titration for intolerance or non-adherence occurs). Participants in the placebo group 
will not receive treatment with MK-1942.
To minimize discontinuation of study intervention, participants unable to tolerate treatment 
with study intervention at or after Visit 6 (Week 2) may undergo a dose modification to the 
intended regimen of MK-1942 in a blinded manner. Participants who are intolerant to 
treatment in the MK-1942 daily dose group will maintain the 10 mg bid dose at 
Visit 6 (Week 2) or will down-titrate from 20 mg bid to 10 mg bid after Visit 6 (Week 2). 
Participants who are intolerant to treatment in the MK-1942 intermittent dose group will 
maintain the 10 mg biw dose at Visit 6 (Week 2) or will down-titrate from 10 mg biw to 
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5 mg biw after Visit 6 (Week 2). Participants in the placebo group will undergo mock dose 
modification reflecting changes in doses relative to the 2 other groups. 
Additionally, participants in the daily dose group who have substantial non-adherence with 
study intervention may also undergo a dose modification to the intended regimen of 
MK-1942 (in a blinded manner), as described below. This is because substantial 
non-adherence could diminish the improved tolerance developed through uptitration to AEs 
(Section 2.2.2) associated with MK-1942 treatment. Guidance on how to assess substantial 
non-adherence and additional details on the management of MK-1942 dosing are provided in 
the Study Operations Manual.
Participants in the daily dose group with substantial non-adherence during the prior week of 
treatment may have their dose of MK-1942 managed as follows: 

Non-adherence prior to Visit 5 (Week 1): The dose of MK-1942 will be uptitrated from 5 
mg bid to 10 mg bid according to the prespecified dosing schedule (Section 1.2).

Non-adherence prior to Visit 6 (Week 2): The 10 mg bid dose of MK-1942 will be 
maintained for the remainder of the study (ie, the participant will not uptitrate to the 
intended maximum study dose of 20 mg bid). 

Non-adherence prior to Visit 7 (Week 3): The dose of MK-1942 will be down-titrated 
from 20 mg bid to 10 mg bid; the 10 mg bid dose will be maintained for the remainder of 
the study.
Participants in the intermittent dose group with substantial non-adherence during the prior 
week of treatment may have their intended dose regimen managed as follows: 

Non-adherence prior to Visit 5 (Week 1) or Visit 6 (Week 2): The 10 mg biw dose of 
MK-1942 will be maintained according to the prespecified dosing schedule (Section 1.2)

Non-adherence prior to Visit 7 (Week 3): The dose of MK-1942 will be down-titrated 
from 10 mg biw to 5 mg biw; the 5 mg biw dose will be maintained for the remainder of 
the study.
Participants in the placebo group with substantial non-adherence will undergo mock dose 
modifications reflecting changes in doses relative to the 2 other groups.
Because it is not possible to comprehensively account for all scenarios of non-adherence, the 
Sponsor should be consulted when management of a participant’s study intervention is in 
question. 
Participants who undergo a dose modification to the intended regimen for intolerance or 
non-adherence with study intervention will not undergo any further dose modifications for 
the remainder of the study. 
All study intervention assignments/modifications will be completed using the IRT system.
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6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.17). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.6.
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 1.3 and 
Section 8.11.5.
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.
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
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, place the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a positive urine or serum pregnancy test. See Section 8.3.6.2 for 
pregnancy testing requirements.

The participant has an ALT ≥3x ULN

The participant has an AST ≥3x ULN with total bilirubin ≥2x ULN and ALP <2x ULN

The participant has an AST ≥3x ULN with ALT value >100 IU/L
Note 1: Liver function tests are to be confirmed by repeat testing within 48 hours of 
initial test results. If test results are unable to be confirmed within this timeframe, the 
study intervention should be withheld until test results are available. Study intervention 
should be discontinued if unable to repeat testing.
Note 2: If the investigator identifies a clear cause for the liver enzyme elevations
unrelated to study intervention, then study intervention may be continued with approval 
by the Sponsor.

The participant meets either of the following criteria for QTcF interval at a visit (Note: 
ECGs will be performed in triplicate [Section 8.3.4]):
o
The average of the 3 QTcF intervals based on either the local ECG printout or 
subsequent central vendor overread is >500 msec.
o
The average of the 3 QTcF intervals based on either the local ECG printout or 
subsequent central vendor overread increased by >60 msec, relative to the central 
vendor overread average at Visit 4 (Day 1). 

The participant reports suicidal ideation with intent, with or without a plan or method 
through an AE or C-SSRS (ie, a positive response to Items 4 or 5 in the assessment of 
suicidal ideation on the C-SSRS) or suicidal behavior. If the reported suicidal ideation is 
passive, and participant expressly denies any intent to act, and who, after evaluation, is
not judged to be at serious risk for self-harm during the study, the participant may 
continue on study intervention. Refer to Sections 8.3.7.1 on Clinical Assessments for 
Suicidal Ideation and Behavior Monitoring (for requirements pertaining to the evaluation 
of such events), and Section 8.4.7 for Events of Clinical Interest.

The participant is unable to tolerate treatment with study intervention before Visit 6
(Week 2). 
Note: Participants who are unable to tolerate study intervention after a dose modification
to the intended regimen should be discontinued from study intervention.
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
The participant begins to use a prohibited medication/therapy/product or a prohibited 
dose of an allowed medication listed in Section 8.1.7.2 (Concomitant Medications, Table 
2). This criterion includes participants who test positive (local or central) for a drug of 
abuse (except cannabis, which is not prohibited if abuse or substance use disorder is ruled 
out). 
Note: Participants who are willing and able to safely (per the investigator) stop using the 
prohibited medication/therapy/product (including drugs of abuse) or reduce from a 
prohibited to an acceptable dose for an allowed medication through Visit 9 (Post-dose 
Follow-up Visit) may continue study intervention at the investigator’s discretion.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Sections 8.1.16 and 8.1.16.1. 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.
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See Section 8.1.15 for guidance on contacting participants who miss a scheduled visit or TC.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
is approximately 80 mL (see the central laboratory manual).
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 future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician (or a qualified designee), to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
Medical history will be obtained by the investigator (or qualified designee).
Clinically significant findings in physical and neurological examinations, laboratory tests, 
ECGs, or other evaluations during the pretreatment period are to be noted in the participant’s 
medical history. 
All available history of psychiatric conditions and symptoms that are not core symptoms of 
depression (eg, agitation, anxiety, insomnia), including those captured in the MINI 
evaluation (Section 8.1.5), are to be recorded in the medical history. Other medical history 
conditions that occurred within the last 5 years are also to be recorded.
8.1.5
Psychiatric History and MINI
A psychiatric history will be obtained by the investigator (or qualified designee). The 
investigator may review and use multiple information sources (eg, medical charts, pharmacy 
verification of medication treatment, participant self-report, and healthcare professional or 
paraprofessional report) to obtain relevant historical information. All psychiatric diagnoses 
specified in the inclusion/exclusion criteria will be made according to the relevant DSM-5™ 
criteria. 
The MINI will be administered by a qualified site rater and used to confirm the diagnosis of 
MDD (without psychotic features). It will also be used to evaluate other psychiatric 
comorbidities, and to assess elements of the psychiatric history.
The investigator (or qualified designee) will use their best estimate based on available 
information sources (as noted above) to determine the onset of a participant’s current episode 
of MDD and the total number of prior episodes in a participant’s lifetime.
8.1.6
MGH-ATRQ
The MGH-ATRQ will be administered by a qualified site rater at Visit 1 (Screening) to 
determine the number of prior antidepressant treatment failures participants experienced for 
the current episode of MDD. The instrument collects drug class and drug name, assesses
adequacy of dose and duration of treatment, and collects degree of symptomatic 
improvement with each treatment. Participants are required to have had an inadequate 
response based on the rater’s clinical judgment to at least 1, but no greater than 4, different 
courses of approved antidepressant therapy (including the current course of antidepressant 
therapy) of sufficient dose and duration for the current episode of moderate-to-severe MDD 
to be eligible for the study (Section 5.1).
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Sites should verify with a pharmacy (verbal or written records) that participant meets 
inclusion criteria for current antidepressant therapy taken for at least 4 weeks before Visit 1. 
Earlier treatment(s) taken for the current episode may be confirmed based on participant or 
provider reporting or other medical records. The Sponsor should be consulted if pharmacy 
verification of antidepressant medications is unable to be obtained during the pretreatment 
period.
8.1.7
Prior and Concomitant Medications Review
8.1.7.1
Prior Medications
The investigator (or qualified designee) will review and record prior antidepressant 
medications and other prior psychiatric medications taken by the participant within 2 years 
before Visit 1 (Screening). Other prior medications taken by the participant within 3 months 
before Visit 1 (Screening) will also be recorded. 
8.1.7.2
Concomitant Medications
The investigator (or qualified designee) will review and record medications/products taken 
by the participant during the study. Participants are to remain on their stable course of 
background antidepressant therapy and permitted psychotropic medications from Visit 1 
(Screening) to Visit 9 (Post-dose Follow-up Visit). 
WOCBP who are taking oral contraceptive medications should remain on them during the 
intervention period and for at least 7 days after the last dose of study intervention. Based on 
the unbound concentrations observed in vivo, induction of CYP enzymes by MK-1942 is not 
anticipated to be clinically relevant or to impact the exposure of common oral contraceptives 
via CYP3A induction.
Prohibited medications/therapies/products and prohibited doses for allowed medications
listed in Table 2 should not be administered from Visit 1 (Screening) to Visit 9 (Post-dose 
Follow-up Visit). These include strong inducers of CYP2C19 because they could affect the 
oxidative metabolism of MK-1942. Sensitive substrates of CYP2C19 are prohibited because 
MK-1942 has the potential to inhibit CYP2C19 metabolism. Additionally, other agents with
glutamatergic activity could influence the effects of MK-1942 and are also prohibited. 
Treatment with other medications/therapies/products listed in Table 2 or with doses above 
the thresholds listed in Table 2 is prohibited to minimize their potential effects on depressive 
symptoms. 
Table 2 categorizes prohibited medications/therapies/products and prohibited doses of 
medications by those that participants must discontinue at Visit 1 (Screening) to wash-off
during the Lead-in Period and those that participants must be off for ≥4 weeks before Visit 1 
(Screening). For the latter category, participants’ medications/products should not be 
discontinued or adjusted before the study for the sole purpose of eligibility. Participants on a 
medication/product or a prohibited dose of a medication in this latter category within the 4 
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weeks before Visit 1 (Screening) should be screen-failed and can be rescreened after the ≥4
week requirement is met (see Section 8.11.1).
The investigator (or qualified designee) must consider if discontinuation or adjustment of a 
medication/product in Table 2 can be done safely without significant destabilization or 
increased suicidality.
The list of prohibited medications/therapies/products in Table 2 is not comprehensive. 
Investigators should contact the sponsor for clarification regarding questions about a 
treatment that may be in a prohibited category but is not on the list.
Table 2
Prohibited Medications/Therapies/Products and Prohibited Dose Strengths for 
Allowed Medications
Prohibited Medications/Therapies/Products and 
Prohibited Dose Strengths for Allowed 
Medications
Eligibility Relative to Visit 1 (Screening)
CYP2C19 Inducers and Substrates
Strong CYP2C19 inducers, such as:
artemisinin, carbamazepine (strong inducer), 
norethisterone, rifampin, primidone.

Participants must be off these medications 
for ≥4 weeks before Visit 1 (Screening).
Sensitive CYP2C19 substrates, such as: 
clopidogrel, fluoxetine (doses >40 mg/day are 
prohibited), moclobemide, tolbutamide, 
voriconazole, warfarin

Participants must not be on doses of 
fluoxetine >40 mg/day or any treatment 
with moclobemide within the 4 weeks
before Visit 1 (Screening).

