A Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants With Major Depressive Disorder (MDD) With Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy
Phase: PHASE3
Conditions: Depressive Disorder, Major, Anhedonia
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 26 January 2024
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled Study to
Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy
in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe
Anhedonia and Inadequate Response to Current Antidepressant Therapy
Protocol 67953964MDD3001 VENTURA-1; Phase 3
Version: Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
JNJ-67953964 Aticaprant
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
Studies conducted at sites in the United States (US)will be conducted under US Food & Drug
Administration Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Numbers:
IND: 111006
EudraCT NUMBER: 2022-000439-22
Status: 
Approved
Date: 
26 January 2024
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-RIM-1071785, 1.0
Local Amendment to EDMS-RIM-621478, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 26 January 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA) 
26-Jan-2024
Amendment 2 
22-Feb-2023
Amendment 1 
09-Aug-2022
Original Protocol 
22-Apr-2022
Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA) (26 January 2024)
Overall Rationale for the Amendment: Addition of a Participant Experience Interview sub-study for the
Czech Republic, Spain, and the USA.
The changes made to the clinical protocol 67953964MDD3001 as part of Protocol Amendment 2/RS-1
Group 1 (Countries CZE, ESP, USA) are listed below, including the rationale for each change and a list of
all applicable sections. Changes made in previous protocol amendments are listed in Section 10.11
Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3. Schedule of
Activities (SOA);
8. Study Assessments
and Procedures;
8.12. Participant
Experience Interview
(Optional)
10.1. Appendix 1:
Abbreviations and
Definitions
An optional Participant Experience Interview
sub-study is added for the Czech Republic, Spain,
and the USA.
An optional participant
experience interview may be
performed in the Czech
Republic, Spain, and the USA
in randomized participants who
consent to the interview. The
interview is conducted to better
characterize the participant’s
understanding of depression
and anhedonia, including
validation and interpretation of
the DARS.
5.1. Inclusion Criteria 
Correction in Inclusion Criterion #12:
Updated “until 4 weeks” to “for 1 month”
Mismatch correction: minimum
duration of contraceptive
requirements after last dose of
study intervention in Inclusion
Criterion #12 updated to match
Exclusion Criterion #26.
5.2. Exclusion Criteria 
Correction in Exclusion Criterion #26
Is a female participant who is pregnant, or
breastfeeding, or planning to become pregnant
while enrolled in this study or within 6 weeks for 1
month after the last dose of study intervention.
Mismatch correction: minimum
duration of contraceptive
requirements after last dose of
study intervention in Inclusion
Criterion #12 updated to match
Exclusion Criterion #26.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 26 January 2024
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT FIGURES ........................................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 16
1.3. 
Schedule of Activities (SoA)........................................................................................................... 17
2. 
INTRODUCTION................................................................................................................................ 22
2.1. 
Study Rationale.............................................................................................................................. 23
2.2. 
Background.................................................................................................................................... 24
2.3. 
Benefit-Risk Assessment............................................................................................................... 30
2.3.1. 
Benefits for Study Participation .................................................................................................. 30
2.3.2. 
Benefit-Risk Assessment for Study Participation ....................................................................... 31
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 32
4. 
STUDY DESIGN ................................................................................................................................ 35
4.1. 
Overall Design................................................................................................................................ 35
4.1.1. 
Study Intervention(s)................................................................................................................... 36
4.1.2. 
Screening Phase ........................................................................................................................ 37
4.1.3. 
Double-blind Treatment Phase................................................................................................... 38
4.1.4. 
Follow-up Phase......................................................................................................................... 40
4.1.5. 
Open-label Long-term Safety Study........................................................................................... 40
4.1.6. 
Additional Details Related to Study Design................................................................................ 40
4.1.7. 
Changes in Study-related Procedures as a Result of the COVID-19 Pandemic........................ 40
4.2. 
Scientific Rationale for Study Design............................................................................................. 41
4.2.1. 
Study Population......................................................................................................................... 41
4.2.2. 
Blinding, Control, Study Phase/Periods, Intervention Groups.................................................... 42
4.2.3. 
Study-Specific Ethical Design Considerations ........................................................................... 43
4.2.4. 
Biomarker Sample Collection ..................................................................................................... 44
4.2.5. 
Pharmacokinetic Assessments................................................................................................... 44
4.3. 
Justification for Dose...................................................................................................................... 45
4.4. 
End of Study Definition................................................................................................................... 45
5. 
STUDY POPULATION ...................................................................................................................... 46
5.1. 
Inclusion Criteria............................................................................................................................ 46
5.2. 
Exclusion Criteria........................................................................................................................... 49
5.3. 
Lifestyle Considerations................................................................................................................. 55
5.3.1. 
Meals and Dietary Restrictions................................................................................................... 55
5.3.2. 
Activity......................................................................................................................................... 55
5.4. 
Screen Failures.............................................................................................................................. 56
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 56
6.1. 
Study Intervention(s) Administered................................................................................................ 56
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 59
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 59
6.4. 
Study Intervention Compliance...................................................................................................... 60
6.5. 
Dose Modification........................................................................................................................... 61
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 61
6.7. 
Treatment of Overdose .................................................................................................................. 61
6.8. 
Concomitant Therapy..................................................................................................................... 62
6.8.1. 
Current (SSRI/SNRI) Antidepressant Therapy........................................................................... 63
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 26 January 2024
6.8.2. 
Prohibited Therapies................................................................................................................... 64
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 65
7.1. 
Discontinuation of Study Intervention ............................................................................................ 65
7.1.1. 
Liver Chemistry Stopping Criteria............................................................................................... 65
7.1.2. 
QTc Stopping Criteria................................................................................................................. 66
7.1.3. 
Temporary Interruption, Restart or Rechallenge ........................................................................ 66
7.2. 
Participant Discontinuation/Withdrawal from the Study................................................................. 66
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 68
7.3. 
Lost to Follow-up............................................................................................................................ 69
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 69
8.1. 
Assessments.................................................................................................................................. 72
8.1.1. 
Screening Assessments ............................................................................................................. 72
8.1.1.1. 
17-item Hamilton Depression Rating Scale (HDRS-17).......................................................... 73
8.1.1.2. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
(MGH ATRQ)........................................................................................................................... 73
8.1.1.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders –Clinical Trials Version
(SCID-CT)................................................................................................................................ 73
8.1.1.4. 
Site Independent Qualification Assessment (SIQA)................................................................ 73
8.1.2. 
Efficacy Assessments................................................................................................................. 74
8.1.2.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS)....................................................... 74
8.1.2.2. 
Snaith-Hamilton Pleasure Scale (SHAPS).............................................................................. 75
8.1.2.3. 
Dimensional Anhedonia Rating Scale (DARS)........................................................................ 75
8.1.2.4. 
Clinical Global Impression-Severity (CGI-S) ........................................................................... 75
8.1.2.5. 
Patient Global Impression of Severity (PGI-S)........................................................................ 76
8.1.2.6. 
Patient Global Impression of Change (PGI-C) ........................................................................ 76
8.1.2.7. 
Patient Health Questionnaire, 9-item (PHQ-9)........................................................................ 76
8.1.2.8. 
PROMIS Short Form v2.0 –Ability to Participate in Social Roles and Activities –8a
(PROMIS-APS 8a)................................................................................................................... 76
8.1.2.9. 
Generalized Anxiety Disorder 7-item Scale (GAD-7).............................................................. 76
8.1.2.10. 
Quality of Life in Depression Scale (QLDS) ............................................................................ 77
8.1.2.11. 
European Quality of Life, 5 Dimension, 5-Level (EQ-5D-5L) Questionnaire........................... 77
8.1.2.12. 
Work Productivity and Activity Impairment: Depression (WPAI:D) ......................................... 77
8.1.2.13. 
Treatment Satisfaction Questionnaire for Medication (TSQM-9) ............................................ 77
8.2. 
Safety Assessments....................................................................................................................... 77
8.2.1. 
Physical Examinations................................................................................................................ 78
8.2.2. 
Vital Signs................................................................................................................................... 79
8.2.3. 
Electrocardiograms..................................................................................................................... 79
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 79
8.2.5. 
Pregnancy Testing...................................................................................................................... 80
8.2.6. 
Columbia Suicidality Severity Rating Scale (C-SSRS)............................................................... 80
8.2.7. 
Arizona Sexual Experiences Scale (ASEX)................................................................................ 80
8.2.8. 
Cognitive Test Battery (Revere.D).............................................................................................. 81
8.2.9. 
Mini Mental State Examination (MMSE) - Screening Only......................................................... 81
8.2.10. 
Menstrual Cycle Tracking ........................................................................................................... 82
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 82
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 82
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 83
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 83
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 83
8.3.5. 
Pregnancy................................................................................................................................... 84
8.3.6. 
Adverse Events of Special Interest............................................................................................. 85
8.4. 
Digital Biomarker Assessments ..................................................................................................... 85
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 26 January 2024
8.4.1. 
Speech/Facial Digital Biomarker Analysis (Optional)................................................................. 85
8.4.2. 
Passive Behavior Sensing Using a Smartphone Application Software (Optional)..................... 86
8.4.3. 
Reward Learning Task (RLT) ..................................................................................................... 86
8.5. 
Pharmacokinetics........................................................................................................................... 86
8.5.1. 
Evaluations ................................................................................................................................. 87
8.5.2. 
Analytical Procedures................................................................................................................. 87
8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 87
8.6. 
Biomarkers..................................................................................................................................... 88
8.7. 
Immunogenicity Assessments ....................................................................................................... 88
8.8. 
Pharmacogenomic and Epigenetic (DNA, RNA) Assessments..................................................... 88
8.9. 
Participant Medical Information Prior to, During and After the Study (Optional Real-world
Data Collection).............................................................................................................................. 89
8.10. 
Ongoing Participant Review........................................................................................................... 89
8.11. 
Medical Resource Utilization and Health Economics .................................................................... 89
8.12. 
Participant Experience Interview (Optional)................................................................................... 89
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 90
9.1. 
Statistical Hypotheses.................................................................................................................... 90
9.2. 
Sample Size Determination ........................................................................................................... 90
9.3. 
Participant Analysis Sets................................................................................................................ 91
9.4. 
Statistical Analyses ........................................................................................................................ 91
9.4.1. 
General Considerations.............................................................................................................. 91
9.4.2. 
Efficacy Analysis......................................................................................................................... 92
9.4.2.1. 
Primary Efficacy Endpoint(s)................................................................................................... 92
9.4.3. 
Secondary Endpoint(s)............................................................................................................... 93
9.4.4. 
Safety Analyses.......................................................................................................................... 94
9.4.5. 
Other Analyses ........................................................................................................................... 95
9.4.5.1. 
Benefit-Risk Analyses.............................................................................................................. 95
9.4.5.2. 
Pharmacokinetic Analyses ...................................................................................................... 95
9.4.5.3. 
Biomarker Analyses................................................................................................................. 96
9.4.5.4. 
Immunogenicity Analyses........................................................................................................ 96
9.4.5.5. 
Exploratory Biomarker Analyses ............................................................................................. 96
9.4.5.6. 
Pharmacokinetic/Pharmacodynamic Analyses ....................................................................... 96
9.4.5.7. 
Pharmacogenomic Analyses................................................................................................... 97
9.5. 
Interim Analysis.............................................................................................................................. 97
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 98
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 98
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 101
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 103
10.3.1. 
Regulatory and Ethical Considerations .................................................................................... 103
10.3.2. 
Financial Disclosure.................................................................................................................. 106
10.3.3. 
Informed Consent Process ....................................................................................................... 107
10.3.4. 
Data Protection ......................................................................................................................... 107
10.3.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 108
10.3.6. 
Committees Structure............................................................................................................... 109
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 109
10.3.8. 
Data Quality Assurance............................................................................................................ 110
10.3.9. 
Case Report Form Completion................................................................................................. 110
10.3.10. Source Documents ................................................................................................................... 111
10.3.11. Monitoring ................................................................................................................................. 112
10.3.12. On-Site Audits........................................................................................................................... 113
10.3.13. Record Retention...................................................................................................................... 113
10.3.14. Study and Site Start and Closure ............................................................................................. 114
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 115
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 26 January 2024
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 115
10.4.2. 
Attribution Definitions................................................................................................................ 116
10.4.3. 
Severity Criteria........................................................................................................................ 116
10.4.3.1. 
Guidance for Assessing Severity of Adverse Events of Special Interest.............................. 117
10.4.4. 
Special Reporting Situations .................................................................................................... 117
10.4.5. 
Procedures ............................................................................................................................... 118
10.4.6. 
Product Quality Complaint Handling......................................................................................... 119
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 120
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 121
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................................ 124
10.6.1. 
Stopping Algorithm ................................................................................................................... 124
10.6.1.1. 
ALT or AST............................................................................................................................ 124
10.6.2. 
Follow-up Assessments............................................................................................................ 127
10.6.2.1. 
Phase 3-4 Liver Chemistry Increased Monitoring Criteria with Continued Study
Intervention............................................................................................................................ 127
10.7. 
Appendix 7: Prohibited Concomitant Therapies .......................................................................... 128
10.8. 
Appendix 8: Administration of a Patient-Reported Outcome (PRO) at Scheduled Visits............ 132
10.9. 
Appendix 9: Study Conduct During a Natural Disaster/Major Disruption/ Pandemic .................. 133
10.9.1. 
Guidance on Study Conduct During the COVID-19 Pandemic................................................ 133
10.9.2. 
Guidance Specific to this Protocol............................................................................................ 134
10.10. Appendix 10: Study Design.......................................................................................................... 137
10.11. Appendix 11: Protocol Amendment History................................................................................. 139
11. REFERENCES................................................................................................................................. 152
INVESTIGATOR AGREEMENT............................................................................................................... 157
LIST OF IN-TEXT FIGURES
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 16
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 26 January 2024
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled Study to Evaluate the
Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with
Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to
Current Antidepressant Therapy .
An increased understanding of the neurobiology of mood disorders allows for targeted research and focus
on specific brain circuits implicated in mood. This provides an opportunity for developing improved
treatments of mood disorders which are informed by the underlying neurobiology. Existing evidence
implicates the dynorphin opioid neuropeptide system in the regulation of mood. Kappa opioid receptor
(KOR) activation by the endogenous dynorphin induces stress and depressive symptoms in humans and
animals and downstream results in decreased dopaminergic function in different brain areas. It is
hypothesized that selective modulation of the KOR would result in improvement of residual symptoms of
depression, including behaviors involving anhedonia, by restoring normal dopamine transmission in the
brain’s reward/motivation circuitry. Preclinical evidence supports the therapeutic potential of KOR
antagonism for the treatment of anhedonia, depression, and anxiety. Based on an emerging body of
scientific evidence, selective KOR antagonism may provide therapeutic benefit in the treatment of major
depressive disorder (MDD).
Aticaprant (JNJ-67953964) is a once daily, highly selective KOR antagonist, with demonstrated selectivity
over mu opioid receptor (MOR) and delta opioid receptor (DOR). Aticaprant is generally well tolerated,
with no clinically significant adverse events (AEs), no clinically meaningful changes and abnormalities in
vital signs, laboratory evaluations or electrocardiograms (ECGs) reported.
The present study is being conducted to investigate the antidepressant effect of 10 mg daily aticaprant
(versus placebo) in participants (18 to 74 years, inclusive: including adult participants [18 to 64 years of
age, inclusive] and elderly participants [65 to 74 years of age, inclusive]) with MDD and particularly in
those with MDD with moderate-to-severe anhedonia (ANH+), who have had an inadequate response to
standard-of-care antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI)/serotonin-
norepinephrine reuptake inhibitor (SNRI). The change in the MADRS total score from baseline (ie, Day 1,
pre-randomization, and hereafter referred to as 'baseline') to Day 43 (ie, at the end of the Double-blind [DB]
Treatment Phase) in participants with MDD ANH+, as assessed using the Structured Interview Guide for
the MADRS [SIGMA]), will be utilized for primary assessment of efficacy.
BENEFIT-RISK ASSESSMENT
There is evidence to suggest that with its targeted mechanism of action the selective KOR antagonism may
result in improvement of symptoms of depression linked to impaired functioning in the reward circuitry
(like anhedonia and amotivation) and which are poorly addressed by the current standard-of-care
SSRIs/SNRIs. Presence and persistence of symptoms like elevated anhedonia predict poor outcome and
chronic course of the disease. Available data from nonclinical and clinical studies (Phase 1 and Phase 2
studies) with aticaprant support the scientific and clinical rationale for the use of selective KOR antagonists
in the treatment of depression with moderate-to-severe anhedonia. Data from the Phase 2 study
67953964MDD2001 showed greater reduction in overall depression severity on the MADRS in participants
with MDD treated with aticaprant added to ongoing antidepressant with inadequate response, compared
with those who continued their current antidepressant plus placebo. The magnitude of the overall
antidepressant efficacy was different when examined based on the presence and severity of anhedonia
defined using an established self-reported assessment (SHAPS) for severity of anhedonia. When treated
with aticaprant, participants with a high level of anhedonia at entry, showed greater improvement of overall
depressive symptoms compared with those with a low level of anhedonia. To date in clinical trials,
NCT05455684
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JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 26 January 2024
aticaprant was generally safe and well tolerated. Participants in this study will help in evaluating the use of
aticaprant in the treatment of MDD and specifically in MDD with moderate-to-severe anhedonia, and in
increasing our understanding of the disease indication. Thus, the knowledge gained from this study has the
potential to benefit many more patients suffering from MDD with moderate-to-severe anhedonia and offers
potential public health benefits.
Participants may also experience some benefit from the participation in a clinical study irrespective of
receiving study intervention, due to regular visits and assessments monitoring their overall health.
Study 67953964MDD3001 is the first Phase 3 study investigating the therapeutic efficacy of adjunctive
aticaprant therapy in patients with MDD with moderate-to-severe anhedonia who have had an inadequate
response to standard-of-care antidepressant treatment with an SSRI/SNRI. Therefore, the benefit-risk
profile of adjunctive aticaprant therapy in this patient population has not been fully established.
The currently available data and the aticaprant Investigator's Brochure (IB) support this clinical study that
investigates the efficacy, safety and tolerability of aticaprant as adjunctive therapy in adult (18 to 64 years,
inclusive) and elderly (65 to 73 years, inclusive) participants with MDD ANH+ who have had an inadequate
response to antidepressant therapy with a SSRI/SNRI in the current depressive episode.
The scientific and clinical evidence (clinical pharmacology data, receptor occupancy modeling, safety
database and efficacy data from Phase 2) supports 10 mg/day as a safe dose that would provide optimal
efficacy in adjunctive treatment, where the ultimate goal is to adequately manage the remaining symptoms
and undertreatment is not desirable. This short-term Phase 3 study will therefore assess a dosage of
10 mg/day for efficacy as part of the primary analysis.
Taking into account the measures taken to minimize risk to participants of this study, the potential risks
identified in association with aticaprant are justified by the anticipated benefits that may be afforded to
participants; this supports further clinical investigation of adjunctive treatment with aticaprant for MDD in
patients with moderate-to-severe anhedonia.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of aticaprant 
10 mg compared with placebo as 
adjunctive 
therapy 
to 
an 
antidepressant 
in 
improving 
depressive 
symptoms 
in  adult
participants 
with 
MDD 
with
moderate-to-severe 
anhedonia
(ANH+) who have had an inadequate
response to current antidepressant
therapy with an SSRI or SNRI.
Change from baseline (ie, Day 1 pre-randomization,
and hereafter referred to as ‘baseline’) to Day 43 in the
Montgomery-Åsberg Depression 
Rating 
Scale
(MADRS) total score.
Key Secondary
To evaluate the efficacy of adjunctive
aticaprant 10 mg compared with
placebo in improving anhedonia in
adult participants with MDD ANH+
who have had an inadequate response
to current antidepressant therapy with
an SSRI or SNRI.
Change from baseline to Day 43 in Dimensional
Anhedonia Rating Scale (DARS) total score.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 26 January 2024
Objectives 
Endpoints
Other Secondary
To evaluate the efficacy of aticaprant 10 mg compared with placebo as adjunctive therapy to an
antidepressant in adult participants with MDD ANH+ who have had an inadequate response to the
current antidepressant therapy (SSRI or SNRI) on the following:
Depressive 
symptoms 
(clinician- 
reported) 
Change from baseline over time in the MADRS total
score.
Response of depressive symptoms 
(clinician-reported) 
Proportion of responders on depressive symptoms
scale, defined as a ≥50% improvement in MADRS
total score from baseline to Day 43.
Remission of depressive symptoms 
(clinician-reported) 
Proportion of participants with remission  of
depressive symptoms, defined as a MADRS total
score ≤10 at Day 43.
Symptoms of depression (patient- 
reported) 
Change from baseline to Day 43 in Patient Health
Questionnaire, 9-Item (PHQ-9) total score.
Anhedonia 
symptoms 
(patient- 
reported)
Change from baseline over time in DARS total score.
Change from baseline over time in the PHQ-9
anhedonia-specific item (PHQ-9, item 1).
Proportion of participants with a score less than 2 in
the PHQ-9 anhedonia-specific item (PHQ-9, item1)at
Day 43.
Social functioning (patient-reported) 
Change from baseline over time in the Patient-
Reported 
Outcomes 
Measurement 
Information
System (PROMIS) Short Form v2.0 - Ability to
Participate in Social Roles and Activities - 8a
(PROMIS-APS 8a).
Work Functioning and Productivity  
(patient-reported) 
Change from baseline over time in the Work
Productivity and Activity Impairment: Depression
(WPAI:D).
Safety
All participants - Safety will be assessed for all MDD participants (adult and elderly).
To assess the safety and tolerability of 
aticaprant 
10 mg 
as 
adjunctive 
therapy to an antidepressant (SSRI or
SNRI) in all MDD participants (adult
and elderly) in short-term treatment 
compared with placebo.
Adverse events (AEs), including AEs of special
interest (AESI).
Vital signs.
12-lead ECG.
Laboratory parameters.
Weight/Body Mass Index (BMI).
Suicidality assessment using the C-SSRS.