Other medications in this category must be 
discontinued at Visit 1 (Screening).
Agents With Glutamatergic Activity
ketamine, esketamine, N-acetylcysteine, lamotrigine, 
topiramate, riluzole

Participants must be off these medications 
for ≥4 weeks before Visit 1 (Screening).
Note: Participants who have been off 
ketamine or esketamine for ≥4 weeks, but 
who had an inadequate response to either 
of these treatments, are not eligible for the 
study (Section 5.2).
Other Medications and Therapies
Atypical antipsychotics (use of low dose atypical 
antipsychotics [eg, quetiapine ≤100 mg/day, or 
equivalent] for sleep is permitted)

Except when taken at low doses for sleep, 
participants must be off these medications 
for ≥4 weeks before Visit 1 (Screening).
Electroconvulsive therapy, deep brain stimulation, 
vagal nerve stimulation, TMS

Any prior treatment with one or more of 
these therapies is exclusionary (Section 
5.2). Electroconvulsive therapy is 
exclusionary if received within the past 10 
years. TMS is exclusionary if received
within 6 weeks before Visit 1 (Screening).
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Prohibited Medications/Therapies/Products and 
Prohibited Dose Strengths for Allowed 
Medications
Eligibility Relative to Visit 1 (Screening)
Herbal drugs/dietary supplements that may affect 
mood, including but not limited to, St. John’s wort, 
artemisinin, ginseng, valerian, cassia, licorice 
(glycyrrhizin), ginkgo

Participants must be off St. John’s wort for 
≥4 weeks before Visit 1 (Screening).

Other products in this category must be 
discontinued at Visit 1 (Screening).
Drugs of abuse, including opiates, barbiturates, 
amphetamine/methamphetamine, cannabis, 
methadone, cocaine, and phencyclidine

Participants on prescribed opiates (except 
methadone, see below), barbiturates, or 
amphetamines must discontinue these 
treatments at Visit 1 (Screening). 
Note: Participants who have a positive test 
result at Visit 1 (Screening) due to 
prescribed opiates (excluding methadone), 
barbiturates, or amphetamines may 
continue in the pretreatment period if the 
prohibited medication is discontinued at 
least 1 week or 5 half-lives (whichever is 
longer) before the first dose of 
investigational intervention (See 
Section 5.2).

Participants on methadone or drugs of 
abuse are not eligible.

Intermittent cannabis is not prohibited if 
abuse or substance use disorder has been 
ruled out.
Prohibited Dose Strengths for Allowed Medications
Doses of lorazepam >3 mg/day or the equivalent dose 
of other benzodiazepines

Participants must not be on prohibited 
doses of benzodiazepines or partial 
benzodiazepines within the 4 weeks before 
Visit 1 (Screening).

For participants on an allowed dose of a 
benzodiazepine or partial benzodiazepine, 
the dose should be stable for ≥4 weeks 
before Visit 1 (Screening). 
Doses of the following partial benzodiazepine 
agonists: zolpidem >10 mg/day, zaleplon 
>20 mg/day, zopiclone >15 mg/day
High-dose biotin (>5 mg/day) is prohibited 1 day before and on the day of pregnancy testing.
8.1.8
External Verification of Diagnosis
A central vendor rater will be used to confirm that each participant randomized to study 
intervention meets entry criteria for currently having an ongoing and stable episode of 
treatment-resistant moderate-to-severe MDD. To support confirmation of eligibility, the site 
will submit information for each participant to the central vendor rater during the 
pretreatment period (Section 8.11.2.1). The required materials are specified in the Study 
Operations Manual. 
A participant is not eligible for randomization until confirmation of eligibility is provided by 
the central vendor rater. 
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8.1.9
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization OR intervention
allocation. Each participant will be assigned only 1 screening number. Screening numbers 
must not be re-used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on rescreening are provided in the
Study Operations Manual.
8.1.10
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.11
IRT Visit Registration, IRT Randomization, and Study Intervention 
Dispensing
The investigator (or designee) will register the participant in IRT at the visits specified in the 
SoA. Participants who satisfy all entry criteria will be assigned a randomization number via 
IRT at Visit 4 (Day 1). Participants who do not meet eligibility criteria will be entered into 
IRT as screen failures. IRT will also be used to identify the study intervention supplies that 
will be dispensed to participants at the visits specified in the SoA. Refer to the IRT user 
manual for details about the IRT system.
8.1.12
Study Intervention Administration
Blinded study intervention will be administered as oral capsules and packaged in blister 
cards. At Visit 4 (Day 1), participants will be educated by a trained member of the site staff 
on appropriate dosing and fasting instructions (see Section 5.3.1), package opening, and the 
requirement to return all blister cards at each visit. At Visit 4 (Day 1), sites will provide 
participants with a copy of the Study Medication Guidance and train participants on how to 
use the guide. Sites will be expected to review this guide during each treatment visit (V5 to 
V8) and provide retraining, as needed. Documentation of participant training will be filed 
with the participant’s source documents.
If the participant’s pregnancy test is positive, study intervention must not be dispensed. Sites 
must hold or discontinue study intervention as described in Section 8.3.6.2 and Section 7.1.
Details on appropriate handling, storage, and accountability of study intervention are 
provided in Section 6.2.2. 
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8.1.12.1
Timing of Dose Administration
The first dose of blinded study intervention is preferred to occur in the morning and will be 
witnessed (see Section 8.1.13) in the clinic at Visit 4 (Day 1) after all assessments and 
procedures (except collection of the post-dose PK sample) specified in the SoA are complete. 
The next dose of blinded study intervention will be taken unsupervised at home in the 
evening after Visit 4 (Day 1). 
Evening clinic visits are not preferred but may be done if morning visits are not feasible for 
participants. Participants should NOT skip the first dose of study intervention from each 
week’s supply (Day 1 AM), even if they conduct a visit in the evening. The PM dose should 
not be the first dose taken on Day 1. See the Study Operations Manual for more information.
Except for days with scheduled clinic visits during the double-blind treatment period, 
administration of study intervention will continue to occur unsupervised at home at 
approximately the same time in the morning and approximately the same time in evening. On 
days with scheduled clinic visits during the double-blind treatment period, participants must
not take a morning dose of study intervention from the blister cards dispensed at the previous 
visit. Participants will take their morning dose of study intervention in the clinic from the 
newly dispensed blister cards. For participants who undergo a dose modification after Visit 6 
(Week 2) (Section 6.6), the timing for administration of study intervention on the day of the 
Down-titration Visit will be determined by when the participant took their previous dose 
(Section 5.3.1). 
MK-1942 should NOT be taken with food. Dosing guidelines relative to meals are provided 
in Section 5.3.1. 
If a participant misses a dose of study intervention in the morning or evening, the missed
dose should be taken as soon as possible. If more than 6 hours have passed since the 
participant’s normal morning or evening dosing time, then the missed dose should be 
skipped, and the next dose should be taken as normal.
8.1.13
Witnessed Dose
Administration of study intervention will be witnessed by a trained member of the site staff 
at visits specified in the SoA. Each witnessed dose will be taken after assessments and 
procedures for the visit are complete (except for collection of the post-dose PK sample at 
Visit 4 [Day 1]). The time of dosing will be recorded.
8.1.14
Study Intervention Accountability
Accounting for compliance and adherence with study intervention is described in Section 6.4.
8.1.15
Telephone Contacts (Site to Participant)
A telephone contact will be performed within the first 3 days after Visit 4 (Day 1), Visit 5 
(Week 1), Visit 6 (Week 2), Visit 7 (Week 3), and the Down-titration Visit (if applicable) by 
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trained site personnel to monitor for AEs and compliance with study intervention and to 
encourage adherence with the fasting guidelines (Section 5.3.1). Visit 10 (Week 6) may be 
completed as a telephone contact, as needed (ie, if a site visit is not feasible). Additional 
telephone contacts/visits may be performed at the investigator’s discretion.
The investigator is responsible for ensuring that all telephone contacts are performed by a 
staff member who is a health care professional qualified to elicit a discussion with the 
participant that will lead to a clinically meaningful disclosure on the participant’s well-being. 
Telephone contacts are to be documented in the source documents and the investigator must 
review the entry within 2 days. However, if the participant reports any clinically concerning 
events (eg, SAEs, ECIs) during a TC, then the investigator must be promptly notified. The 
investigator will contact the participant to determine if a clinic visit is warranted. 
If the participant cannot be reached by telephone at the regularly scheduled time or misses a 
visit, the site should make at least 3 attempts (in addition to the initial phone call) to contact 
the participant within 48 hours of the missed scheduled time. The participant’s reliable 
contact person should be called if attempts to contact the participant are not successful. All 
phone contacts and attempts should be recorded in source documents.
8.1.16
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 7.1.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT/DC Visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.16.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
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the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.17
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. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the 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.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.18
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.
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8.2
Efficacy Assessments
Rating scale assessments at clinic visits will be performed by site raters who meet the 
qualification and training requirements per scale. Rater qualifications, training and applicable 
certification processes are established in the Study Operations Manual. Each assessment 
scale may require different raters, but it is strongly encouraged that the same rater evaluates 
the same participant for the duration of the study. As a best practice, back-up raters should be 
identified for each participant to improve continuity and reliability of the ratings. 
To avoid the influence of participant fatigue at in-clinic visits, it is recommended that sites 
administer the BAC SC first, followed by the MADRS (primary endpoint) and the HAM-
D17. The CGI-S is recommended as the last clinical assessment so that all relevant 
information can be reviewed when completing the CGI-S. 
While concerns have been raised that recording assessments could theoretically compromise 
participant privacy, this issue must be balanced with the need to conduct methodologically 
adequate and scientifically rigorous studies that are capable of testing key hypotheses. Given 
that the key endpoints in this study involve subjective clinical judgments, monitoring the 
adequacy of participant interviews and ratings is essential and part of strong research 
methodology. Prior studies suggest that the failure to adequately monitor such ratings can 
substantially increase the risk of failed studies [Khan, A., et al 2013]. 
To ensure the highest level of data quality, both the data and audio recordings (MINI and 
MGH-ATRQ, MADRS, HAM-D17) of some study assessments will be collected using a 
tablet and the audio recordings will be reviewed by the central rater vendor. The vendor will 
use the audio recordings to provide feedback and suggestions to raters regarding scale 
administration and scoring, as needed, to ensure consistency across all raters and sites. 
Vendor feedback may be used to refine scores entered by the site for an individual rating, at 
the discretion of the site rater. Data for both the audio recordings and the tablet are encrypted 
in order to protect the participant’s privacy and are automatically uploaded to a secure cloud-
based server. Additional details are provided in the Study Operations Manual. 
8.2.1
MADRS, HAM-D17, CGI-S, BAC SC
This study will use 3 rating scales to assess depressive symptoms (MADRS, HAM-D17, 
CGI-S) and a test to assess cognitive function (BAC SC). The MADRS and HAM-D17 will 
be administered in accordance with a structured interview guide [Williams, J. B. W. 2008] 
[Williams, J. B. W. 2013]. A subset of 6 items (HAM-D6) derived from the HAM-D17 will 
also be evaluated. The scales and the cognitive test are described in Section 4.2.1.1 and will 
be administered at the visits specified in the SoA. During the double-blind treatment period, 
the scales and the cognitive test will be administered before the witnessed dose of study 
intervention (Section 8.1.13).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
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pre-study to post-study visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in the central laboratory manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical and Neurological Examinations
A complete physical examination, including a neurological examination, will be conducted at 
the visits specified in the SoA, per institutional standard. The investigator (or qualified 
designee, consistent with local requirements) will perform the examinations of the following 
organ systems:

Head, eyes, ears, nose, and throat

Neck

Respiratory system

Cardiovascular system

Abdomen

Skin and extremities

General appearance

Neurological system (see Appendix 8)
Height and weight will also be measured and recorded (Section 8.3.3).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any medical conditions found during the physical and neurological examinations
will be recorded in the Sponsor database.
8.3.2
Vital Signs
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include 
temperature, blood pressure, pulse rate, and respiratory rate.
It is recommended that individual sites use the same method for measuring temperature (eg, 
oral, tympanic) in all participants throughout the study.
For blood pressure readings, the correct size of the blood pressure cuff and correct 
positioning on the participant’s arm is essential for accurate measurements. It is 
recommended that individual sites use the same method (manual or automated) for 
measuring blood pressure and pulse throughout the study.
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8.3.3
Height/Weight
Height (inches/centimeter) will be measured and recorded at the visits specified in the SoA. 
Measurements should be rounded to the nearest inch/centimeter (without shoes).
Body weight will be measured using a standardized scale (provided by the Sponsor if 
requested) and should be rounded to the nearest pound/kilogram. Participants’ weight should 
be measured after voiding and while wearing light clothing (eg, no coats or heavy 
sweatshirts). The site should follow their local procedures to ensure the body weight scale is 
working properly.
8.3.4
ECGs
Twelve-lead ECGs will be performed when the participant is in the supine position after 5 to 
10 minutes of rest using a central ECG machine that automatically calculates heart rate and 
measures PR, QRS, QT, and QTcF intervals according to the instructions in a separate ECG 
instruction manual. Cardiologist overread will be provided by the central ECG vendor. 
All scheduled ECGs will be performed in triplicate. ECG measurements should be obtained 
in close succession; ie, less than 2 minutes apart with all 3 measurements completed in less 
than 4 minutes.
At Visit 1 (Screening), the average of the 3 QTcF intervals based on the central vendor 
overread will be used to assess eligibility. At Visit 4 (Day 1), the average of the 3 QTcF
intervals based on the local ECG printout will be used to assess eligibility (Section 5.2).
During the double-blind treatment period, participants will discontinue study intervention if 
the average of the 3 QTcF intervals at a visit is either >500 msec or increases by >60 msec 
relative to Visit 4 (Day 1). Details on discontinuation of study intervention due to QTcF 
results are in Section 7.1.
If ECG assessments were missed entirely at the scheduled visit during treatment or if all
ECGs at a visit were invalid due to technical issues, the ECG should be obtained at the next 
scheduled visit.
8.3.5
Alcohol Screen (Breathalyzer)
An alcohol breath test will be performed at Visit 1 (Screening) and Visit 4 (Day 1). 
Participants must have a negative alcohol breath test at both visits to be eligible for the study
(Section 5.2). A breathalyzer will be provided to each site by the Sponsor.
8.3.6
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 
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changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention or through 
completion of Visit 10, whichever is later, 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.
8.3.6.1
Confirmation of Postmenopausal State
Female participants whose postmenopausal status is in question are required to have 2 
pretreatment FSH measurements (approximately 2 weeks apart with a minimum interval of 
10 days) in the postmenopausal range (Appendix 5). The first FSH measurement will be 
obtained at Visit 1 (Screening). Participants whose first FSH measurement is in the 
postmenopausal range, but who cannot have a second measurement within approximately 2 
weeks of Visit 1 (Screening), should be excluded. These participants may be rescreened after 
consulting with the Sponsor.
8.3.6.2
Pregnancy Testing
General Guidance
Pregnancy testing will be performed as specified in the SoA and is not required during a 
Down-titration Visit. 
During the screening period (pre-randomization):

If urine test is positive, a serum pregnancy test is required to confirm or dismiss the 
initial result. The participant should be excluded unless a negative status is confirmed 
by 2 negative serum pregnancy tests performed approximately 24 hours apart.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required and must be negative to proceed to randomization. The 
participant must be excluded from participation if the serum pregnancy result is 
positive.
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During the treatment and follow-up period:

If urine test is positive, a serum pregnancy test is required. Study intervention should 
be held until a negative status is confirmed by 2 negative serum pregnancy tests
performed approximately 24 hours apart.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. Study intervention should be held until a negative serum 
pregnancy test is obtained.

Participants with a positive serum pregnancy test (or positive urine test and 
participant refuses the required follow-up serum test) must be discontinued from 
study intervention and followed as specified in Section 7.1.
Local serum tests may be performed in the event that the central laboratory results would not 
be available in time for prompt decision making.
Participants should not take products containing high-dose biotin (>5 mg/day) 1 day before 
and on the day of pregnancy testing as this might interfere with the results of the test.
WOCBP
All WOCBP (see Section 10.5.1 for definition) participating in the study will have a highly 
sensitive local urine pregnancy test AND serum pregnancy test at the visits indicated in the 
SoA and when pregnancy is suspected. A negative pregnancy test is required immediately 
(ie, on the same day) before dosing at each scheduled visit.
WONCBP
All WONCBP (see Section 10.5.1 for definition) participating in the study will have a highly 
sensitive urine pregnancy test at Visits 1, 4, and 8.
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 specified time points, as 
specified in the SoA, as well as at unscheduled visits as clinically indicated. Site staff should 
review the contents of the C-SSRS for completeness.
If the C-SSRS is administered by someone other than the investigator, consider providing the 
completed C-SSRS to the investigator for review, prior to their assessment of the participant 
and to further inform their evaluation.
The C-SSRS is not explicit about whether the participant specifically has ideation at the time 
of screening. If a participant reports a prior history of ideation/behavior, the assessor should 
also inquire and document if this is also present at the time of the screening visit.
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Participants who at any time during this study report suicidal ideation or behavior that is 
considered to be an AE, either between visits or during visit interviews, must be assessed by 
the investigator. Participants who report suicidal ideation with intent, with or without a plan 
or method (ie, a positive response to items 4 or 5 in the assessment of suicidal ideation on the 
C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker, or mental health 
nurse practitioner (or comparable professional qualification in countries outside the United 
States). After that evaluation, only those participants whose suicidal ideation is considered by 
the evaluator to be passive, and who expressly deny any intent to act, and who, after 
evaluation, are not judged to be at serious risk for self-harm during the course of the study 
may continue in the study; other participants must be discontinued from study participation 
and receive appropriate clinical follow-up care to ensure their safety. In addition, all AEs of 
suicidal ideation or behavior must be recorded as an ECI (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
Contraceptive Use Confirmation
Male (where appropriate) and WOCBP participants are required to use contraception to 
prevent pregnancy during the study as defined by Section 5.1 Inclusion Criteria, No 8 and No 
9, respectively. WOCBP must have continual contraception use for at least 3 months before 
screening. Participants who do not meet the 3-month requirement may be rescreened. 
Participants will be asked at study visits per the SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in the source documents for each visit. In addition, for 
WOCBP, sites should complete the applicable CRF according to the data entry guidelines.
In cases of contraception non-compliance, that in the investigator’s judgment increases the 
risk for pregnancy, the investigator should hold study intervention until the case is discussed 
with the Sponsor and a final determination made.
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 events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
From the time of intervention allocation/randomization through 14 days following cessation 
of study intervention or through the completion of Visit 10, whichever is later, all AEs, 
SAEs, and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
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 unless the 
participant has 
received study 
intervention.
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
- hepatic-related 
events listed in 
Section 8.4.7
- require regulatory 
reporting
Not required
Within 24 hours 
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:
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-hepatic-
related events as 
listed in Section 
8.4.7 (unless 
serious)
- do not require 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 calendar 
days of learning 
of event
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 
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Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of “ectopic” pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
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. Elevated AST ≥3x ULN
2. Elevated ALT ≥2x ULN or twice the baseline value
3. Elevated total bilirubin ≥2x ULN with ALP <2x ULN
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4. AEs of dizziness that are rated by the investigator as being moderate or severe in 
intensity.
5. AEs related to gait disturbance, independent of feelings of dizziness.
6. Suicidal ideation and/or behavior or any self-injurious behavior reported as an AE.
7. QTcF interval meeting either of the criteria specified for study intervention 
discontinuation (Section 7.1).
Note that the above AEs and QTcF criteria are classified as ECIs only after the first dose of 
study intervention is administered. Sites should refer to the study ECI guidance document for 
details on assessment and follow-up, including follow-up on elevated liver function tests that 
met ECI criteria as assessed at Visit 10.
8.5
Treatment of Overdose
In this study, an overdose is defined as any dose that exceeds the morning or evening dose 
prescribed in this protocol (Section 6.1). 
No specific information is available on the treatment of overdose of MK-1942. Appropriate 
supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma MK-1942
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the central laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research 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 
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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.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the Operations/Laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:

Leftover DNA for future research

Leftover main study PK plasma samples stored for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
This section is not applicable.
8.11
Visit Requirements
Visit requirements are outlined in the SoA. Specific procedure-related details are provided in
Section 8.
Scheduling Visits
The interval between visits during the double-blind treatment is short (7 days), and the visits 
at which study intervention is dispensed are followed by a TC within the first 3 days after the 
visit (Section 8.1.15). The site should carefully schedule visits and phone calls to minimize 
participant burden. 
It is preferable for visits (in-clinic and Lead-in calls) to be scheduled at about the same time 
of day in the mornings for consistency, and for in-clinic visits, to minimize prolonged fasting 
durations (fasting guidance is provided in Section 5.3.1). Evening clinic visits are not 
preferred but may be done if morning visits are not feasible for participants. Participants with 
evening clinic visits should be scheduled at about the same time of day in the evening for 
consistency. See the Study Operations Manual for more information on evening clinic visits.
A visit should occur within the scheduling window shown in the SoA. Visits during the 
double-blind treatment period should be scheduled relative to Visit 4 (Day 1), regardless of 
the actual day the previous visit occurred on. If any visits deviate from the schedule, an 
attempt should be made to follow the original visit schedule for subsequent visits.
Visit Reminders
During the double-blind treatment period, it is recommended that site personnel contact 
participants on the day before each clinic visit to remind them to (1) fast according to Section 
5.3.1, (2) hold their morning doses of study intervention from the blister cards dispensed at 
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the previous visit (not applicable at Visit 4 [Day 1]), (3) bring their opened and unopened 
blister cards to the visit (not applicable at Visit 4 [Day 1]), and (4) bring their Study 
Medication Guidance (not applicable at Visit 4 [Day 1]).
8.11.1
Screening
Participants must provide documented informed consent before any study-specific 
procedures are performed. Screening period may be less than 3 weeks if all assessments are 
completed.
At Visit 1 (Screening), participants will be evaluated to determine if they fulfill the eligibility 
requirements in Sections 5.1 and 5.2. A psychiatric diagnostic assessment will be performed 
using the MINI to confirm the diagnosis MDD (without psychotic features), and the MADRS 
will be administered to assess participants’ depressive symptom severity. The HAM-D17 will 
be administered by the site at Visit 1 (Screening) and by the central vendor rater at Visits 2 
and 3 (Lead-in Calls 1 and 2, respectively) (see Section 8.11.2). Additional assessments of 
psychiatric symptoms and safety evaluations will be performed as specified in the SoA. The 
participant’s medical history, prior and concomitant medications, and demographic 
information will be obtained. If available results support eligibility, then participants will 
discontinue taking any prohibited medications/products listed in Table 2 that must be stopped 
at Visit 1 (Screening). There are other prohibited medications/products and prohibited doses
of allowed medications in Table 2 that participants must be off for ≥4 weeks before Visit 1 
(Screening). Participants who do not meet the ≥4 week requirement for one or more of these 
prohibited medications/products will be screen-failed, but can rescreen once the ≥4 week 
requirement is met (additional information on rescreening is provided below and in the Study 
Operations Manual). 
Results from the scales assessing MDD and documentation of prior treatment failures for the 
current episode of MDD will be submitted to the central vendor rater (required information is 
provided in the Study Operations Manual). These data, and those from the HAM-D17 at 
Visits 2 and 3 (Lead-in Calls 1 and 2, respectively) (see Section 8.11.2), will be used by the 
central vendor rater to determine eligibility. A participant may not be randomized until 
confirmation from the central vendor rater is received.
A participant’s central laboratory results, final central ECG interpretation, and confirmation 
of having treatment-resistant moderate-to-severe MDD by the central vendor rater will be 
pending at Visit 1 (Screening). If the participant is later deemed ineligible based on review of 
these data, the participant will be screen-failed before randomization.
Split Screening Visit Option
To reduce participant burden, Visit 1 (Screening) may be split into more than 1 day. If this 
screening option is chosen, it is required that documented informed consent for the main 
study is obtained (Section 8.1.1.1) and a screening number is assigned (Section 8.1.9) on the 
first day of screening. Additionally, it is recommended that the MINI, MADRS, and HAM-
D17 are each administered on the same screening day. Otherwise, the distribution of Visit 1 
(Screening) procedures across more than 1 day is at the site’s discretion.
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Rescreening
In some circumstances, participants who are excluded may be rescreened. Such 
circumstances may include, but are not limited to, rescreening due to FSH testing 
requirements (Section 8.3.6.1), after laboratory abnormalities resolve, after the required off
drug period for a prohibited medication/product is attained (Section 8.1.7.2), or if needed to 
meet contraceptive requirements (Section 8.3.8). Sites should consult the Sponsor before
rescreening participants due to FSH testing requirements (Section 8.3.6.1). Additional details 
on rescreening procedures and other reasons for rescreening are described in the Study 
Operations Manual. Sponsor consultation is required if a participant is to be rescreened for 
reasons not described in the protocol or Study Operations Manual OR if a participant is to be 
rescreened more than 1 time due to screen failure.
8.11.2
Lead-in Calls
At Lead-in Calls 1 and 2 (Visits 2 and 3, respectively), the central vendor rater will 
administer the HAM-D17. Site personnel and participants will be blinded to the eligibility 
criterion associated with the HAM-D17 (Section 5.1). The central vendor rater will inform 
the site if a participant is eligible for randomization based on the results from the HAM-D17
and other materials provided to assess MDD (Section 8.11.2.1). The participant may not be 
randomized until confirmation from the central vendor rater is available.
Lead-in Calls 1 and 2 should occur when the participant is in a private and comfortable 
location. If preferred, the participant may go to the site to take the Lead-in Calls from the 
central vendor rater. In this case, the participant should be in a room without site personnel.
The site will be contacted by the central vendor rater if there is any indication of suicidality 
based on responses to the HAM-D17. 
8.11.2.1
Central Vendor Rater Review of Participant Eligibility
A participant may not be randomized until confirmation of eligibility is received from the 
central vendor rater. The following information will be reviewed by the central vendor rater 
to assess eligibility:

Documentation assessing MDD (diagnostic interviews, symptom severity scales, and 
supporting records)

Documentation of prior treatment failures for the current episode of MDD

HAM-D17 total scores at Visit 1 (Screening) and Visits 2 and 3 (Lead-in Calls 1 and 2, 
respectively)
The information listed above is not comprehensive; additional details are provided in the
Study Operations Manual.
The central vendor rater will inform the site if a participant is eligible before Visit 4 (Day 1).
Participants who do not meet eligibility criteria will be screen-failed.
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8.11.3
Treatment Period
Each visit should be performed as specified in the SoA 
Participants who satisfy all entry criteria will be randomized (via IRT) to double-blind study 
intervention at Visit 4 (Day 1). Participants will be educated by a trained member of the site 
staff on appropriate dosing instructions (including missed doses, Section 8.1.12.1) and 
fasting guidance (Section 5.3.1). The first dose of study intervention will be witnessed by a 
member of the site staff in the clinic. Witnessed dosing will continue at all visits where study 
intervention is dispensed, including the Down-titration Visit (if applicable, and depending on 
when the participant took their last dose of study intervention; see Section 5.3.1).
Telephone contacts will be performed within the first 3 days after Visit 4 (Day 1), Visit 5 
(Week 1), Visit 6 (Week 2), and Visit 7 (Week 3), and the Down-titration Visit (if 
applicable) by trained site personnel (Section 8.1.15) to monitor for AEs and compliance 
with study intervention and to encourage adherence with the fasting guidance (Section 5.3.1).
Compliance with study intervention and adherence with the fasting guidance will also be 
reinforced at each clinic visit during the double-blind treatment period.
If there are extenuating circumstances that do not enable the participant to attend a scheduled 
clinic visit (ie, incapacitating health conditions or local or national emergency situations), a 
telephone, video, or home visit using site staff or a nursing service may be used, if allowed 
by local regulations, in accordance with Sponsor guidelines.
8.11.4
Down-titration Visit
To minimize discontinuation of study intervention, participants who are unable to tolerate or 
who have substantial non-adherence with study intervention after Visit 6 (Week 2) may 
down-titrate MK-1942/matching placebo to a lower dose (Section 6.6). If this occurs between 
scheduled visits, the participant will return to the clinic (with the previously dispensed blister 
cards) for the Down-titration Visit and undergo the procedures specified in the SoA. 
The timing of the first dose of study intervention from the blister cards dispensed at the 
Down-titration Visit will be determined by when the participant took their previous dose. 
Details are provided in Section 5.3.1. 
8.11.5
EOT/DC Visit
EOT/DC Visit procedures specified in the SoA will be performed at the end of the treatment 
period (Visit 8 [Week 4]). Additionally, participants who discontinue study intervention 
prematurely should have an EOT/DC Visit as soon as possible after the decision to 
discontinue study intervention is made. For participants who discontinue study intervention 
prematurely, prohibited medications/products/therapies (Table 2) can be started after the 
EOT/DC Visit.
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8.11.6
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Any participant who prematurely discontinues study intervention will be encouraged to 
continue their participation in the study off study intervention and be followed for all
remaining study visits (Section 7.1) as outlined in the SoA. Note that PK samples will not be 
collected if a participant discontinues study intervention. 
8.11.7
Post-dose Follow-up Period
Visit procedures specified in the SoA will be performed at the Post-dose Follow-up visits
(Visit 9 [Week 5] and Visit 10 [Week 6]). Since participants will be off study intervention, 
there are no fasting requirements associated with these visits. 
Because there are efficacy assessments at the Post-dose Follow-up Visit 9, participants who 
completed the double-blind treatment period on study intervention should not start prohibited 
medications/products/therapies (Table 2) until after the completion of this visit. 
Safety assessments will be performed 14 days after the last dose of study intervention or at 
Visit 10, whichever is later, to collect laboratory test specimens, AEs, SAEs, C-SSRS, and 
other reportable safety events. As needed, instead of a site visit, Visit 10 laboratory 
assessments may be performed at a local laboratory and Visit 10 non-laboratory assessments 
may be performed by TC.
8.11.8
Poststudy
Participants will not be followed after completion of the study follow-up period.
Medical Management Poststudy Sessions (Optional)
At the discretion of the investigator based on medical need as a result of being in the trial and 
the transition off of the trial to standard of care, a participant may be offered up to 
4 additional, optional sessions (reimbursed per the site study budget) with site medical staff 
to support the participant’s transition off of the trial to standard of care. Additional 
medication or other medical procedures/treatments recommended or provided by site staff as 
after-study care will not be part of the additional sessions and will be the responsibility of the 
site or participant. These sessions may be conducted by phone or in person. These sessions 
may occur only up until six (6) months after the participant’s last study visit. No additional 
data collection is required from these sessions beyond that already specified in the protocol 
(eg, safety reporting per Protocol Section 8.4).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
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to exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in an sSAP and referenced in 
the CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
Other planned analyses (eg, those specific to the analysis of PK data, patient-reported 
outcomes, and future biomedical research) will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A Phase 2a, randomized, placebo-controlled clinical study to evaluate 
the efficacy and safety of the addition of MK-1942 in participants with 
TRD on stable antidepressant therapy.
Treatment Assignment
The study will be conducted as a double-blind study under in-house 
blinding procedures. Treatment allocation/randomization will occur 
centrally using IRT. Participants will be randomized in a 2:1:2 ratio to 
(1) daily treatment with MK-1942 administered as 5 mg bid (Visit 4/Day 
1 to Visit 5/Week 1), 10 mg bid (Visit 5/Week 1 to Visit 6/Week 2), and 
20 mg bid (Visit 6/Week 2 to Visit 8/Week 4), (2) intermittent treatment 
with MK-1942 administered twice-weekly (10 mg biw), or (3) placebo. 
MK-1942 or matching placebo will be administered as oral capsules.
Randomization will be stratified by the number of treatment failures (1; 
>1) for the current episode of moderate-to-severe MDD.
Analysis Populations
Efficacy: FAS
Safety: APaT
PK: PP
Primary Efficacy Estimand
The primary objective is to assess the efficacy of MK-1942 added to 
stable antidepressant therapy in participants with TRD.

Treatment: For the MK-1942 daily dose group, this will include 
dose modification allowed for intolerability or non-adherence at or
after 2 weeks of treatment with primary evaluation after 3 weeks of 
therapy. For the MK-1942 intermittent dose group, the primary 
evaluation will be after 1 week of therapy.

Population: The population targeted by the scientific question: 
individuals aged 18 to 65 years diagnosed with TRD.

Variable: Week 3 change from baseline in MADRS total score for 
the MK-1942 daily dose group and Week 1 change from baseline in 
MADRS total score for the MK-1942 intermittent dose group.

Intercurrent events: The intercurrent events are IE1) 
discontinuation of study medication, IE2) discontinuation of stable 
antidepressant therapy, IE3) initiation of a non-study antidepressant 
therapy, and IE4) premature unblinding of either the investigator or 
participant.

Population level-summary: difference (MK-1942 daily dose versus
placebo) in mean change from baseline at Week 3 and difference 
(MK-1942 intermittent dose versus placebo) in mean change from 
baseline at Week 1.
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Primary Endpoint(s)

Change from baseline in MADRS total score at Week 3 (MK-1942 
daily dose versus placebo)

Change from baseline in MADRS total score at Week 1 (MK-1942 
intermittent dose versus placebo)
Key Secondary Endpoints

Change from baseline in HAM-D17 total score at Week 3
(MK-1942 daily dose versus placebo)

Change from baseline in HAM-D17 total score at Week 1
(MK-1942 intermittent dose versus placebo)

Change from baseline in CGI-S score at Week 3 (MK-1942 daily 
dose versus placebo)

Change from baseline in CGI-S score at Week 1 (MK-1942 
intermittent dose versus placebo)
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will be evaluated by comparing MK-1942 to 
placebo with respect to mean change from baseline in MADRS total 
score at Week 3 (MK-1942 daily dose versus placebo) and Week 1 
(MK-1942 intermittent dose versus placebo) using a longitudinal 
ANCOVA model.
Statistical Methods for Key 
Safety Analyses
95% CIs (Tier 2 endpoints) will be provided for between-treatment 
differences in the percentage of participants with events; these analyses 
will be performed using the Miettinen and Nurminen method.
Interim Analyses
A non-binding interim futility analysis will be performed when the first 
~60% of the randomized participants either complete Week 3 or 
discontinue before Week 3. Results will be reviewed by an siDMC. 
Futility may be declared if the conditional power based on the change 
from baseline at Week 3 (MK-1942 daily dose versus placebo) and 
change from baseline at Week 1 (MK-1942 intermittent dose versus 
placebo) is less than 10% for both treatment comparisons. Details are
provided in Section 9.7.
Multiplicity
The Type-1 error will be strongly controlled across the primary and key 
secondary hypotheses using a Bonferroni procedure to control for the 2
different MK-1942 dose comparisons to placebo in conjunction with 
sequential testing to control for the primary and 2 key secondary
endpoints (see Section 9.8).
Sample Size and Power 
The planned sample size is 140 (56 in the MK-1942 daily dose group, 28 
in the MK-1942 intermittent dose group, and 56 in the placebo group). 
There is ~92% probability that at least 1 of the 2 MK-1942 groups will 
be superior to placebo as measured by change in MADRS total score at 
Week 3 (MK-1942 daily dose versus placebo) or Week 1 (MK-1942 
intermittent dose versus placebo) under the primary assumptions as 
provided in Table 10.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
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This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. The official, final database will not be unblinded until the participant completes 
the last study-related TC or visit, withdraws from the study, or is lost to follow-up.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.3.1
Estimands
In the language of ICH E9(R1) [Food and Drug Administration 2021], there are 4
‘intercurrent events’ of interest: IE1) discontinuation of study intervention, IE2) 
discontinuation of stable antidepressant therapy, IE3) initiation of a non-study antidepressant 
therapy, and IE4) premature unblinding of either the investigator or participant.
Primary Objective
Primary Estimand [based on ‘hypothetical strategy’ in ICH E9(R1)]
To address the primary objective, an estimand based on HS will be used. This ‘HS estimand’ 
is intended to contrast the effect of MK-1942 (daily and intermittent dosing), relative to 
placebo, when initiated with stable antidepressant therapy under a hypothetical scenario in 
which there is no discontinuation of study intervention nor stable antidepressant therapy, no 
initiation of a non-study antidepressant therapy, and no premature unblinding of either the 
investigator or participant during an envisioned follow-up period of up to 4 weeks (with 
primary assessment at Week 3 for the MK-1942 daily dose group and at Week 1 for the MK-
1942 intermittent dose group).
The HS estimand consists of the following attributes:

Target population: individuals aged 18 to 65 with TRD

Endpoint: Week 3 change from baseline in MADRS total score for the MK-1942 daily 
dose group and Week 1 change from baseline in MADRS total score for the MK-1942 
intermittent dose group

Treatment regimen: MK-1942 or placebo initiated with stable antidepressant therapy 
without discontinuation of study intervention or stable antidepressant therapy, without 
initiation of a non-study antidepressant therapy, and without premature unblinding of 
either the investigator or participant during an envisioned follow-up period of up to 4 
weeks (with primary assessment at Week 3 for the MK-1942 daily dose group 
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[and dose modification allowed for intolerability or non-adherence at or after 2 weeks of 
treatment] and at Week 1 for the MK-1942 intermittent dose group)

Population-level summary: mean of the endpoint noted above, compared between 
treatment regimens (MK-1942 daily dose versus placebo and MK-1942 intermittent dose 
versus placebo)
(Note: for estimating the HS estimand, data collected after the occurrence of IE1, IE2, IE3 or 
IE4 will be discarded in the main analysis.)
Supplemental Estimand [based on ‘treatment policy strategy’ in ICH E9(R1)]
A supplemental estimand based on TPS will be used. This ‘TPS estimand’ is intended to 
contrast the effect of MK-1942 (daily and intermittent dosing), relative to placebo, when 
initiated with stable antidepressant therapy, regardless of how long study medication, stable 
antidepressant therapy or non-study antidepressant therapy are used or if premature 
unblinding of either the investigator or participant occurs during an envisioned follow-up 
period of up to 4 weeks (with primary assessment at Week 3 for the MK-1942 daily dose 
group and at Week 1 for the MK-1942 intermittent dose group). 
The TPS estimand has the same target population, endpoint, and population level-summary 
as the HS estimand of the primary objective, but differs in the treatment regimen attribute.
The TPS estimand consists of the following attributes:

Target population: individuals aged 18 to 65 with TRD

Endpoint: Week 3 change from baseline in MADRS total score for the MK-1942 daily 
dose group and Week 1 change from baseline in MADRS total score for the MK-1942 
intermittent dose group

Treatment regimen: MK-1942 or placebo initiated with stable antidepressant therapy 
without discontinuation of study intervention or stable antidepressant therapy, without 
initiation of a non-study antidepressant therapy, and without premature unblinding of 
either the investigator or participant during an envisioned follow-up period of up to 4 
weeks (with primary assessment at Week 3 for the MK-1942 daily dose group [and dose 
modification allowed for intolerability or non-adherence at or after 2 weeks of treatment]
and at Week 1 for the MK-1942 intermittent dose group). 