Cognitive assessments (Revere.D) in English-
speaking countries/territories.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 26 January 2024
Objectives 
Endpoints
Proportion of participants with clinically relevant
sexual dysfunction  over time in the Arizona Sexual
Experiences Scale (ASEX) score.
Clinical Pharmacology Assessments
To assess the pharmacokinetics (PK)of aticaprant (10 mg) in participants with MDD when used as
adjunctive treatment.
To assess the exposure-response relationship of aticaprant and MADRS in participants with MDD.
To assess the exposure-response relationship of aticaprant and selected AEs.
Hypothesis
The hypothesis for this study is that adjunctive treatment with aticaprant 10 mg is superior to placebo in
treating depressive symptoms, as measured by change in MADRS total score from baseline to Day 43 in
adult participants with MDD ANH+ who have had an inadequate response to treatment with an SSRI/SNRI.
OVERALL DESIGN
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to assess the
efficacy, safety and tolerability of adjunctive aticaprant 10 mg in adult participants (18 to 64 years of age,
inclusive) who have MDD with moderate-to-severe anhedonia (MDD ANH+), adult participants who do
not have moderate-to-severe anhedonia (MDD ANH-), and elderly participants (65 to 74 years of age,
inclusive) with MDD (ANH+ and ANH-). All participants must have had an inadequate response to an
SSRI/SNRI in the current depressive episode.
In addition, PK, pharmacogenomics, and biomarkers will also be evaluated.
This study will consist of the following phases:
Screening Phase (evaluate eligibility): up to 30 days prior to first dose administration.
Double-blind (DB) Treatment Phase: 43 days.
Follow-up Phase: up to 14 days.
Participants will be randomized in a 1:1 ratio to receive aticaprant 10 mg or placebo for 42 days. The study
intervention will be administered orally as 2 film-coated tablets to be taken together, once daily, around the
same time and preferably in the morning.
The study population will include participants who meet Diagnostic and Statistical Manual of Mental
Disorders-5th Edition (DSM-5) diagnostic criteria for recurrent or single episode MDD, without psychotic
features, based upon clinical assessment and confirmed by the Structured Clinical Interview for DSM-5
Axis I Disorders - Clinical Trials Version (SCID-CT). Participants 65 years of age or older must have had
the first onset of depression prior to 55 years of age. Eligible participants must have a 17-item Hamilton
Depression Rating Scale (HDRS-17) total score ≥20 at the first and second screening interviews with no
greater than 20% improvement from the first to the second independent HDRS-17 assessments at screening.
Moreover, all participants must have had an inadequate response to at least 1 oral antidepressant treatment
(SSRI or SNRI), administered at an adequate dose (at or above the minimum therapeutic dose per MGH
ATRQ) and duration (at least 6 weeks) in the current depressive episode. An inadequate response is defined
as <50% reduction in depressive symptom severity but with some improvement (>0%) (ie, there may be
minimal to moderate symptomatic improvement since the initiation of treatment, but some of the initial
symptoms are still present, troubling to the participant and affecting behavior and function) as assessed by
the MGH ATRQ. The inadequate response must include the participant’s current SSRI/SNRI treatment. A
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 26 January 2024
Site Independent Qualification Assessment will assess the validity of the participants’ diagnosis and
antidepressant treatment response for inclusion in the study.
All participants will continue their current SSRI/SNRI antidepressant at the same dose without change and
taken approximately around the same time of the day as prior to entering the Screening and DB Treatment
Phase.
Participants are considered to have completed the DB Treatment Phase of the study if they have completed
the Day 43 visit of the DB Treatment Phase (Visit 2.7), including the MADRS assessment at the end of the
6-week DB Treatment Phase (ie, Day 43 MADRS), and have not discontinued study intervention early
during the DB Treatment Phase.
Participants who have completed the DB Treatment Phase (Day 43) and were compliant to the study
intervention may  be eligible to participate in a separate 52-week open-label long-term safety study
67953964MDD3003. The investigator and the participant will determine, based on efficacy and tolerability
of the DB  treatment, whether it is in the best interest of the participant to continue treatment in the
open-label long-term safety study. The decision to enroll in the 67953964MDD3003 study or enter the
Follow-up Phase will be documented in the electronic case report form (eCRF). Participants who complete
the DB Treatment Phase, are eligible and decide to roll-over to the open-label long-term safety study are
not expected to complete the Follow-up Phase.
Participants who complete the DB Treatment Phase will be considered to have completed the study if they
roll over to Study 67953964MDD3003 or complete the Follow-up Visit, including the MADRS and DARS
assessments at this visit. If a participant enters the open-label safety study, the Follow-up Visit (Visit 3.1)
will not be conducted.
Participants who discontinue study intervention in DB Treatment Phase will be considered to have
completed the study if they completed the Follow-up Phase (Visit 3.1), including the MADRS and DARS
assessments at this visit.
Participants who discontinue study intervention early (ie, prior to completion of Day 43 visit) or who are
non-compliant to the study intervention (ie, have missed either 4 or more consecutive doses of study
intervention or a total of 8 or more doses during the DB Treatment Phase), will not be eligible to participate
in the open-label safety study.
Participants who discontinue study intervention during the DB Treatment Phase and participants who
completed the DB Treatment Phase who are not rolling over to the open-label long-term safety study
(67953964MDD3003) will complete the End-of-Treatment (EOT)/Early Withdrawal (EW) visit and will
then enter the Follow-up Phase of the study.
No study intervention will be administered during the Follow-up Phase; further clinical/standard-of-care
for the treatment of depression will be arranged by the study investigator and/or participant's treating
physician, and changes to current antidepressant treatment are permitted in this study phase.
The worldwide COVID-19 pandemic may impact the conduct of clinical studies due to the challenges from
quarantines, site closures, travel limitations, and other considerations if site personnel or study participants
become potentially exposed to or infected with COVID-19. To assure the safety of study participants,
maintain compliance with Good Clinical Practice (GCP), and minimize risks to study integrity, if necessary,
in consultation with the sponsor, the method of assessments may be changed (eg, paper assessments
replaced by electronic assessments and vice versa). In addition, site visits may be replaced with telephone,
internet-based videoconferencing applications, or home visits by qualified health care professionals (HCP).
Rating scales/safety assessments can continue to be administered via video teleconferencing (MADRS) or
phone (other assessments). Every effort should be made to complete the MADRS assessment via video
teleconferencing and within the scheduled timeframe; if this cannot occur, the sponsor medical monitor or
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 26 January 2024
delegate should be contacted for direction. Normal procedures, as detailed in this protocol, will be resumed
as soon as possible thereafter. For participants who receive an approved or authorized vaccine, it is
recommended that this occurs at least 5 days prior to the start of dosing, or once randomized at least 5 days
prior to the next scheduled visit.
An Independent Data Monitoring Committee (IDMC) will be commissioned to periodically review safety
data for this study.
NUMBER OF PARTICIPANTS
Approximately 538 participantsa, including adult (18 to 64 years of age, inclusive) and elderly (65 to
74 years of age, inclusive) will be enrolled in this study. This includes approximately 324 adult participants
with MDD ANH+, 106 adult participants with MDD ANH-, and 108 elderly participants (with
MDD ANH+/MDD ANH-) that will be enrolled in this study.
Criteria defining MDD ANH+ and MDD ANH- subgroups are blinded to the sites and provided in an
addendum to the study protocol.
INTERVENTION GROUPS AND DURATION
The assigned study intervention (aticaprant 10 mg or placebo) will be self-administered by the participant
at home once daily, around the same time and preferably in the morning during the DB Treatment Phase.
When participants visit the site, study intervention should be taken at the site and witnessed by the
investigator or a properly trained designee. The maximum duration of participation in the study for an
individual participant (including Screening, DB Treatment and Follow-up phases) will be up to 87 days (up
to 30 days for Screening, 43 days for the DB Treatment Phase, and up to 14 days for the Follow-up Phase).
EFFICACY EVALUATIONS
The efficacy of the study intervention will be evaluated using the MADRS  (SIGMA), Snaith-Hamilton
Pleasure Scale (SHAPS), Dimensional Anhedonia Rating Scale (DARS), Clinical Global Impression-
Severity (CGI-S) (depression), PHQ-9, Patient Global Impression of Severity (PGI-S) (depression), PGI-S
(anhedonia), Patient Global Impression of Change (PGI-C) (anhedonia), Quality of Life in Depression Scale
(QLDS), PROMIS Short Form v2.0 - Ability to Participate in Social Roles and Activities - 8a
(PROMIS-APS 8a), Generalized Anxiety Disorder 7-item Scale (GAD-7), Work Productivity and Activity
Impairment (WPAI:D) (depression), Treatment Satisfaction Questionnaire for Medication (TSQM-9) and
European Quality of Life, 5 Dimension, 5-Level questionnaire (EQ-5D-5L).
PHARMACOKINETIC EVALUATIONS
Sparse blood samples will be collected for measurement of plasma concentrations of aticaprant and any
relevant metabolite(s), if warranted, as indicated in the SoA.
SAFETY EVALUATIONS
Safety evaluations during the DB  Treatment Phase will include collection of AEs and concomitant
medications, as well as assessment with physical examination including a brief neurologic examination,
body weight, BMI, vital signs, 12-lead ECG, urine drug test, alcohol breath test, and clinical laboratory
a 
The study may enroll more than approximately 538 participants to ensure that 324 adult participants with MDD
ANH+ are enrolled. Once the required number of 324 adult participants with MDD ANH+ are enrolled,
recruitment of adult MDD ANH- and/or elderly participants may stop if it takes considerably longer to achieve the
planned number of participants.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 26 January 2024
tests (hematology, serum chemistry panel, lipid panel, hemoglobin A1c [HbA1c], thyroid-stimulating
hormone [TSH], free thyroxine [FT4], and urinalysis). Serum or urine pregnancy tests will be performed
for female participants of childbearing potential. Additional serum and urine pregnancy tests and drug and
alcohol tests may be conducted as needed per the investigator’s judgment. Menstrual cycles will be tracked
during the study in female participants who are still having their menses, using a participant diary and
participant’s verbal report. In addition, emergence of suicidal ideation will be assessed using the Columbia
Suicide Severity Rating Scale (C-SSRS) and sexual functioning will be assessed using the Arizona Sexual
Experiences Scale (ASEX). Cognitive function will be assessed using the self-administered Revere.D
computerized cognitive test battery in English-speaking countries/territories).
STATISTICAL METHODS
Sample Size Calculation
Approximately 538 participants, including adults and elderly will be enrolled in this study.
Participants entering the DB Treatment Phase will be randomized in a 1:1 ratio to receive adjunctive
aticaprant 10 mg or adjunctive placebo. Across the 2 treatment groups, a minimum of 324 adult participants
with MDD ANH+ and approximately 106 adult participants with MDD ANH- will be enrolled. Assuming
an effect size of 0.4 for the change in MADRS total score, and a 1-sided significance level of 0.025
(equivalently, 2-sided 0.05), this sample size of 324 adult participants with MDD ANH+ will provide
approximately 90% power for the comparison between aticaprant 10 mg and placebo for the primary
efficacy endpoint (in adult participants with MDD ANH+), accounting for a dropout rate of approximately
15%.
The effect size used in the sample size calculation was based on the results of Study 67953964MDD2001
where the effect size was 0.45 (mean difference between treatment groups of -4.1 and a pooled standard
deviation of 8.98) for the change from baseline to Day 43 in MADRS total score for the relevant study
population, and clinical judgment. Given that 67953964MDD2001 was a Phase 2 study, the sample size for
the primary efficacy analysis for this Phase 3 study was determined using a smaller effect size of 0.4 to
allow for greater variability that can be expected for a global study that is larger in scope.
It is expected that approximately 108 elderly participants (65 years to 74 years of age, inclusive) will be
enrolled in the study. This subset of participants will be analyzed as an exploratory evaluation and will not
be included in the primary analysis set.
Efficacy Analyses
The primary analysis set is the full analysis set (FAS_ANH+) which is defined as all randomized adult
participants with MDD ANH+ who take at least 1 dose of study intervention.
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline in MADRS total score at Day 43 in the
FAS_ANH+ analysis set.
Primary Estimand: This estimand is defined to address the primary objective when the study intervention
is taken as directed. This estimand has the following components:
Study Intervention:
Experimental: Aticaprant 10 mg as an adjunctive treatment to SSRI or SNRI
Control: Placebo as an adjunctive treatment to SSRI or SNRI
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 26 January 2024
Population: Adult participants (18 to 64 years of age, inclusive) with MDD ANH+ who have had an
inadequate response to current antidepressant therapy with an SSRI/SNRI, as reflected by the
inclusion/exclusion criteria.
Endpoint: Change in MADRS total score from baseline to Day 43.
Intercurrent events: The following intercurrent events will be managed using a hypothetical strategy (ie, as
if the intercurrent event did not occur):
Discontinuation of study intervention only,
Discontinuation of both study intervention and current antidepressant,
Switch of study intervention only(ie, initiation of another antidepressant after discontinuation of study
intervention),
Switch of current antidepressant therapy only,
Switch of study intervention and current antidepressant therapy.
Summary measure: difference in treatment means.
Primary analysis: Change from baseline in MADRS total score will be analyzed by a Mixed-Effect Model
for Repeated Measures (MMRM) based on observed case. The fixed terms included in the model will be
intervention group (aticaprant 10 mg and placebo), country/territory, time, and time-by intervention
interaction, and the baseline MADRS total score as a covariate. The within-subject covariance between
visits will be estimated via an unstructured variance-covariance matrix. In case of convergence problems,
alternative variance-covariance structures will be tried in the following order, with the first structure that
converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate
subjectrandom effect. The Kenward-Roger method will be used for approximating the denominator degrees
of freedom. Comparison between aticaprant 10 mg and placebo at Day 43 will be performed using the
appropriate contrast. Difference in least square means and 2-sided 95% confidence intervals (CI) will be
presented.
Sensitivity analysis: Delta adjustment tipping point will be conducted as a sensitivity analysis.
Any supplementary estimands that are identified will be described in the statistical analysis plan (SAP).
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the change from baseline to Day 43 in DARS total score in
participants belonging to FAS_ANH+.
The same estimand as described above (except the endpoint) and corresponding analyses as for the primary
endpoint will be used for the key secondary endpoint.
Testing Procedure for Primary and Key Secondary Endpoints
A fixed sequence testing procedure will be applied to control the family-wise error rate (FWER) at 2-sided
0.05 level accounting for multiplicity due to the primary (MADRS total score) and the key secondary
efficacy endpoint (DARS total score). The testing procedure will first test the primary endpoint at 2-sided
0.05 level. If the hypothesis corresponding to the primary endpoint is rejected, then the key secondary
endpoint will be tested at 2-sided 0.05 level; if the hypothesis corresponding to the primary endpoint is not
rejected, then the testing procedure will stop.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date: 26 January 2024
Safety Analyses
Safety analyses will be based on the safety analysis set, which consists of all randomized participants (adults
and elderly) who take at least 1 dose of study intervention.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported
treatment-emergent AEs, ie, AEs with onset during the DB Treatment Phase, or AEs that are a consequence
of a pre-existing condition that has worsened since baseline, will be included in the analysis. For each
treatment-emergent AE, and AESI, the percentage of participants who experience at least 1 occurrence of
the given event will be summarized by study intervention. Serious adverse events will be summarized
separately.
The effects on ECG measurements (heart rate, PR interval, QT interval, and QTc interval) will be evaluated
using descriptive statistics and frequency tabulations. QTc intervals will be calculated using the Bazett and
Fridericia correction methods, and descriptive statistics of QTc intervals and changes from baseline will be
summarized at each scheduled time point. The percentage of participants with QTc interval higher than pre-
specified levels will be summarized, as will the percentage of participants with QTc interval increases from
baseline >30 milliseconds or >60 milliseconds.
Laboratory data will be summarized by type of laboratory test and study intervention. Descriptive statistics
will be calculated for each laboratory analyte at baseline and for observed values and changes from baseline
at each scheduled time point. The proportion of participants with markedly abnormal results will be
presented for each analyte and study intervention group.
Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), body temperature for observed
values will be provided and changes from baseline, will be summarized at each scheduled time point by
study intervention group. Changes in body weight and BMI will be summarized descriptively.
Results from the ASEX, C-SSRS, and cognitive function assessment will be tabulated by study intervention
group.
Interim Analysis
A blinded interim analysis will be performed to evaluate the measurement properties of the DARS, and to
determine meaningful change threshold (MCT) (or range of thresholds) in the DARS total score using
anchor-based approaches along with distribution-based analyses. The interim analysis will be conducted
when approximately 200 adult MDD participants, regardless of anhedonia status, have completed the DB
Treatment Phase of the study. Details of the analysis will be described in a separate analysis plan.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 26 January 2024
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
Approximately 538 participants (430 adult and 108 elderly) will be enrolled. The adult MDD ANH+ population randomized to
aticaprant 10 mg or placebo will be included in the primary and key secondary analysis.
All participants will continue to take their current SSRI or SNRI antidepressant therapy (at the same dose and at approximately the
same time of the day) throughout the study.
Abbreviations: SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date: 26 January 2024
Generalized Anxiety Disorder 7-item Scale; HbA1c test = glycated hemoglobin test; HDRS-17 = 17-item Hamilton Depression Rating Scale; MADRS =
Montgomery-Åsberg Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; MMSE = Mini
Mental State Examination; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PHQ-9 = Patient Health Questionnaire, 9-
item; PRO = Patient-Reported Outcomes; PROMIS-APS 8a = Patient-Reported Outcomes Measurement Information System Short Form v2.0 - Ability to Participate
in Social Roles and Activities - 8a; QLDS = Quality of Life in Depression Scale; RC = Remote Contact; RLT = Reward Learning Task; SCID-CT = Structured
Clinical Interview for DSM-5 Axis I Disorders-Clinical Trials version; SHAPS = Snaith-Hamilton Pleasure Scale; SIQA = Site Independent Qualification
Assessment; TSH = thyroid-stimulating hormone; TSQM-9: Treatment Satisfaction Questionnaire for Medication; USA = United States of America; WPAI:D: Work
Productivity And Impairment: Depression.
Note:
On Clinic (C) Visit days, time 0 is defined as the time of the study intervention intake. Therefore, post-dose time points are referenced from this.
During the site visits, when blood and urine is collected in a fasted condition, it is recommended that procedures should be performed in the following sequence:
Blood and urine collection (when in fasted condition), dosing, breakfast, PRO, interview with site-based rater (MADRS [SIGMA version] via videoconference, if
not completed before the actual visit; CGI-S), C-SSRS, and safety assessments. Blood collections for PK and PD assessments should be kept as close to the specified
time as possible. Of note, at Visit 2.1 (Day 1), PROs, MADRS, CGI-S, and C-SSRS must be completed prior to randomization and dosing.
Footnotes:
a. 
All screening assessments performed at Visits 1.1 and 1.2 may be conducted on days differing from the actual dates of Visits 1.1 and 1.2. All screening
assessments must be performed early enough in order to obtain the results and confirm the eligibility prior to randomization.
b. 
An optional period is foreseen in the duration of the Screening Phase to taper and discontinue prohibited therapies before baseline. Tapering and discontinuation of
therapies should be based on the local prescribing information or clinical judgment of the therapy by the investigator or treating physician. Tapering and
discontinuation of prohibited therapies should be initiated after completion of the second HDRS-17 (Visit 1.2) assessment and the SIQA and confirmation these
were passed. Participants who do not require a taper and are thus eligible to immediately proceed to the DB Treatment Phase can have their Baseline (ie, Visit 2.1)
on the next day following Visit 1.2 provided eligibility is confirmed.
c. 
If a participant prematurely discontinues from study intervention before the end of the DB Treatment Phase (ie, before completing Visit 2.7) for reasons other than
withdrawal of consent, an EOT/EW visit (ie, Visit 2.7) should be conducted preferably the day after the last dose of study intervention, followed by the Follow-up
Phase. If Visit 2.7 is conducted on the same day as a scheduled visit, duplicate assessments are not required.
d. 
The ICF must be signed before the first study-related activity. Rescreened participants will be assigned new participant numbers, will need to sign a new ICF and
restart a new Screening Phase.
e. 
An optional Participant Experience Interview may be offered in the Czech Republic, Spain, and the USA. Consent may occur anytime during the DB Treatment
Phase, but no later than Visit 2.7, following the first dose of study intervention and the collection of PRO assessments for the visit. Consent should occur prior to
the interview.
f. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Source Documentation in Section 10.3. Verify
inclusion/exclusion criteria before randomization of each participant.
g. 
HDRS-17 will be performed by independent remote raters via telephone. The first remote interview will be scheduled as soon as possible after Visit 1.1 and to
occur within the first week of the Screening Phase. The second interview should occur at least 1 week (7 days) after the first interview.
h. 
Two different versions of the MGH ATRQ scale will be used based on age (for participants 18 to 64 years of age, inclusive and for participants 65 to 74 years of
age, inclusive).
i. 
The MMSE screening assessment is to be performed only in participants of 65 to 74 years of age, inclusive.
j. 
Applicable to female participants of childbearing potential.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 January 2024
k. 
The first administration of study intervention on Day 1 (Visit 2.1) will occur on-site. At home: study intervention should be taken around the same time and
preferably in the morning. At all subsequent clinic visits: study intervention will be administered on-site using dose from the blisters dispensed at that visit and
self-administration should be witnessed by the responsible site staff personnel. The exact date and time when the study intervention is administered on-site and the
time of the dose on the previous day is required for all visits with PK sampling.
l. 
Dispense the study intervention diary at Visit 2.1 and review it at all clinical visits (C).
m. All PRO assessments should be conducted in the order listed in the above SoA table. The following PRO assessments will be collected electronically in a 1- to
2-day window prior to the clinic visit: PROMIS-APS 8a, GAD-7, EQ-5D-5L, QLDS, WPAI:D, and TSQM-9. If a participant does not complete the PRO
assessments ahead of the clinic visit, the PROs will be collected at the clinic visit.
n. 
For participants that require translation of the PROMIS-APS 8a into their local language, the collection of the PROMIS-APS 8a is optional until the final,
approved translation is available.
o. 