Population-level summary: mean of the endpoint noted above, compared between 
treatment regimens (MK-1942 daily dose versus placebo and MK-1942 intermittent dose 
versus placebo)
(Note: for estimating the TPS estimand, data collected after occurrence of IE1, IE2, IE3 or 
IE4 will be included in the main analysis)
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Secondary Objectives
Both HS and TPS estimands, as described for the primary efficacy endpoint will be applied 
to the key secondary efficacy endpoints. For all other efficacy endpoints, only the HS
estimand, as described for the primary efficacy endpoint, will be applied.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
9.4.1
Efficacy Endpoints
A summary of the primary, secondary, and tertiary/exploratory efficacy endpoints by 
MK-1942 dosing regimen is provided in Table 4.
Primary Endpoint
The MADRS is a 10-item clinician-rated instrument for assessing severity of depressive 
symptoms; these 10 items are summed to obtain the MADRS total score. Change from 
baseline in MADRS total score at Week 3 (MK-1942 daily dose versus placebo) and Week 1 
(MK-1942 intermittent dose versus placebo) are primary endpoints.  
Key Secondary Endpoints
The HAM-D17 is a 17-item clinician-rated instrument for assessing the effects of 
antidepressant treatments on depressive symptoms; these 17 items are summed to obtain the 
HAM-D17 total score. Change from baseline in HAM-D17 total score at Week 3 (MK-1942 
daily dose versus placebo) and Week 1 (MK-1942 intermittent dose versus placebo) are key 
secondary endpoints. 
The CGI-S is a single-item clinician-rated scale for assessing global illness severity. Change 
from baseline in CGI-S at Week 3 (MK-1942 daily dose versus placebo) and Week 1 
(MK-1942 intermittent dose versus placebo) are key secondary endpoints.
Tertiary/Exploratory Endpoints
The BAC SC consists of digit symbol pairs followed by a list of digits for assessing cognitive 
performance. The number of correct matches within the allowed time (90 seconds) 
constitutes the score and will be evaluated as an exploratory endpoint for both treatment 
comparisons at Week 3.
The 6-item HAM-D6 is a subset of the HAM-D17. It consists of 6 items (depressed mood, 
work and activities, somatic symptoms general, feelings of guilt, anxiety psychic, and 
retardation); these items are summed to obtain the HAM-D6 total score. Change from 
baseline in HAM-D6 total score at Weeks 1, 2, 3, and 4 (for the 2 treatment comparisons) are 
exploratory endpoints.
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Change from baseline in MADRS total score, HAM-D17 total score, and CGI-S score at time
points not specified as primary or secondary (for the 2 treatment comparison) are exploratory 
endpoints.
MADRS remission, defined as a MADRS total score ≤12, will be used to assess
improvement in depressive symptoms. The percentage of participants in remission will be 
evaluated as an exploratory endpoint for both treatment comparisons at each time point.
MADRS response defined as a ≥50% reduction from baseline in MADRS total score will be
used to assess improvement in depressive symptoms. The percentage of participants with a 
≥50% reduction from baseline in MADRS total score will be evaluated as an exploratory 
endpoint for both treatment comparisons at each time point.
Table 4
Efficacy Measures by Dosing Regimen and Timepoint
MK-1942 Daily Dose
MK-1942 Intermittent Dose
Primary Efficacy Measure
Change from baseline in MADRS total score at 
Week 3
Change from baseline in MADRS total score at Week 
1
Key Secondary Efficacy Measures
Change from baseline in HAM-D17 total score at 
Week 3
Change from baseline in HAM-D17 total score at 
Week 1
Change from baseline in CGI-S at Week 3
Change from baseline in CGI-S at Week 1
Tertiary/Exploratory Efficacy Measures
Change from baseline in BAC SC at Week 3
Change from baseline in BAC SC at Week 3
Change from baseline in MADRS total score at 
Weeks 1, 2 and 4
Change from baseline in MADRS total score at Weeks 
2, 3, and 4
Change from baseline in HAM-D17 total score at 
Weeks 1, 2, and 4
Change from baseline in HAM-D17 total score at 
Weeks 2, 3, and 4
Change from baseline in HAM-D6 total score at 
Weeks 1, 2, 3, and 4
Change from baseline in HAM-D6 total score at 
Weeks 1, 2, 3, and 4
Change from baseline in CGI-S score at Weeks 1, 
2, and 4
Change from baseline in CGI-S score at Weeks 2, 3, 
and 4
The percentage of participants in remission defined 
as a MADRS total score ≤12 at Weeks 1, 2, 3, and 
4
The percentage of participants in remission defined as 
a MADRS total score ≤12 at Weeks 1, 2, 3, and 4
The percentage of participants with a response 
defined as a ≥50% reduction from baseline in 
MADRS total score at Weeks 1, 2, 3, and 4
The percentage of participants with a response defined 
as a ≥50% reduction from baseline in MADRS total 
score at Weeks 1, 2, 3, and 4
BAC SC=Brief Assessment of Cognition Symbol Coding, CGI-S=Clinical Global Impression–Severity, HAM-D6=6-
item Hamilton Depression Rating Scale, HAM-D17=17-item Hamilton Depression Rating Scale, MADRS=Montgomery-
Asberg Depression Rating Scale
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Table 5 describes the directionality of improvement in efficacy measures.
Table 5
Directionality of Improvement in Efficacy Measures
Measurement
Direction of Improvement
Direction of Treatment Differences (Versus
Placebo) Including Favorable Efficacy
MADRS total score
Decrease
Negative
HAM-D17 total score
Decrease
Negative
HAM-D6 total score
Decrease
Negative
CGI-S score
Decrease
Negative
BAC SC # correct
Increase
Positive
BAC SC=Brief Assessment of Cognition Symbol Coding, CGI-S=Clinical Global Impression–Severity, HAM-D6=6-
item Hamilton Depression Rating Scale, HAM-D17=17-item Hamilton Depression Rating Scale, MADRS=Montgomery-
Asberg Depression Rating Scale
Details pertaining to the imputation and calculation of MADRS total score and HAM-D17
total score when 1 or more of the items is missing is discussed in Section 9.4.4. The number 
and percent of participants with a ≥50% response in MADRS total score will be summarized 
by treatment group and timepoint according to the following equation.
%-response in MADRS total score = (postdose – baseline)/baseline)
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, ECGs, and vital signs.
Responses on the C-SSRS are classified according to 11 prespecified categories (Ideation: 
Passive, Active-nonspecific, Active-method, Active-method and intent, and Active-method, 
intent and plan; Behavior: Preparatory actions or behaviors, Aborted attempt, Interrupted 
attempt, Suicide attempt, and Completed suicide; Non-suicidal Self-Injurious Behavior). The 
most severe treatment-emergent event within each of 3 broad categories (suicidal ideation, 
suicidal behavior, and non-suicidal self-injurious behavior) reported at a visit will be used for 
analysis and reporting. An event is considered treatment-emergent during the assessment 
phase if it is either newly emerged or is more severe than the most severe event reported to 
have occurred in the study-defined pretreatment reference period.
9.4.3
Pharmacokinetic Endpoints
The PK endpoint is MK-1942 plasma concentrations.
9.4.4
Derivation of Efficacy Endpoints
Because it is possible to have missing items within the MADRS (primary endpoint), the 
following rules will be implemented to derive the total score. If ≤20% of the items are 
missing (eg, at most 2 of the 10 items are missing), then the missing items will be replaced 
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with the average (rounded to the nearest unit) of the remaining items for that participant at 
that visit; otherwise, the total score will be missing at that visit. The sum of the 10 items is 
the total score.
The HAM-D17 consists of 17 items. Eight of the items are rated from 0 to 2 and 9 of the 
items are rated from 0 to 4. Because it is possible to have missing items within the 
HAM-D17, the following rules will be implemented to derive the total score. If ≤20% (or at 
most 3 items) are missing, then the missing items will be imputed as follows for that 
participant at that visit. Since items 1, 2, 10, 11, 12, 13, 14, 16 and 17 are rated on a unit 
scale from 0 to 4, and items 3, 4, 5, 6, 7, 8, 9 and 15 are rated on a unit scale from 0 to 2, if 
any of the items rated from 0 to 2 are missing, then it will be imputed by dividing items rated 
from 0 to 4 by 2 and averaged with the existing items (and rounded to the nearest unit); 
otherwise, for imputation of other missing items, items rated from 0 to 2 score will be 
multiplied by 2 and averaged with the existing items (and rounded to the nearest unit). If 
more than 3 items are missing from the HAM-D17, the total score will be missing at that 
visit. The sum of the 17 items is the total score.
The single imputation approach described above allows the total score to be calculated using 
the strength of the other items collected at that time, for that participant. The Sponsor
believes this approach to be more accurate than either setting the entire score to missing or to 
imputing the worst possible score. More complicated missing data approaches are not 
thought to be warranted, since the amount of missing data within an assessment is expected 
to be extremely low.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who:

receive at least 1 dose of study intervention

have at least 1 post-randomization observation for the analysis endpoint subsequent to at 
least one dose of study intervention