At Visits 2.1 (Study Day 1) and 2.5 (Study Day 29), 12-lead ECG will be performed pre-dose and post-dose (ie, 1 to 4 hours after dosing). At Visit 2.7 (EOT/EW),
a 12-lead ECG will be performed. During Screening or at Visit 2.1 (Day 1), if QTcF is prolonged based on site evaluated ECG, a total of three 12-lead ECGs
should be obtained at least 4 minutes apart. The average QTcF of the three 12-lead ECGs will then be used to determine participant’s eligibility. During DB
Treatment Phase, if a clinically significant finding is identified in QTcF, the average QTcF of three 12-lead ECGs, recorded 4 minutes apart, will be used to assess
QTc stopping criteria.
p. 
The cognitive battery tests will only be performed in English-speaking countries/territories.
q. 
During the screening phase, compliance to the current antidepressant treatment must be confirmed by documented records (eg, medical/pharmacy/prescription
record, a letter from a treating physician, etc). During the DB Treatment Phase, the compliance to the SSRI or SNRI (the one that is continued in this phase) will be
assessed by documented records (medical/pharmacy/prescription records, pill counts etc). In absence of other options to assess compliance, blood or urine levels
can be used by the site to evaluate the adherence to the antidepressant treatment.
r. 
If blood sampling or vital sign measurement is scheduled for the same time point as 12-lead ECG recording, the procedures are recommended to be performed in
the following order: 12-lead ECG, vital signs, blood draw.
s. 
At Visits 2.1 (Study Day 1) and 2.5 (Study Day 29), PK samples will be collected from all participants pre-dose and at around peak (1 to 4 hours after dosing). At
Visit 2.3 (Study Day 15), only a pre-dose PK sample will be collected. At Visit 2.7 (EOT/EW), a PK sample will be collected. In addition, an optional unscheduled
blood sample may be collected throughout the DB Treatment Phase visits for determination of plasma concentrations of aticaprant in participants who discontinue
study intervention for an AESI or SAE which is related to AESI. This blood sample should be collected as close as to the AESI or AESI-related SAE occurrence,
but preferably within 72 hours of the last study intervention administration. This sample is not collected in case of discontinuation due to AE, but only for AESI or
AESI-related SAE.
t. 
Biomarker samples will be collected under fasting conditions and prior to study intervention administration.
u. 
Only applicable to female participants with a menstrual cycle.
v. 
Blood samples will be collected only from participants who have consented to provide optional DNA and RNA samples for research. Samples will be collected at
the same time as the protein blood biomarker samples.
w. For RNA, an optional second sample may be collected at the end of the DB Treatment Phase (Visit 2.7).
x. 
The Passive Behavior Sensing assessments performed using smartphone applications are optional and will only be performed on a subset of participants with a
dedicated personal smartphone. Besides setting up and closing the study, the smartphone application data collection will run continuously in the background once
set up is established at screening for participants who have opted for this.
y. 
The RLT will only be performed in English-speaking countries/territories.
z. 
Study procedure or assessment must be performed before randomization.
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2. 
INTRODUCTION
An increased understanding of the neurobiology of mood disorders allows for targeted research
and focus on specific brain circuits implicated in mood. This provides an opportunity for
developing improved treatments of mood disorders which are informed by the underlying
neurobiology (Machado-Vieira 2011). Existing evidence implicates the dynorphin opioid
neuropeptide system (Chavkin 1982) in the regulation of mood (Chartoff 2009; Pecina 2019;
Schwarzer 2009; Shirayama 2004). Kappa opioid receptor (KOR) activation by the endogenous
dynorphin induces stress and depressive symptoms in humans and animals (Bruchas 2010;
Escobar 2020) and downstream results in decreased dopaminergic function in different brain areas
(Margolis 2006; Tejeda 2017). It is hypothesized that selective modulation of the KOR would
result in improvement of residual symptoms of depression, including behaviors involving
anhedonia, by restoring normal dopamine transmission in the brain’s reward/motivation circuitry
(Carlezon 2009b; Carlezon 2016; Krystal 2020; Rorick-Kehn 2014). Preclinical evidence supports
the therapeutic potential of KOR antagonism for the treatment of anhedonia, depression, and
anxiety (Beardsley 2005; Carr 2010; Lutz 2014; Mague 2003; Rorick-Kehn 2014; Walker 2008).
Based on an emerging body of scientific evidence, selective KOR antagonism may provide
therapeutic benefit in the treatment of major depressive disorder (MDD).
Aticaprant (JNJ-67953964) is a once daily, highly selective KOR antagonist, with demonstrated
selectivity over mu opioid receptor (MOR) and delta opioid receptor (DOR) (Carlezon 2009a;
Naganawa 2016), that is being developed for adjunctive treatment of MDD  in patients with
moderate-to-severe anhedonia (MDD ANH+).
Aticaprant has shown antidepressant-like effects in preclinical studies and had synergistic effects
when administered with a subactive dose of imipramine. Clinical data from multiple Phase 1 and
results from 2 well-controlled Phase 2 studies provide complimentary positive evidence for
efficacy of aticaprant in patients with major depression with anhedonia (Krystal 2020). Study
67953964MDD2001 provides proof of efficacy showing that after 6 weeks of treatment, MDD
participants randomized to aticaprant added to ongoing antidepressant achieved statistically
significant and clinically meaningful reduction in overall depression severity on the
Montgomery-Åsberg Depression Rating Scale (MADRS, primary endpoint) compared with those
who continued on the current antidepressant plus placebo. Furthermore, MDD participants with a
high level of anhedonia at entry (measured by higher total Snaith-Hamilton Pleasure Scale
[SHAPS] score) when treated with 10 mg/day aticaprant added to a selective serotonin reuptake
inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI)showed greater improvement
in overall depression severity. The clinical outcomes in Study 67953964MDD2001 are
complemented by the results from an investigator-initiated study (IIS) FAST-MAS, which showed
that KOR antagonism by aticaprant has a coherent effect on measures of anhedonia across units of
analysis on brain activity, behavior, and self-report, thereby establishing proof of mechanism that
by blocking the KOR, aticaprant can modulate neuronal circuits relevant to reward and hedonic
response. Overall, aticaprant has been safe and well tolerated in patients.
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For the most comprehensive nonclinical and clinical information regarding aticaprant, refer to the
latest version of the Investigator's Brochure (IB)and Addenda.
The term “study intervention” throughout the protocol, refers to study intervention as defined in
Section 6.1.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
Depression is a common and serious psychiatric disorder affecting approximately 280 million
individuals worldwide (according to the World Health Organization [WHO] Fact Sheet 2021
[WHO 2021]). Depression is a leading cause of disability worldwide and is associated with
elevated mortality and suicide risk (WHO 2021; Walker 2015). A noticeable increase in the global
burden of depressive disorders has been observed due to the COVID-19 pandemic with an
estimated additional 53.2 million cases of MDD globally (COVID-19 Mental Disorders
Collaborators 2021; Ettman 2020).
An inadequate response to first-line standard-of-care antidepressant treatment for MDD remains a
significant problem resulting in persistent impairment and high utilization of health care resources
(Kennedy 2004). While switching antidepressants and using adjunctive treatments may improve
response, almost 40% of patients remain symptomatic and fail to achieve full remission  (Rush
2006). Symptoms such as loss of interest/pleasure (anhedonia), insomnia, and fatigue have been
reported to persist in patients treated with current antidepressants (Spijker 2001; Taylor 2010;
Wardenaar 2012).
Persistence of anhedonia has been linked to poorer outcomes in patients with MDD and has been
associated with increased overall severity ofdepressive symptoms (Gong 2017); a chronic course
of depression over a 10-year period (Moos 1999); longer time to remission (McMakin 2012;
Spijker 2001; Uher 2012) and functional and quality-of-life impairment (McMakin 2012;
Vrieze 2013). MDD patients with anhedonia have higher incidence of acute cardiac events and
mortality (Davidson 2010).
Opioid receptors are widely found throughout the central nervous system and are believed to be
involved in several important functions. Three distinct subtypes of opioid receptors have been
identified and characterized: mu (MOR), delta (DOR) and kappa (KOR). The KORs and the
endogenous ligand dynorphin are highly expressed within the prefrontal cortico-striatal loop,
which mediates reward and affective states (Carlezon 2009b; Naganawa 2014; Naganawa 2016).
As such the kappa opioid system is one of the most preponderant systems controlling dopamine
transmission  in the reward/motivation circuit. Emerging evidence has implicated the role of
overactivation of the KOR system in regulation of mood symptoms (Gray 1999), especially
anhedonia (Williams 2018). Selective blockade of the KOR by KOR antagonists like aticaprant
has shown to modulate neuronal circuits relevant to reward and hedonic response (Krystal 2020;
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Pizzagalli 2020) and by  restoring the dopamine release homeostasis leads to improvement in
depressive symptoms (Carlezon 2009a; Krystal 2020).
The therapeutic mechanism of action (Carlezon 2016; Urbano 2014) and evidence gathered so far
support considerations for added benefit to the standard-of-care SSRI/SNRI in improving
depressive symptoms based on the underlying neurobiology ie, by modulation of neuronal circuits
relevant to reward and hedonic capacity and restoring dopamine release homeostasis.
The proposed study is a randomized, double-blind, placebo-controlled, 6-week study to assess the
efficacy, safety, and tolerability of aticaprant as adjunctive therapy to SSRI/SNRI in adult (18 to
64 years, inclusive) participants with MDD ANH+ who have had an inadequate response to an
SSRI/SNRI in the current depressive episode.
2.2. 
Background
Nonclinical Studies
Nonclinical Pharmacology
Kappa Opioid Receptor Studies: Aticaprant (JNJ-67953964) is a potent, high-affinity antagonist
(inhibition constant [Ki]=0.807 nM) for KORs, with demonstrated selectivity over MORs and
DORs, as assessed by in vitro binding and functional assays. In vivo, aticaprant produced a dose-
dependent increase in KOR occupancy in both rat and mouse, with a calculated dose that produces
50% of maximum effect (ED50) of 
 mg/kg in the rat and 90% occupancy at 
 mg/kg in both
species. At pharmacologic doses, aticaprant showed no appreciable occupancy at MORs and
DORs, but dose-dependent pharmacodynamic effects were observed at supratherapeutic doses. In
various pharmacology assays, including reversal of kappa- and mu-agonist-induced analgesia
effects and prepulse inhibition, aticaprant produced potent and selective blockade of kappa, but
not mu, agonist-mediated effects. 
Aticaprant (1 µM) has no appreciable affinity at several non-opioid cell surface receptor targets,
including monoaminergic, muscarinic, cholinergic, and adrenergic receptors, as well as the central
benzodiazepine binding site, ion channels, or transporters.
In vivo studies conducted in mice have demonstrated the therapeutic potential of the KOR
antagonist aticaprant in blocking signs of (i) spontaneous nicotine withdrawal and (ii) nicotine
withdrawal induced pharmacologically with the nicotine antagonist mecamylamine.
JNJ-67953964 also reduced high alcohol intake behavior in alcohol-preferring rats with a chronic
alcohol drinking history, without affecting food or water intake. Aticaprant showed
antidepressant-like effects in mice and had synergistic effects when administered with a subactive
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dose of imipramine. Antidepressant-like effects of aticaprant were demonstrated in the mouse
Forced Swim test. This is a validated animal model of clinical MDD that demonstrates predictive
validity for all known classes of effective antidepressants, with antidepressant-like activity
indicated by reductions in immobility. aticaprant reduced the time spent immobile in a dose-
dependent manner, with 
 mg/kg achieving efficacy comparable to that of the tricyclic
antidepressant imipramine (15 mg/kg intraperitoneal)(refer to the IB).
Aticaprant had no effect on dopamine release in the nucleus accumbens suggesting low potential
for abuse liability.
Safety Pharmacology
Aticaprant was evaluated in a variety of in vitro and in vivo models for effects on the
cardiovascular, respiratory and central nervous systems, and did not show any potential for adverse
effects. No noticeable changes in hemodynamic and electrocardiographic parameters (quantitative
and qualitative; rhythm/waveforms), and on body temperature up to
 mg/kg were observed.
No treatment-related effects on QT or QT intervals by Fridericia’s method (QTcF) intervals were
observed in repeat-dose toxicity studies in dogs up to 
 mg/kg/day. Aticaprant showed no
major effect on neurobehavioral functions in rats. Aticaprant does not disrupt motor functioning
of attentional processes. No relevant adverse effects on the rat central or peripheral nervous
systems up to 
mg/kg/day. Single doses of 
 mg/kg were associated with
calmer animals in their home cage between 1 hour and up to 24 hours after dosing (duration related
to dose). Aticaprant up to 
 mg/kg did not exert any noticeable effects on the respiratory rate,
tidal volume or minute volume in rats from 30 to 360 minutes (0.5 to 6 hours) after dosing (refer
to the IB).
Toxicology
The toxicity profile of aticaprant has been extensively evaluated and characterized in both in vitro
and in vivo single and repeat-dose, reproductive, genotoxicity, and safety pharmacology, studies
conducted in various species (rat, mouse, rabbit, dog, and monkey).
In nonclinical safety pharmacology studies with aticaprant in rats, there were no effects on the
central and peripheral nervous systems or the respiratory function up to 
mg/kg. In dogs, a
cardiovascular safety study of single doses up to 
 mg/kg, found no statistically significant
changes in blood pressure, heart rate, or QT and QTcF intervals. Repeat-dose studies of up to 3
and 9 months in rats and dogs, up to 2 weeks in mice, and up to 7 days in monkeys have been
completed. A single dose of 
mg/kg/day in mice, and repeated doses of 
 mg/kg/day in
rats, and 
 mg/kg/day in rabbits exceeded the maximum tolerated dose resulting in adverse
clinical signs, decreased food consumption and body weight, and mortality/euthanasia. Target
organs were the
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No effects on fertility or embryofetal development were observed up to 
 mg/kg/day in rabbits
and
 mg/kg/day or
 mg/kg/day in female and male rats, respectively.
 A 2-year
carcinogenicity study by oral (gavage) administration in rats is ongoing and a 6-month transgenic
mice study is planned.
In general, data from these studies demonstrated an adequate characterization of the toxicology
profile, showed dose dependency of the effects, and partial to full reversibility of all toxic effects.
Pharmacokinetic Profile in Animals
Aticaprant is orally bioavailable and brain penetrant. Aticaprant is 
 in human, dog, rat, and mouse. Metabolism is primarily through CYP
 and CYP
Based on the available in vitro data, the 
 The circulating metabolites of aticaprant are considered qualitatively
comparable between the species used in toxicology studies and humans, based on a (preliminary)
identification of circulating metabolites in human plasma.
Clinical Studies
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Efficacy Studies
A completed Phase 2a investigator-initiated study (IIS) (FAST-MAS) designed to determine
whether KOR antagonism could have effects supportive of therapeutic benefit for anhedonia in
patients with mood-anxiety spectrum disorders and anhedonia, revealed a significant Group×Time
interaction in reward gain anticipation (p=0.019) (a priori primary outcome) and loss anticipation
(p<0.001). In this study, participants with self-reported anhedonia (with a mood or anxiety
disorder) were administered monotherapy for a period of 8 weeks: 10-mg aticaprant (n=45) or
placebo (n=44). Treatment with aticaprant 10 mg given as a monotherapy, resulted in significantly
higher learning rate and a more sustained preference toward the more frequently rewarded
stimulus, although reward sensitivity was unaltered compared with placebo. A significant
reduction in the severity of anhedonia symptoms was seen on the SHAPS (p=0.0345) with a
significant treatment effect on the Temporal Experience of Pleasure Scale consummatory subscale
(p<0.02). The results of this study established that KOR antagonism by aticaprant had the
hypothesized effect, ie, a coherent effect on measures of anhedonia across units of analysis on
brain activity, behavior, and self-report, thereby establishing proof of concept that engaging this
target can modulate neuronal circuits relevant to reward and hedonic response (Krystal 2020;
Pizzagalli 2020).
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JNJ-67953964 Aticaprant
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2.3. 
Benefit-Risk Assessment
The theoretical and potential risks of exposure to aticaprant based on its mechanism of action are
summarized below. More detailed information about the known and expected benefits and risks of
aticaprant may be found in the IB.
2.3.1. 
Benefits for Study Participation
There is evidence to suggest that with  its targeted mechanism of action  the selective KOR
antagonism may result in improvement of symptoms of depression linked to impaired functioning
in the reward circuitry (like anhedonia and amotivation) (Borsini 2020) and which are poorly
addressed by the current standard-of-care SSRIs/SNRIs, (Calabrese 2014; Craske 2019;
Vrieze 2013). Presence and persistence of symptoms like elevated anhedonia predict poor outcome
and chronic course of the disease (Moos 1999; Spijker 2001; Uher 2012). Available data from
nonclinical and clinical studies (Phase 1 and Phase 2 studies) with aticaprant support the scientific
and clinical rationale for the use of selective KOR antagonists in the treatment of depression with
moderate-to-severe anhedonia. Data from the Phase 2 study 67953964MDD2001 showed greater
reduction in overall depression severity on the MADRS in participants with MDD treated with
aticaprant added to ongoing antidepressant with inadequate response, compared with those who
continued their current antidepressant plus placebo. The magnitude of the overall antidepressant
efficacy was different when examined based on the presence and severity of anhedonia defined
using an established self-reported assessment (SHAPS) for severity of anhedonia. When treated
with aticaprant, participants with a high level of anhedonia at entry, showed greater improvement
of overall depressive symptoms compared with those with a low level of anhedonia. In a post hoc
item-level analysis of the MADRS scale, the subgroup of participants with a high level of
anhedonia when treated with aticaprant showed overall better effect on symptoms of dysphoria
like apparent and reported sadness compared with participants with a low level of anhedonia, and
there was improvement in items that reflect the positive affect, namely the anhedonia-specific item
inability to feel, and several other items like pessimistic thoughts, lassitude and concentration
difficulties, which are related to the hedonic capacity as they reflect on individual’s interest,
engagement, motivation, and activity. Improvement in MADRS scores of symptoms of depression
(eg, sadness, tension, appetite, insomnia, and fatigue) were observed. Furthermore, aticaprant was
generally safe and well tolerated. Participants in this study will help in evaluating the use of
aticaprant in the treatment of MDD and specifically in MDD with moderate-to-severe anhedonia,
and in increasing our understanding of the disease indication. Thus, the knowledge gained from
this study has the potential to benefit many more patients suffering from MDD with moderate-to-
severe anhedonia and offers potential public health benefits.
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Participants may also experience some benefit from the participation in a clinical study irrespective
of receiving study intervention, due to regular visits and assessments monitoring their overall
health.
2.3.2. 
Benefit-Risk Assessment for Study Participation
Study 67953964MDD3001 is the first Phase 3 study investigating the therapeutic efficacy of
adjunctive aticaprant therapy in participants with MDD with moderate-to-severe anhedonia who
have had an inadequate response to standard-of-care antidepressant treatment with an SSRI/SNRI.
Therefore, the benefit-risk profile of adjunctive aticaprant therapy in this patient population has
not been fully established.
The currently available data (see Section 2.2), and the aticaprant IB support this clinical study that
investigates the efficacy, safety and tolerability of aticaprant as adjunctive therapy in adult (18 to
64 years, inclusive) and elderly (65 to 73 years, inclusive) participants with MDD ANH+ who
have had an inadequate response to antidepressant therapy with a SSRI/SNRI in the current
depressive episode.
Aticaprant was generally well tolerated in healthy participants after single-dose administration up
to 
 mg or after multiple-dose administration up to 35 mg for 14 days, with no clinically
significant AEs, vital sign measurements, 12-lead ECGs, or clinical laboratory evaluations
reported (see Section 2.2).
In this study, 10 mg/day given once daily will be evaluated. The 10 mg/day dose selection is based
on the results from the completed Phase 2a Studies FAST-MAS and Study 67953964MDD2001,
as well as PK/PD and RO modeling.
The expected exposure in Study 67953964MDD2001 after 10 mg aticaprant once daily is
predicted to result in a nearly complete inhibition of KORs at Cmax. Moreover, the median RO is
predicted to be
% and
% of the maximum RO at the trough and peak levels, respectively. This
relatively modest variation across the interdose interval is expected to achieve 
% kappa RO at
the 10 mg/day dose in most participants.
To date, clinical studies have only been conducted with aticaprant dose of 10 mg in younger adults
up to 65 years of age. The data from these studies did not yield safety and tolerability effects that
might be of concern for older adults (ie, no cardiovascular effects, metabolic effects, or sedation).
Considering the PK/PD and observed safety for aticaprant, it is expected that older adults (up to
74 years) may exhibit a similar tolerability and efficacy profile to younger adults.
The scientific and clinical evidence (clinical pharmacology data, receptor occupancy modeling,
safety database and efficacy data from Phase 2) supports 10 mg/day as a safe dose that would
provide optimal efficacy in adjunctive treatment, where the ultimate goal is to adequately manage
the remaining symptoms and undertreatment is not desirable. This short-term Phase 3 study will
therefore assess a dosage of 10 mg/day for efficacy as part of the primary analysis.
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Taking into account the measures taken to minimize risk to participants ofthis study, the potential
risks identified in association with aticaprant are justified by the anticipated benefits that may be
afforded to participants; this supports further clinical investigation of adjunctive treatment with
aticaprant for MDD in patients with moderate-to-severe anhedonia.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the efficacy of aticaprant 
10 mg compared with placebo as 
adjunctive 
therapy 
to 
an 
antidepressant 
in 
improving 
depressive 
symptoms 
in 
adult
participants 
with 
MDD 
with
moderate-to-severe 
anhedonia
(ANH+) who have had an inadequate
response to current antidepressant
therapy with an SSRI or SNRI.
Change from baseline (ie, Day 1 pre-randomization,
and hereafter referred to as 'baseline') to Day 43 in the
Montgomery-Åsberg 
Depression 
Rating 
Scale
(MADRS) total score.
Key Secondary
To evaluate the efficacy of adjunctive 
aticaprant 10 mg compared with 
placebo in improving anhedonia in
adult participants with MDD ANH+
who have had an inadequate response
to current antidepressant therapy with
an SSRI or SNRI.
Change from baseline to Day 43 in Dimensional
Anhedonia Rating Scale (DARS) total score.