have baseline data for those analyses that require baseline data
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention. Participants will be included 
in the treatment group corresponding to the study intervention they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
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they are randomized except for participants who take incorrect study intervention for the 
entire treatment period; such participants will be included in the treatment group 
corresponding to the study intervention actually received. 
At least 1 laboratory, vital sign or ECG measurement obtained subsequent to at least 1 dose 
of study intervention is required for inclusion in the analysis of the respective safety 
parameter. To assess change from baseline, a baseline measurement is also required.
9.5.3
Pharmacokinetic Analysis Populations
The PP Population consists of the set of data generated by the subset of participants who 
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit 
the effects of treatment. 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. Any participants or data values
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.
At the end of the study, all participants who are compliant with the study procedure as
aforementioned and have available data will be included in the PP dataset. This population 
will be used for the PK analyses.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type-1
error control strategy are described in Section 9.8. Nominal p-values and 90% CIs will be 
computed for other efficacy analyses but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.
9.6.1
Statistical Methods for Efficacy Analysis
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
The treatment regimen intended for evaluation of the primary efficacy objectives is the 
randomized treatment administered as add-on therapy to stable antidepressant therapy as 
directed. For the MK-1942 daily dose group, this will include dose modification allowed for 
intolerability or non-adherence at or after 2 weeks of treatment with primary evaluation after 
3 weeks of therapy. For the MK-1942 intermittent dose group, the primary evaluation will be 
after 1 week of therapy. The primary analysis strategy (HS) will exclude data collected after 
discontinuation of study intervention or stable antidepressant therapy, initiation of a non-
study antidepressant therapy or premature unblinding of either the investigator or participant. 
A supplemental analysis strategy (TPS) will also be evaluated in which data collected after 
these intercurrent events will be included. 
A single statistical model including data from all 3 treatment groups through Week 4 will be 
used to contrast the treatment comparisons/timepoints of interest for each of the primary and 
secondary efficacy endpoints. The primary analysis is based on a longitudinal ANCOVA 
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model including calculated change from baseline at Week 1, Week 2, Week 3, and Week 4.
The model will handle missing data (both intermittent missing and monotone missing due to 
dropout) using the missing at random assumption. This model will be used to generate 
confidence intervals and p-values (compared with placebo). This model assumes a different 
mean for each treatment at each of the repeated time points in the analysis. In this model, 
time is treated as a categorical variable so that no restriction is imposed on the trajectory of 
the means over time. The analysis model will include categorical terms for treatment, number 
of treatment failures (1; >1) for the current episode of moderate-to-severe MDD, and week, 
as well as a continuous term for baseline response. In addition, the model will also include 
the interaction terms of week-by-treatment and week-by-baseline response. The treatment 
difference in terms of the mean change from baseline at a given time point will be estimated, 
and as appropriate, tested from the model. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. The Kenward-Roger approximation 
will be used to compute the degrees of freedom [Kenward, M. G. and Roger, J. H. 1997]. A 
sensitivity analysis will be performed for the primary and key secondary hypotheses to assess 
the robustness of the primary findings with respect to the handling of missing data. 
Specifically, a control-based mean imputation approach, with a tipping-point component, 
will be applied [Mehrotra, D. V., et al 2017]. Details related to this sensitivity analysis will 
be provided in the sSAP.
As outlined in Table 6, supportive analyses will be performed for the primary and the key
secondary hypotheses to assess the robustness of the primary findings with respect to (1) the 
impact of intercurrent events; and (2) the handling of missing data. Details related to 
supportive analyses will be provided in the sSAP.
Basic summary statistics will be computed for all efficacy endpoints over time. This 
minimally includes means and standard deviations for continuous-type endpoints and counts 
and percentages for categorical endpoints.
Table 6 summarizes the key efficacy analyses.
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Table 6
Analysis of Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Methodb
Analysis 
Population
Missing Data 
Approach
Primary Hypotheses
Change from baseline at 
Week 3 in MADRS total 
score (MK-1942 daily dose 
versus placebo)
P
Longitudinal ANCOVAc
with HS estimand 
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
Change from baseline at 
Week 1 in MADRS total 
score (MK-1942 intermittent 
dose versus placebo)
P
Longitudinal ANCOVAc
with HS estimand
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
Secondary Hypotheses
Change from baseline at 
Week 3 in HAM-D17 total 
score (MK-1942 daily dose 
versus placebo)
P
Longitudinal ANCOVAc
with HS estimand
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation 
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
Change from baseline at 
Week 1 in HAM-D17 total 
score (MK-1942 intermittent 
dose versus placebo)
P
Longitudinal ANCOVAc
with HS estimand
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation 
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Methodb
Analysis 
Population
Missing Data 
Approach
Change from baseline at 
Week 3 in CGI-S (MK-1942 
daily dose versus placebo)
P
Longitudinal ANCOVAc
with HS estimand
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation 
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
Change from baseline at 
Week 1 in CGI-S (MK-1942 
intermittent dose versus 
placebo)
P
Longitudinal ANCOVAc
with HS estimand
FAS
Model-basedd
S
Longitudinal ANCOVA 
with HS estimand and
Control-Based Mean 
Imputationc
FAS
Control-based 
mean 
imputation
S
Longitudinal ANCOVAc
with TPS estimand
FAS
Model-basedd
ANCOVA=Analysis of covariance, CGI-S=Clinical Global Impression-Severity; FAS=full analysis set, HAM-D17=17-
item Hamilton Depression Rating Scale; HS=hypothetical strategy; MADRS=Montgomery-Asberg Depression Rating 
Scale; MDD= major depressive disorder; TPS=treatment policy strategy
  a
P=Primary approach, S=Supportive approach
  b
Statistical models are described in further detail below.
  c
Longitudinal data analysis model with terms for treatment, number of treatment failures (1 treatment failure; 
>1 treatment failure [for the current episode of moderate-to-severe MDD]), week, and baseline response. In addition, 
the model will also include the interaction terms of week-by-treatment and week-by-baseline response.
  d
Imputation for missing items as noted in Section 9.4.4 will be conducted prior to using this model-based approach.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and an 
interim analysis is described in Section 9.7 (Interim Analyses) and in Section 9.8 
(Multiplicity), respectively.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 7). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet PDLC criteria in laboratory, vital signs, and ECG 
parameters are either prespecified as “Tier 1” endpoints, or will be classified as belonging to 
"Tier 2" or "Tier 3" based on the number of events observed.
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Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no Tier 1 events for this protocol as the evaluation of safety and tolerability is focused on 
estimating rather than testing treatment differences and the incidence of AEs of special 
interest is anticipated to be rare.
Tier 2 Events
Membership in Tier 2 requires that at least 7% of participants (corresponding to at least 4 
participants in the MK-1942 daily dose group, 2 participants in the MK-1942 intermittent 
dose group, and 4 participants in the placebo group) in any treatment group exhibit the event. 
The threshold of at least 7% was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events (and when a treatment group of half-
allocation has less than 2 events) and thus would add little to the interpretation of potentially 
meaningful differences. Because many 95% confidence intervals may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events and safety parameters that 
meet predefined limits of change.
In addition to individual events that occur in 7% or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a 
drug-related AE, a serious AE, an AE which is both drug-related and serious, and 
discontinuation due to an AE will also be considered Tier 2 endpoints.
Dizziness AEs of moderate or severe intensity and gait disturbance independent of feelings 
of dizziness AEs are Tier 2 AEs.
Tier 3 Events
Safety endpoints that are not Tier 2 events are considered Tier 3 events. Only point estimates 
by treatment group are provided for Tier 3 safety parameters.
Categorical Safety Measures
C-SSRS
The percentage of participants with any treatment-emergent suicidal ideation or with any 
treatment-emergent suicidal behavior will be analyzed per the tiered analysis strategy 
outlined above, and will be considered as either Tier 2 or Tier 3 events, depending on the 
number of participants with an event observed within each treatment group. Additionally, the 
11 prespecified categories of suicidal ideation and behavior will be summarized. Participant 
counts (and cumulative counts) for each category will be based upon the most severe 
treatment-emergent event observed during the assessment period.
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In constructing the treatment-emergent C-SSRS analyses, a pretreatment reference period is 
required, from which a baseline score for each of the 3 categories (ideation, behavior, 
nonsuicidal self-injury) is derived. For this study, the baseline score for each of the 3 
categories will be taken as the maximum score arising from the 3 predose C-SSRS 
administrations. The first predose administration references lifetime history. Each subsequent
predose administration references the timeframe since the last predose administration.
It is noted that the first predose administration actually consists of 2 separate administrations; 
1 using lifetime as the reference period and another using fixed-time intervals (6 months for 
behavior and 2 months for ideation). The fixed-time administration is solely included for 
inclusion/exclusion purposes (noting that the contemporaneous maximum lifetime baseline 
score may not be less than the maximum fixed-time baseline score by definition).
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
Table 7 summarizes the safety analysis.
Table 7
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to an AE
X
X
Specific AEs, SOCs, or PDLCs 
(incidence ≥7%) of participants in 1 of the 
treatment groups)
X
X
Dizziness AEs of moderate or severe 
intensity 
X
X
Gait disturbance independent of feelings of 
dizziness AEs
X
X
Tier 3
Specific AEs, SOCs or PDLCsa (incidence 
<7% of participants in all treatment 
groups)
X
Change from baseline results (Labs, ECGs, 
Vital Signs)
X
AE=adverse event, CI=confidence interval, ECG=electrocardiogram, PDLC=Pre-Defined Limit of Change, 
SOC=System Organ Class, X=results will be provided
aIncludes only those endpoints not prespecified as Tier 2 endpoints. 
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9.6.3
Statistical Methods for Pharmacokinetic Analysis
Plasma concentrations will be summarized by nominal timepoint using the following (non-
model-based) descriptive statistics: N (number of participants with non-missing data), 
arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 × standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV 
(calculated as 100 × sqrt (exp(s2) -1), where s2 is the observed variance on the natural log-
scale). The effect of genetic polymorphism of CYP2C19 on MK-1942 PK may be assessed 
and described in a separate document.
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. 
The number and percentage of participants screened and randomized and the primary reasons 
for screening failure and discontinuation will be displayed. Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
One non-binding interim futility analysis will be performed in this study. The interim 
analysis will be performed when the first ~60% of randomized participants either complete 
Week 3 or discontinue before Week 3. The interim analysis calculation assumes the same 
SDs used for the study power and sample size estimates, and assumes that the remaining data 
(after interim analysis) will be distributed similarly to that observed at the interim. The
endpoints, timing, and purpose of the interim analysis are summarized in Table 8 below.
Table 8
Summary of Interim Analysis Strategy
Key Endpoints for Interim 
Analysis
Timing of Interim Analysis
Purpose of Interim Analysis
Change from baseline at Week 3
in MADRS total score (MK-1942 
daily dose versus placebo)
First ~60% of randomized
participants either complete Week 3
or discontinue prior to Week 3
Assess futility
Change from baseline at Week 1 
in MADRS total score (MK-1942 
intermittent dose versus placebo)
MADRS=Montgomery-Asberg Depression Rating Scale
Study enrollment is likely to be ongoing at the time of the interim analysis. Blinding to 
treatment assignment will be maintained at all investigational sites. The results of the interim 
analysis will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an internal unblinded statistician and 
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statistical programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
Treatment-level results and/or participant-level data from the interim analysis will be 
provided by the unblinded statistician to the siDMC which consists of Sponsor personnel 
(and external experts, as appropriate). Limited additional Sponsor personnel may be 
unblinded to the treatment level results of the interim analysis, if required, in order to act on 
the recommendations of the siDMC. The extent to which individuals are unblinded with 
respect to results of the interim analysis will be documented by the unblinded statistician.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the Sponsor. The protocol-specific siDMC charter will 
be referenced in the CSR. Prior to final study unblinding, individuals who have been 
unblinded at any level will not be involved in any discussions regarding modifications to the 
protocol, statistical methods, identification of protocol deviations, or data validation efforts 
after the interim analyses.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline, the ITT principle and the CHMP guideline on adaptive designs.
The decision of whether to terminate the study for futility will be based on CP, ie, the 
likelihood of correctly detecting a (standardized) treatment difference at the end of the study 
given the results at the interim, corresponding to the primary hypotheses (ie, MADRS change 
from baseline at Week 3 (MK-1942 daily dose versus placebo) and at Week 1 (MK-1942 
intermittent dose versus placebo). If the CP is <10% for both primary hypotheses, the study 
may be stopped for futility. If the truth is a SES of 0.230 for MK-1942 daily dose versus 
placebo and 0.277 for MK-1942 intermittent dose versus placebo (ie, not only do we observe 
it at the interim, but the remaining data also have that distribution), this equates to a CP of 
10% for each contrast. The interim analysis will include data for participants who completed 
the study or dropped out as well as the partial data of ongoing participants. Additional details 
regarding the calculation of the CP will be described in the sSAP.
The operating characteristics of the interim futility analysis are in Table 9. Based on this 
information and assuming a correlation of 0.5 between treatment comparisons, the 
probability the study may be deemed futile if both alternative hypotheses are true is 2.5%
based on the marginal probabilities (7.6% and 8.6%). The probability the study may be
deemed futile if both null hypotheses are true is 70.7% based on the marginal probabilities 
(81.3% and 81.4%).
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Table 9
Operating Characteristics of the Interim Futility Analysis
Daily Dose Group
Intermittent Dose Group
Probability Study Futile
Timing of Futility 
Interim Analysis
Futility 
CP 
Criterion
Futility 
SES 
Boundary
Probability 
Futile Based 
on SES=0
Probability 
Futile Based 
on SES=0.6
Futility 
SES 
Boundary
Probability 
Futile Based 
on SES=0
Probability 
Futile
Based on 
SES=0.7
Both Null
Hypotheses
True
Both 
Alternative
Hypotheses 
True
First ~60% 
randomized who 
complete or 
discontinue before 
Week 3
<10%
0.230
81.3%
7.6%
0.277
81.4%
8.6%
70.7%
2.5%
CP=conditional power, SES=standardized effect size
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9.8
Multiplicity
The study has 2 MK-1942 treatment dose comparison “families” of interest (MK-1942 daily 
dose versus placebo and MK-1942 intermittent dose versus placebo). Each family has 3
hypotheses that correspond to the primary endpoint and two key secondary endpoints and 
will be tested and controlled at the 2-sided α=0.05 level using a closed testing sequential 
approach. Specifically, within each of the two dose families, the primary hypothesis will be 
tested at the 2-sided α=0.05 level. If the primary null hypothesis is rejected, then testing will 
proceed to the first secondary hypothesis (still at 2-sided α=0.05 level). Testing will continue 
to the remaining key secondary hypothesis (ie, with formal significance declared for a given 
hypothesis only if that hypothesis is significant and all hypotheses preceding it within that 
family are significant).
Since the study will be considered positive if either treatment comparison is positive (at the 
5% level), the family-wise error at the study level is 10%. It is noted that if all 3 hypotheses 
within a dose family are rejected at the 2-sided α=0.05 level, then the other dose family may 
proceed to be tested using the full 2-sided α=0.10 level (again following the sequential 
ordering within the family). Figure 2 outlines the testing strategy used to address the
multiplicity issues.
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Figure 2
Testing Strategy to Address Multiplicity
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
Sample size was determined based on change from baseline in MADRS total score at Week 3 
(for MK-1942 daily dose versus placebo) and Week 1 (for MK-1942 intermittent dose versus 
placebo). This study will randomize 56 participants into the MK-1942 daily dose group, 28
into the MK-1942 intermittent dose group, and 56 into the placebo group. With these sample 
α=0.10
α=0.05
α=0.05
MK-1942 Daily
1) Week 3 CFB MADRS vs. Pbo
2) Week 3 CFB HAM-D17 vs.  Pbo
3) Week 3 CFB CGI-S vs. Pbo
MK-1942 Intermittent
1) Week 1 CFB MADRS vs. Pbo
2) Week 1 CFB HAM-D17 vs.  Pbo
3) Week 1 CFB CGI-S vs. Pbo
Apply                       
Bonferroni
Primary
Secondary
Secondary
If all three rejected at 
α=0.05 proceed to test 
MK-1942 intermittent 
family at α=0.10
If all three rejected at 
α=0.05 proceed to 
test MK-1942 daily 
family at α=0.10
CFB=change from baseline; CGI-S=Clinical Global Impressions-Severity; HAM-D17= 17-item Hamilton 
Depression Rating Scale; MADRS=Montgomery-Asberg Depression Rating Scale 
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sizes and assuming an 8% dropout rate after 1 week and 10% dropout rate after 3 weeks,
each treatment comparison has at least 80% (marginal) power to demonstrate superiority 
compared to placebo at the 2-sided 5% α-level; the probability that at least 1 MK-1942 
dosing regimen demonstrates superiority compared with placebo is 92%. These calculations 
assume the underlying SES for change from baseline in MADRS total score at Week 3 (MK-
1942 daily dose versus placebo) is -0.6 (eg, corresponds to a mean treatment difference of -6
points and a standard deviation of 10.0 points) and the underlying SES for change from 
baseline in MADRS total score at Week 1 (MK-1942 intermittent dose versus placebo)
is -0.7 (eg, corresponds to a mean treatment difference of -6.5 points and a standard deviation 
of 9.3 points) and use a normal test. The intermittent dose group has a smaller sample size 
due to the anticipation that rapid effect will be seen. Therefore, the primary timepoint of 
interest is Week 1. Because of the shorter time frame, the sample size has been adjusted to 
account for lower variance, larger treatment difference, and smaller dropout rate versus the 
daily dose group, where given the 2 week titration, the primary timepoint of interest is Week 
3.The underlying treatment SESs are regarded as a clinically relevant for the difference 
between the 2 treatments. The sample size calculation also accounts for the interim futility 
analysis. The SESs for this study were based on results of prior publications for MDD and 
TRD [Sanacora, G., et al 2014] [Canuso, C. M., et al 2018].
Table 10 provides the assumptions for mean differences, standard deviations, and SESs as 
well as the marginal power for each treatment comparison, and the probability that at least 1
MK-1942 dosing regimen is successful.  
Table 10
Primary Assumptions, Marginal Power, and Probabilities for MADRS Total 
Score
Assumed Week
3/Week 1 Mean 
Treatment 
Difference in CFB 
(Daily Dose, 
Intermittent Dose)
Assumed Week
3/Week 1 CFB 
SD (Daily Dose, 
Intermittent 
Dose)
Assumed
Week 3/Week 
1 SES (Daily
Dose, 
Intermittent
Dose)
Marginal 
Power for 
Daily Dose 
Versus 
Placebo
Marginal 
Power for 
Intermittent 
Dose Versus 
Placebo
P (At Least 
One 
Hypothesis is 
Positive, 
corr.=.5)
(6.0, 6.5)
(10.0, 9.3)
(0.60, 0.70)
83.0%
80.8%
92.0%
CFB=change from baseline; corr=correlation; MADRS=Montgomery-Asberg Depression Rating Scale; SD=standard 
deviation; SES=standardized effect size  
Sample sizes are 56 participants in the MK-1942 daily dose group, 56 participants in the placebo group, and 28 
participants in the MK-1942 intermittent dose group.       
Assumes dropout rate is 8% at Week 1 and 10% at Week 3.
9.9.2
Sample Size and Power for Safety Analyses
Table 11 and Table 12 summarize the percentage point differences between 2 treatment 
groups for a variety of hypothetical underlying incidences of AEs. These calculations assume 
(1) 56 participants in the MK-1942 daily dose group and 56 participants in the placebo group 
(Table 11) and (2) 28 participants in the MK-1942 intermittent dose group and 56
participants in the placebo group (Table 12). The calculations are based on a 2-sided 5% 
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α-level and the method proposed by Miettinen and Nurminen [Miettinen, O. and Nurminen, 
M. 1985]; no multiplicity adjustments are considered.
Table 11
Differences (95% CIs) in Incidence in AEs Between MK-1942 Daily Dose and 
Placebo
Incidence of Adverse Event
Risk Difference
MK-1942 Daily Dose 
(%)
Placebo (%)
Percentage Points
95% CIa
10.7
5.4
5.4
(-5.5, 17.0)
14.3
5.4
8.9
(-2.4, 21.3)
19.6
5.4
14.3
(2.2, 27.4)
14.3
10.7
3.6
(-9.3, 16.7)
19.6
10.7
8.9
(-4.7, 22.8)
25.0
10.7
14.3
(0.0, 28.7)
19.6
14.3
5.4
(-8.9, 19.7)
25.0
14.3
10.7
(-4.2, 25.6)
30.4
14.3
16.1
(0.6, 31.3)
AE=adverse event, CI=confidence interval
Incidences presented here are hypothetical and do not represent actual AEs in either group.
a Based on Miettinen and Nurminen method with 56 participants per treatment group using a 2-sided 5% α level.
Table 12
Differences (95% CIs) in Incidence in AEs Between MK-1942 Intermittent Dose 
and Placebo
Incidence of AE
Risk Difference
MK-1942 Intermittent 
Dose (%)
Placebo (%)
Percentage Points
95% CIa
10.7
5.4
5.4
(-6.3, 22.6)
14.3
5.4
8.9
(-3.6, 26.9)
21.4
5.4
16.1
(1.9, 35.0)
14.3
10.7
3.6
(-10.5, 22.1)
21.4
10.7
10.7
(-4.9, 30.2)
25.0
10.7
14.3
(-2.1, 34.0)
21.4
14.3
7.1
(-9.2, 27.0)
25.0
14.3
10.7
(-6.3, 30.9)
28.6
14.3
14.3
(-3.4, 34.6)
AE=adverse event, CI=confidence interval
Incidences presented here are hypothetical and do not represent actual AEs in either group.
a Based on Miettinen and Nurminen method with 28 participants in the MK-1942 intermittent dose group and 
56 in the placebo group using a 2-sided 5% α level.
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9.10
Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 90% CI) for the primary and 
key secondary endpoints will be estimated and plotted within each category of each 
subgroup. Confidence intervals will only be produced if both treatment groups (MK-1942
dose group and placebo) have at least 25% of their sample within each subgroup. Summary 
statistics for subgroups will be provided regardless of sample size. The following are 
examples of classification variables: 