Other Secondary
To evaluate the efficacy of aticaprant 10 mg compared with placebo as adjunctive therapy to an
antidepressant in adult participants with MDD ANH+ who have had an inadequate response to the
current antidepressant therapy (SSRI or SNRI) on the following:
Depressive 
symptoms 
(clinician- 
reported) 
Change from baseline over time in MADRS total
score.
Response of depressive symptoms 
(clinician-reported) 
Proportion of responders on depressive symptoms
scale, defined as a ≥50% improvement in MADRS
total score from baseline to Day 43.
Remission of depressive symptoms 
(clinician-reported) 
Proportion of participants with remission  of
depressive symptoms, defined as a MADRS total
score ≤10 at Day 43.
Symptoms of depression (patient- 
reported) 
Change from baseline to Day 43 in Patient Health
Questionnaire, 9-Item (PHQ-9) total score.
Anhedonia 
symptoms 
(patient- 
reported)
Change from baseline over time in DARS total score.
Change from baseline over time in the PHQ-9
anhedonia-specific item (PHQ-9, item 1).
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Objectives 
Endpoints
Proportion of participants with a score less than 2 in
the PHQ-9 anhedonia-specific item (PHQ-9, item 1)at
Day 43.
Social functioning (patient-reported) 
Change from baseline over time in the Patient-
Reported 
Outcomes 
Measurement 
Information
System (PROMIS) Short Form - Ability to Participate
in Social Roles and Activities - 8a (PROMIS-APS 8a).
Work Functioning and Productivity 
(patient-reported) 
Change from baseline over time in the Work
Productivity and Activity Impairment (WPAI:D).
Safety
All participants - Safety will be assessed for all MDD participants (adult and elderly).
To assess the safety and tolerability of 
aticaprant 
10 mg 
as 
adjunctive
therapy to an antidepressant (SSRI or
SNRI) in all MDD participants (adult 
and elderly) in short-term treatment
compared with placebo.
AEs, including AEs of special interest (AESI).
Vital signs.
12-lead ECG.
Laboratory parameters.
Weight/Body Mass Index (BMI).
Suicidality assessment using the C-SSRS.
Cognitive assessments (Revere.D) in English-
speaking countries/territories.
Proportion of participants with clinically relevant
sexual dysfunction  over time in the Arizona Sexual
Experiences Scale (ASEX) score.
Exploratory
To assess the efficacy of aticaprant 10 mg compared with placebo as adjunctive therapy to an
antidepressant (SSRI or SNRI) in adult participants with MDD ANH+, adult participants with MDD
ANH-, and all MDD participants (adult and elderly participants with MDD ANH+ and MDD ANH-)
who have had an inadequate response to their current antidepressant therapy on the following:
Depressive symptoms (clinician- and 
patient-reported) 
Change from baseline over time in the MADRS total
score (applicable to adult MDD ANH- and All MDD).
Change from baseline over time in the MADRS-6
score.
Change from baseline over time in PHQ-9 total score.
Anhedonia 
symptoms 
(patient- 
reported) 
Change from baseline over time in DARS total score
(applicable to adult MDD ANH- and All MDD).
Change from baseline over time in the subscales of the
DARS 
(hobbies/pastimes, 
food/drink, 
social
activities, and sensory experiences).
Change from baseline in the Snaith-Hamilton Pleasure
Scale (SHAPS) over time.
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Objectives 
Endpoints
DARS improvement response at Day 43 (reduction in
DARS total score ≥ meaningful change threshold [or
range of thresholds] determined by anchor-based
analyses of blinded interim data, as indicated in
Section 9.5).
Severity of depressive symptoms 
(clinician- and patient-reported) 
Change from baseline over time in the Clinical Global
Impression-Severity (CGI-S) score.
Change from baseline over time in the symptoms of
depression as assessed using the Patient Global
Impression of Severity (PGI-S) for depression.
Severity of anhedonia symptoms 
(patient-reported) 
Change from baseline over time in anhedonia
symptoms using the PGI-S for anhedonia.
Score at Day 43 in anhedonia symptoms using the
PGI-C for anhedonia.
Health-related quality of life (patient- 
reported) 
Change from baseline over time in health-related
quality of life EQ visual analogue scale (EQ-VAS)
and health status, as assessed by the European Quality
of Life, 5 Dimension, 5-Level (EQ-5D-5L)
questionnaire.
Change from baseline over time in health-related
quality of life as assessed by the Quality of Life in
Depression Scale (QLDS).
Anxiety symptoms (patient-reported) 
Change from baseline to Day 43 in symptoms of
anxiety using the Generalized Anxiety Disorder
7-item Scale (GAD-7).
Treatment satisfaction  
Scores at the end of the Double-blind Treatment Phase
using the Treatment Satisfaction Questionnaire for
Medication (TSQM-9).
Clinical Pharmacology Assessments
To assess the PK of aticaprant (10 mg) in participants with MDD when used as adjunctive treatment.
To assess the exposure-response relationship of aticaprant and MADRS in participants with MDD.
To assess the exposure-response relationship of aticaprant and selected AEs.
Biomarker Signatures
To evaluate diagnostic biomarker signatures which might be predictive of clinical improvement on
depression symptoms and anhedonia upon treatment with aticaprant.
To explore genetic and other factors that may influence the efficacy, PK, safety, or tolerability of
aticaprant.
To evaluate the diagnostic value of 
biosignatures to predict treatment 
response. 
Proportions of biosignature positive participants at
baseline at different cut-offs and combinations of the
biomarkers.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date: 26 January 2024
Objectives 
Endpoints
Change from baseline to Day 43 in MADRS total
score in different biosignature positive participants
and respective biosignature negative participants.
Digital Biomarkers
To evaluate the association between digital biomarkers at baseline (derived from speech, video,
passive behavior sensing, Reward Learning Task [RLT], and cognitive tasks) and treatment
response.
To evaluate the correlation of digital biomarkers with measures of anhedonia and other depression
characteristics, and Biomarker Signature defined subgroup.
To evaluate the change of exploratory digital endpoint (for example, RLT from block 1 to block 2
or from block 1 to block 3, learning rate, and reward sensitivity [ie, baseline to Day 43]).
To quantify lifestyle behavior changes as captured by passive behavior sensing over time compared
to baseline in the aticaprant 10 mg arm and in the placebo arm.
HYPOTHESIS
The hypothesis for this study is that adjunctive treatment with aticaprant 10 mg is superior to
placebo in treating depressive symptoms, as measured by change in MADRS total score from
baseline (Day 1, pre-randomization) to Day 43 in adult participants with MDD ANH+ who have
had an inadequate response to treatment with an SSRI/SNRI.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to assess
the efficacy, safety and tolerability of adjunctive aticaprant 10 mg in adult participants (18 to
64 years of age, inclusive) who have MDD with moderate-to-severe anhedonia (MDD ANH+),
adult participants who do not have moderate-to-severe anhedonia (MDD ANH-), and elderly
participants (65 to 74 years of age, inclusive) with MDD (ANH+ and ANH-). All participants must
have had an inadequate response to an SSRI/SNRI in the current depressive episode.
In addition, PK, pharmacogenomics, and biomarkers will also be evaluated.
This study will consist of the following phases (Figure 1):
Screening Phase (evaluate eligibility): up to 30 days prior to first dose administration.
Double-blind (DB) Treatment Phase: 43 days.
Follow-up Phase: up to 14 days.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date: 26 January 2024
A target of approximately 538 participants,a including adults (18 to 64 years of age, inclusive) and
elderly (65 to 74 years of age, inclusive) will be enrolled in this study. Participants entering the
DB Treatment Phase will be randomized in a 1:1 ratio to receive adjunctive aticaprant 10 mg or
placebo. A minimum of 324 adult participants with MDD ANH+ and approximately 106 adult
participants with MDD ANH- will be enrolled. With this sample size, it is estimated that
approximately 108 elderly participants with MDD (ANH+ and ANH-) will be randomized. The
criteria that define MDD ANH+ will be included in an addendum to the protocol and will be
blinded to the study sites.
The adult MDD ANH+ population randomized to aticaprant 10 mg or placebo will be included in
the primary analysis set. The elderly will be analyzed as an exploratory objective along with all
adult participants regardless of anhedonia status.
4.1.1. 
Study Intervention(s)
Participants will be randomized to receive aticaprant 10 mg or placebo. The study intervention will
be administered orally as 2 film-coated tablets to be administered together, once daily, around the
same time and preferably in the morning.
Participants will receive either aticaprant (10 mg) or matching placebo administered orally once
daily in addition to their current antidepressant (SSRI/SNRI) therapy which will be continued
during the entire study.
All participants will continue their current SSRI/SNRI antidepressant at the same dose without
change and taken approximately around the same time of the day as prior to entering the Screening
and DB Treatment Phase.
Participants who have completed the DB Treatment Phase (Day 43) may be eligible to participate
in a separate 52-week open-label long-term safety study 67953964MDD3003. The investigator
and the participant will determine, based on efficacy and tolerability of the DB treatment, whether
it is in the best interest of the participant to continue treatment in the open-label long-term safety
study. The decision to enroll in the 67953964MDD3003 study or enter the Follow-up Phase will
be documented in the electronic case report form (eCRF).
The maximum duration of participation in the study for an individual participant (including
Screening, DB Treatment and Follow-up phases) will be up to 87 days (up to 30 days for Screening,
43 days for the DB Treatment Phase, and up to 14 days for the Follow-up Phase).
a 
The study may enroll more than approximately 538 participants to ensure that 324 adult participants with MDD
ANH+ are enrolled. Once the required number of 324 adult participants with MDD ANH+ are enrolled,
recruitment of adult MDD ANH- and elderly participants may stop if it takes considerably longer to achieve the
planned number of participants.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date: 26 January 2024
4.1.2. 
Screening Phase
After providing signed informed consent, all the participants experiencing a major depressive
episode will be screened to evaluate their eligibility for study participation. Participants must meet
Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) diagnostic criteria for
recurrent or single episode MDD, without psychotic features, based upon clinical assessment and
confirmed by the Structured Clinical Interview for DSM-5 Axis I Disorders - Clinical Trials
Version (SCID-CT). Participants 65 years of age or older must have had the first onset of
depression prior to 55 years of age.
Eligible participants must have a HDRS-17 total score ≥20 at the first and second screening
interviews with no greater than 20% improvement from the first to second independent HDRS-17
assessments at screening.
At the start of screening participants must have had an inadequate response to at least 1 oral
antidepressant treatment (SSRI or SNRI), administered at an adequate dose (at or above the
minimum therapeutic dose per MGH ATRQ) and duration (at least 6 weeks) in the current
depressive episode (see Section 5.1, Inclusion Criterion 5). The current antidepressant cannot be
the first antidepressant treatment for the first lifetime episode of depression. An inadequate
response is defined as <50% reduction in depressive symptomseveritybut with some improvement
(>0%) (ie, there may be minimal to moderate symptomatic improvement since the initiation of
treatment, but some of the initial symptoms are still present, troubling to the participant and
affecting behavior and function) as assessed by the MGH ATRQ. This must apply to the
participant’s current antidepressant treatment. Medical/pharmacy/prescription records or records
of conversation with the treating physician, or other equivalent documents can be used to verify
the adequacy of the current antidepressant trial.