Gender (female; male)

Age group (<median; ≥ median years)

Race (white; other)

Prior Antipsychotics Use

Baseline MADRS total score (<median; ≥median score)

Baseline duration of current depressive episode (<median; ≥median duration)

Number of prior depressive episodes (<median; ≥median number)

Baseline BMI (<median; ≥median value)

Number of treatment failures (1 treatment failure; >1 treatment failure) for the current 
episode of moderate-to-severe MDD
HAM-D17 anxiety/somatization factor score (<7: ≥7)
-
7 (somatic symptoms gastrointestinal)
-
9 (somatic symptoms general)
-
12 (anxiety psychic)
-
13 (anxiety somatic)
-
14 (hypochondriasis)
-
15 (insight)
In addition, a forest plot will be produced, which provides the estimated treatment 
differences and confidence intervals for the treatment effect across the categories of 
subgroups listed above.
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9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant, the number of capsules remaining in study packaging will be counted, 
reviewed, and recorded at regular intervals. Study intervention records will be used to 
calculate participant compliance.
A day within the study will be considered an “On-Therapy” day if the participant takes all of 
the prescribed capsules for that day.
For a participant who is followed for the entire study period, the “Number of Days Should be 
on Therapy” is the total number of days from randomization to the last scheduled day for 
treatment administration for that participant. For a participant who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from randomization to the date of the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
9.12
Extent of Exposure
The extent of exposure to study intervention will be evaluated by summary statistics (N, 
mean, median, standard deviation). Additionally, the total number of days each participant
took a particular total daily dose of study intervention will be identified and summarized (as 
participant counts and percentages) within duration categories (eg, for the Treatment period: 
<1 week, ≥1 week but <2 weeks, ≥2 weeks but <3 weeks, ≥3 weeks but <4 weeks, and ≥4 
weeks, where 1 week is defined as 7 days). 
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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 & 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate siDMC will 
monitor the interim data from this study. The siDMC is comprised of members of Sponsor 
Senior Management, none of whom are directly associated with the conduct of this study. 
The siDMC will monitor the study at an appropriate frequency (details are provided in the 
siDMC charter ) for evidence of adverse effects of study intervention. The siDMC will also 
evaluate the results of an interim futility analysis performed after the first approximately 60% 
of randomized participants either complete Week 3 or discontinue before Week 3. The 
interim futility analysis will include a review of efficacy, safety, and tolerability data (see
Section 9.7). The siDMC will determine whether the study should continue (or other 
modifications, prespecified or otherwise, should be made) according to the protocol, 
considering the overall risk and benefit to study participants. The siDMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both participant 
safety and the continued ethical integrity of the study.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.4.2
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors 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, 
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www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
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 
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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
Laboratory tests performed in this study are shown in Table 13.
Notes on Laboratory Testing:

The investigator (or qualified designee) must document their review of each laboratory 
safety report.

Additional laboratory tests may be performed at any time during the study as determined 
by the investigator or required by local regulations.

Local laboratory tests may be performed in the event that the central laboratory results 
would not be available in time for timely decision making on either study intervention 
administration and/or response evaluation. If a local test is performed, it is important that 
a sample for central analysis is obtained at the same time. For Visit 10, if a participant 
cannot attend the in-person site visit, scheduled safety laboratory assessments may be 
performed at a local laboratory and other non-laboratory assessments will be performed
by TC. Results from the local laboratory should be entered into the appropriate CRF.

Screening laboratory tests may NOT to be repeated if the initial results are exclusionary, 
except where repeat tests are allowed in the eligibility criteria (Section 5.2). Rescreening 
may be performed after a participant’s laboratory abnormality initially leading to 
exclusion resolves (information on rescreening is provided in Section 8.11.1). Laboratory 
criteria for study intervention discontinuation are in Section 7.1.

If laboratory tests were not performed at a scheduled visit or results are invalid, then they 
must be obtained at the next scheduled visit. If a pregnancy test was missed at a 
scheduled visit, the test should be obtained as soon as possible (eg, at an unscheduled 
visit, if necessary).
Guidance on Pregnancy Testing:

Pregnancy testing:
- Pregnancy testing should be conducted at the visits specified in the SoA. Highly-
sensitive, local urine tests are required immediately (ie, on the same day) before 
dosing for WOCBP, with central serum tests performed every 2 weeks during 
treatment and in case of positive or ambiguous urine results.  
- A positive pregnancy test during the double-blind treatment period requires 
discontinuation of study intervention as described in Section 8.3.6.2 and Section 7.1.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
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- Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
Table 13
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
WBC
WBC count with differential (absolute, percentage):

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
Platelets
RBC 
Morphology, MCV, RDW
Hemoglobin
MCH, MCHC
Hematocrit
Chemistry
Creatinine
(includes eGFR
calculation)
Phosphorus
Calcium
CK
Sodium
Potassium
Chloride
CO2 or bicarbonate
AST (SGOT)
ALT (SGPT)
Albumin
Total protein 
Alkaline phosphatase
Lactate Dehydrogenase
Gamma-Glutamyl 
Transpeptidase 
Globulin
Urea Nitrogen
Uric Acid
Total bilirubin
Indirect bilirubin and 
Direct bilirubin
Glucose
Urinalysis
Color & clarity
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
Microscopic examination (reported if detected), includes bacteria, casts, crystals, 
epithelial cells, RBC, WBC, yeast, oval fat bodies, fat, mucous, sperm, trichomonas
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Laboratory 
Assessments
Parameters
Other Tests
Central serum hCG pregnancy test
Local urine pregnancy test 
INR at Visit 4 (Day 1) only
TSH with reflex FT4 
FSH – female only, if applicable
Urine drug screen includes:

Amphetamines/MDMA

Barbiturates 

Benzodiazepines

Cannabinoids  

Cocaine  

Methadone 

Opiates  

Phencyclidine 
Breathalyzer for alcohol use
Genotyping for CYP2C19
Serology (HIV antibody, HbsAg, and hepatitis C virus antibody) 
•
Serologies are at the discretion of the investigator
ALT=alanine amino transferase, AST=aspartate aminotransferase, CK=creatine kinase, eGFR=estimated glomerular 
filtration rate, FSH=follicle-stimulating hormone, FT4=free thyroxine T4, HbsAg=hepatitis B surface antigen, INR = 
international normalized ratio, RBC=red blood cell, SGOT=serum glutamic-oxaloacetic transaminase, SGPT=serum 
glutamate-pyruvate transaminase, TSH=thyroid-stimulating hormone, WBC=white blood cell 
10.2.1
Drug Screening (Local and Central)
The investigator (or qualified designee) should instruct the participant to refrain from using 
drugs of abuse (including opiates, barbiturates, amphetamine/methamphetamine, methadone, 
cocaine, and phencyclidine) and should limit alcohol use to moderate amounts during the 
study (Section 5.3.2). Drug screens (local and central) will be performed at visits specified in 
the SoA. Participants with a positive test result for these drugs of abuse based on either the 
local or central assessment at Visit 1 (Screening) or the local assessment at Visit 4 (Day 1) 
are not eligible for the study. However, participants who have a positive test result at Visit 1 
(Screening) for prescribed opiates (excluding methadone), barbiturates, or amphetamines 
may continue in the pretreatment period if the prohibited medication is discontinued at least 1 
week or 5 half-lives (whichever is longer) before the first dose of investigational 
intervention. The participant may be enrolled if the Visit 4 (Day 1) local assessment for drugs 
of abuse is negative. Retesting is not permitted for positive test results for non-prescription 
drugs of abuse.
Participants who have a positive test result for cannabis at Visit 1 (Screening) must be 
evaluated by the investigator and may be enrolled if abuse or substance use disorder are ruled 
out.
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Participants who test positive for a drug of abuse (except cannabis, which is not prohibited if 
abuse or substance use disorder is ruled out) during the double-blind treatment period (Table 
2) will be counseled to abstain from future use during the study, and may continue on study 
intervention at the discretion of the investigator. Participants who are unwilling to abstain 
from future use with a drug of abuse will be discontinued from study intervention. Urine drug 
screens can be performed at the discretion of the investigator if a participant is thought to be 
under the influence of a drug of abuse.
Local urine drug screens are employed in this study for early detection, with central urine 
drug screens performed at the same visits for confirmation of results.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the participant.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if 
the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
Is a cancer
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
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Assessment of causality

Did the Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦If yes, did the AE resolve or improve?
◦If yes, this is a positive dechallenge.
◦If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦If yes, did the AE recur or worsen?
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◦If yes, this is a positive rechallenge.
◦If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
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
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
If the EDC tool is not operational, facsimile transmission or secure 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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb,e
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc
•
IUSd (confirmed to be in place within the last year by treating healthcare provider)
•
Non-hormonal IUD (confirmed to be in place within the last year by treating healthcare provider)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 
days. 
Note: Documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records or medical examination.
Highly Effective Contraceptive Methods That Are User Dependentb,e
Failure rate of <1% per year when used consistently and correctly.
Note: Barrier method (eg, condoms) must be used in addition to these user-dependent 
contraceptive methods.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
o
Oral
o
Intravaginal
o
Transdermal
•
Progestogen-only hormonal contraceptionc
o
Oral
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
Investigator must confirm that the contraceptive method will not expire during the study.
c.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
d.
IUS is a progestin releasing IUD.
e.
Must have continual use for at least 3 months before screening.
Note: The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.

Male condom with cap, diaphragm, or sponge with spermicide.

Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that 
is a sign of a normal or abnormal process or of a condition or disease. A biomarker 
may be used to see how well the body responds to a treatment for a disease or 
condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA 
characteristics as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical 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.
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3.
Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at 
a study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated 
in the SoA. If delayed, present consent at next possible Participant Visit. Consent 
forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.
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 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers 
will appear on the specimen tube.
5.
Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future biomedical research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that 
their biospecimens not be used for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if 
the investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this 
situation, the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of 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 main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
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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 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.
Questions3,4
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: General Neurological Examination
The general neurological examination will be performed at the time points specified in the 
SoA.
Note to the investigator: If at any time abnormalities are observed in the general 
neurological examination, the investigator should do additional examinations as needed 
based on his or her medical judgment.
The general neurological examination includes all of the modules listed below, with the 
exception of Module 1, and is intended to be a general screening examination and is
sufficient for this study and participant population. 
MODULE 2 – CRANIAL NERVE ASSESSMENT
A. II – Visual Fields and Acuity
B. II, III – Pupil Size and Reactivity
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus)
Note: Observe for nystagmus during eye movements, increased nystagmus at the end of gaze 
or other oculomotor changes (mild nystagmus at extremes of gaze is normal). Note direction 
of nystagmus
D. V – Facial Sensation, Jaw Strength
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile)
F. VIII – Auditory Acuity (assessed using a bed-side screening test, eg, by rubbing fingers 
on each side of participant’s head or by whispering numbers)
G. XI – Shoulder Shrug
H. XII – Tongue Protrusion (midline)
Score: left and right (except for H)
Grade: NORMAL or ABNORMAL
MODULE 3 – MOTOR SYSTEM
A. Muscle Tone
1. Ask the participant to relax.
2. Flex and extend the participant’s elbows and knees (bilaterally).
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3. There is a small, continuous resistance to passive movement.
4. Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone.
Score: left and right
Grade: NORMAL, INCREASED, or DECREASED
B. Muscle Strength
1. Ask the participant to stand up from sitting without using hands
Grade: NORMAL or ABNORMAL
2. Test proximal limb strength by having the participant flex and extend the knees and 
elbows against your resistance (test bilaterally, and compare 1 side to the other).
Score: left and right
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement against 
gravity but not against resistance; 2/5: visible movement but not against gravity; 1/5: visible 
contraction; 0/5: no visible activity
3. Test distal limb strength by having the participant conduct dorsiflexion and plantar 
flexion of the participant’s feet; finger abduction and handgrip strength against your 
resistance (test bilaterally, and compare 1 side to the other).
Score: left and right
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement against 
gravity but not against resistance; 2/5: visible movement but not against gravity; 1/5: visible 
contraction; 0/5: no visible activity
C. Pronator Drift
1. Ask the participant to hold both arms straight forward with, palms up and eyes closed for 
~10-15 seconds as tolerated; watch for how well the arm position is maintained.
Score: left and right
Grade: NORMAL or ABNORMAL
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MODULE 4 – REFLEXES
A. Biceps
B. Knee
Note: Other deep tendon reflexes may be tested at investigator's discretion (eg, elbow, wrist 
or Achilles tendon)
Score: left and right
Grade: NORMAL, INCREASED, DECREASED or ABSENT
C. Babinski
Score: left and right
Grade: NORMAL or ABNORMAL
MODULE 5 – COORDINATION AND GAIT
A. Rapid, Rhythmic Alternating Movements
1. Testing each hand separately, ask the participant to tap the distal thumb with the tip of 
each finger, in sequence, as fast as possible. 
Score: left and right
Grade: NORMAL or ABNORMAL
Reminder: If the rapid alternate movements are disturbed, the participant will be asked to 
strike his/her hand on the thigh, raise the hand, turn it over and then strike the back of the 
hand down on the same place.
B. Point-to-Point Movements
1. Ask the participant to touch your index finger and their nose alternately several times. 
Move your finger about as the participant performs this task.
Score: left and right
Grade: NORMAL or ABNORMAL
2. Ask the participant to place 1 heel on the opposite knee and then run it down the shin to 
the big toe. Repeat this for both sides.
Score: left and right
Grade: NORMAL or ABNORMAL
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C. Romberg
1. Ask the participant to stand with both feet together and eyes closed for 20 to 30 seconds 
without support.
2. Be prepared to catch the participant if they are unstable.
Grade: NORMAL or ABNORMAL
D. Gait
1. Ask the participant to walk across the room, turn and come back (assess posture, balance, 
swinging of arms and movement of the legs).
Grade: NORMAL or ABNORMAL
2. Ask the participant to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or ABNORMAL
MODULE 6 – SENSORY
A. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally.
B. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally.
C. Vibration: tuning fork vibration detection in finger (thumb or distal finger), toe 
bilaterally.
D. Position sense: perception of thumb and toe movement, bilaterally.
Score: left and right
Grade: NORMAL OR ABNORMAL (for each A to D)
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
AD
Alzheimer’s disease
AE
adverse event 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
all-participants-as-treated
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
AxMP
auxiliary medicinal product
BAC SC
Brief Assessment of Cognition Symbol Coding
bid
twice-daily
biw
twice-weekly
BMI
body mass index
CFB
change from baseline
CGI-S
Clinical Global Impression-Severity
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CK
creatinine kinase
Cmax
maximum plasma concentration
CNS
central nervous system
CO2
carbon dioxide
corr
correlation
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome
coronavirus 2
CP
conditional probability
CRF
case report form 
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale 
Ctrough
plasma concentration at last timepoint before next dose
CYP
cytochrome P450
CYP2C19
cytochrome P450 2C19
CYP3A
cytochrome P450 3A
DC
discontinuation
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee 
DNA
deoxyribonucleic acid 
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data capture
EEA
European Economic Area 
eGFR
estimated glomerular filtration rate
EM
exposure margins
EMA
European Medicines Agency
EOT
end of treatment
EU CTR
European Union Clinical Trial Regulation
FAS
full analysis set
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Abbreviation
Expanded Term
FBR
future biomedical research
FDA
US Food and Drug Administration
FSH
Follicle-stimulating hormone 
FT4
free T4 test
GCP
Good Clinical Practice 
GM
geometric mean
HAM-D6
6-item Hamilton Depression Rating Scale
HAM-D17
17-item Hamilton Depression Rating Scale
HBsAg
hepatitis B surface antigen
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HS
hypothetical strategy
IB
investigator’s brochure 
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IND
investigational new drug 
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ITT
intention-to-treat
IU/L
international units per liter
IVRS
interactive voice response system
LDL
low density lipoprotein
MADRS
Montgomery-Asberg Depression Rating Scale
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MD
doctor of medicine
MDD
major depressive disorder
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
mGluR2
metabotropic glutamate receptor 2
MINI
Mini International Neuropsychiatric Interview
mRNA
messenger RNA
NA
not applicable
NAM
negative allosteric modulator
NDA
new drug application
NIMP
non-investigational medicinal product
NMDA
N-methyl-D-aspartate
NOAEL
no observed adverse effect level
NSAE
nonserious adverse event
PD
pharmacodynamics
PDLC
predefined limit of change
PET
positron emission technology
PK
pharmacokinetic
PoC
proof-of-concept
PP
per-protocol
QD
once daily
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Abbreviation
Expanded Term
QTcF
QTc using the Fridericia formula
RBC
red blood cell
RDW
red cell distribution width
RNA
ribonucleic acid
RO
receptor occupancy
SAC
scientific advisory committee
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SES
standardized effect size
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamate-pyruvate transaminase
siDMC
standing internal data monitoring committee
SLAB
supplemental laboratory
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TC
telephone call
Tmax
time to maximum concentration
TMS
transcranial magnetic stimulation
TPS
treatment policy strategy
TRD
treatment-resistant depression
TSH
thyroid-stimulating hormone
ULN
upper-limit of normal
WBC
white blood cell
WOCBP
woman of childbearing potential
WONCBP
woman of nonchildbearing potential
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11
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