To characterize the presence and severity of anhedonia from the participant perspective, SHAPS
will be collected at screening and at baseline (Day 1, pre-randomization).
A Site Independent Qualification Assessment (SIQA) will assess the validity of the participants’
diagnosis and antidepressant treatment response for inclusion in the study.
All participants will continue their current antidepressant (SSRI/SNRI) therapy during the
Screening and DB Treatment Phase. The following antidepressants are permitted: citalopram,
duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine,
sertraline, venlafaxine, and desvenlafaxine. Participants will only continue one of these allowed
antidepressants at an adequate and tolerated dose during the study. No changes in background
antidepressant or dose are permitted from screening until the end of the study treatment phase (see
Section 6.8.1 for details). The sponsor will not supply these antidepressant medications.
Prohibited medications will be stopped prior to the start of the DB Treatment Phase. Tapering or
time of discontinuation of a prohibited medication prior to the start of the DB Treatment Phase
should be based on drug’s half-lives, potential drug-drug interactions, local prescribing
information or clinical judgment (see Section 6.8.2 for details). Tapering and discontinuation of
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date: 26 January 2024
prohibited therapies should be initiated after completion of the second HDRS-17 (Visit 1.2, see
Section 1.3) assessment and the SIQA and confirmation these are passed. Eligible participants who
do not require a tapered discontinuation of their prohibited treatment(s) can immediately proceed
into the DB Treatment Phase.
If needed (eg, a longer tapering required for prohibited therapies or other circumstances) the
screening period may be extended for up to 3 weeks after consultation with sponsor’s medical
monitor or designee.
Of note, participants taking benzodiazepines (at dosages equal to or less than the equivalent of
4 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (eg, zolpidem,
zaleplon) during the Screening Phase can continue these medications. No dose increases of the
benzodiazepines beyond the equivalent of 4 mg/day of lorazepam or start of new benzodiazepine
medications are permitted during the Screening Phase.
Safety evaluations (eg, physical examination including a brief neurologic examination, vital signs,
12-lead ECG, C-SSRS, urine drug test, alcohol breath test, and clinical laboratory tests) will be
performed to assess eligibility. Menstrual cycle evaluation in premenopausal female participants
will also be performed. Adverse events will be collected from the time a signed and dated informed
consent form (ICF) is obtained until the completion of the last study procedure on the final
Follow-up Visit.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened only after sponsor's approval as assessed on a case-by-case basis (see Section 5.4).
4.1.3. 
Double-blind Treatment Phase
The DB Treatment Phase starts on the day of the first dose of study intervention intake and
continues until the premature discontinuation of study intervention (ie, Early Withdrawal [EW])
or the scheduled End-of-Treatment (EOT) on Day 43. Evaluations that will be performed during
this phase are outlined in Section 1.3.
In the DB Treatment Phase, participants who meet all inclusion criteria and none of the exclusion
criteria will be randomly assigned in a 1:1 ratio to receive placebo or aticaprant 10 mg for 42 days.
Participants should take their assigned study intervention at home, once daily, from Day 1 to Day
42, inclusive. All participants will continue their current SSRI/SNRI antidepressant at the same
dose without change and taken approximately around the same time of the day as prior to entering
the Screening and DB Treatment Phase. For clinical site visits, participants will be asked not to
take study intervention in the morning before they come to the site for site visit and the study
intervention will be self-administered on-site and witnessed by the investigator or a properly
trained designee.
Note: Participants taking benzodiazepines and/or permitted non-benzodiazepine sleep medications
(eg, zolpidem, zaleplon) during the Screening Phase can continue these medications during the DB
Treatment Phase. No dose increases of benzodiazepines beyond the equivalent of 4 mg/day of
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved,  Date: 26 January 2024
lorazepam or start of new benzodiazepine medications are permitted during the DB Treatment
Phase. Benzodiazepines and non-benzodiazepine sleeping medication (eg, zolpidem, zaleplon,
eszopiclone, and ramelteon) are prohibited within 12 hours prior to cognition testing (Revere.D).
Participants are considered to have completed the DB Treatment Phase of the study if they have
completed the Day 43 Visit of the DB Treatment Phase (Visit 2.7), including the MADRS
assessment at the end of the 6-week DB Treatment Phase (ie, Day 43 MADRS) and has not
discontinued study intervention early during the DB Treatment Phase.
Participants who have completed the DB Treatment Phase (Day 43) may be eligible to participate
in a separate 52-week open-label long-term safety study 67953964MDD3003. The investigator
and the participant will determine, based on efficacy and tolerability of the double-blind treatment,
whether it is in the best interest of the participant to continue treatment in the open-label long-term
safety study.
Participants who complete the DB Treatment Phase, are eligible, and decide to roll-over to the
open-label long-term safety study are not required to complete the Follow-up Phase (see
Section 1.3 and Section 10.10). Participants that discontinue study intervention early (ie, prior to
completion of Day 43 Visit) or who are non-compliant to the study intervention (ie, have missed
either 4 or more consecutive doses of study intervention or a total of 8 or more doses during the
DB Treatment Phase) will not be eligible to participate in the open-label long-term safety study.
Missingstudy intervention doses due to temporary interruption (eg, adverse event per Section 7.1.3
or other clinically relevant reason) will not be considered noncompliance.
Participants who discontinue study intervention during the DB Treatment Phase and participants
who completed the DB Treatment Phase who are not rollingover to the open-label long-term safety
study (67953964MDD3003) will complete the EW/EOT Visit (Visit 2.7, see Section 1.3)and will
then enter the Follow-up Phase of the study (Visit 3.1, see Section 1.3 and Section 10.10).
No study intervention will be administered during the Follow-up Phase; further clinical/standard-
of-care for the treatment of depression will be arranged by the study investigator and/or
participant's treating physician, and changes to current antidepressant treatment are permitted in
this study phase.
End-of-Treatment/Early Withdrawal Visit
The EOT/EW  Visit (Visit 2.7) will take place on Day 43 or earlier in case of premature
discontinuation of study intervention. In all cases, the EOT/EW Visit and assessments (including
MADRS) will be performed per the SoA, preferably on the day after the last dose. If the EW Visit
is conducted on the same day as a scheduled visit, duplicate assessments are not required (see
Section 10.10).
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date: 26 January 2024
4.1.4. 
Follow-up Phase
Participants will enter the Follow-up Phase and complete the Follow-up Visit (ie, Visit 3.1) unless
they complete the DB Treatment Phase and decide to roll-over to the open-label long-term safety
study (67953964MDD3003) or if they withdraw consent for further study assessments.
Follow-up Visit
Participants will return to the study site for a Follow-up Visit within 7 to 14 days after Visit 2.7
(EOT/EW). At the Follow-up Visit, safety and efficacy assessments/procedures will be completed
per the SoA (see Section 1.3, and Section 10.10).
4.1.5. 
Open-label Long-term Safety Study
Participants who have completed the DB Treatment Phase (Day 43) may be eligible to participate
in a separate 52-week open-label long-term safety study 67953964MDD3003. The investigator
and the participant will determine, based on efficacy and tolerability of the double-blind treatment,
whether it is in the best interest of the participant to continue treatment in the open-label long-term
safety study.
If a participant enters the open-label long-term safety study, the Follow-up Visit (Visit 3.1, see
Section 1.3) will not be conducted.
Participants that discontinue study intervention early (ie, prior to completion of Day 43 Visit) or
who are non-compliant to the study intervention (ie, have missed either 4 or more consecutive
doses of study intervention or a total of 8 or more doses during the DB Treatment Phase) will not
be eligible to participate in the open-label safety study. Missing study intervention doses due to
temporary interruption (eg, adverse event per Section 7.1.3 or other clinically relevant reason) will
not be considered noncompliance.
4.1.6. 
Additional Details Related to Study Design
An IDMC will be commissioned to review safety data for this study. Refer to Committees Structure
in Section 10.3.6 for details.
A diagram of the study design is provided in Section 1.2.
4.1.7. 
Changes in Study-related Procedures as a Result of the COVID-19
Pandemic
The worldwide COVID-19 pandemic may impact the conduct of clinical studies due to the
challenges from quarantines, site closures, travel limitations, and other considerations if site
personnel or study participants become potentially exposed to or infected with COVID-19. To
assure the safety of study participants, maintain compliance with GCP, and minimize risks to study
integrity, if necessary, in consultation with the sponsor, the method of assessments may be changed
(eg, paper assessments replaced by electronic assessments and vice versa). In addition, site visits
may be replaced with telephone, internet-based videoconferencing applications, or home visits by
qualified healthcare professionals (see Section 10.9 for further details). Rating scales/safety
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date: 26 January 2024
assessments can continue to be administered via video teleconferencing (MADRS) or phone (other
assessments). Every effort should be made to complete the MADRS assessment via video
teleconferencing and within the scheduled timeframe; if this cannot occur, the sponsor medical
monitor or delegate should be contacted for direction. Normal procedures, as detailed in this
protocol, will be resumed as soon as possible thereafter.
4.2. 
Scientific Rationale for Study Design
4.2.1. 
Study Population
Up to 70% of individuals who are on antidepressant (AD) therapy are inadequately treated for their
depression (Rush 2006). Suboptimal response to first-line standard-of-care antidepressant
treatment for MDD remains a significant problem resulting in persistent impairment and high
utilization of health care resources (Kennedy 2004). Symptoms such as loss of interest/pleasure
(anhedonia), insomnia, and fatigue are reported to persist in these patients, keeping them
symptomatic and leading to progressive worsening of their overall depressive symptoms
(Spijker 2001; Taylor 2010; Wardenaar 2012).There remains unmet need to identify new
personalized treatments addressing depression symptoms insufficiently managed by current ADs
and impeding the achievement of, or prolonging the time to remission (Uher 2012).
Anhedonia, defined as an impaired capacity to experience or anticipate pleasure (Berrios 1995;
Ho 2013) is a very common symptom of MDD, reported in ~75% of patients (Franken 2007) and
is one of the required criteria for MDD (depressed mood and/or anhedonia) (Moayedoddin 2013;
Schrader 1997). In addition to being a common symptom of MDD, as noted in the outset, it is a
persisting dimension amongst individuals with MDD with inadequate response to SSRI/SNRI
(Van Roekel 2017).
Data from the Phase 2 study 67953964MDD2001 showed greater reduction in overall depression
severity on the MADRS in participants with MDD treated with 10 mg aticaprant added to ongoing
antidepressant, compared with those who continued their current antidepressant plus placebo.
Participants with MDD with a high level of anhedonia showed better improvement in overall
depression, as well as improvement in items that reflect positive affect, namely the anhedonia-
specific item inability to feel, and several other items like pessimistic thoughts, lassitude, and
concentration difficulties, all of which are related to hedonic capacity as they reflect on
individual’s interest, engagement, motivation, and connection to the world.
The study population will include participants from the general MDD population (adults
18-64 years of age, inclusive, and elderly 65-74 years of age, inclusive) with an inadequate
response to their current ongoing standard-of-care antidepressant (SSRI/SNRI) who are moderate
to severely depressed and with either moderate-to-severe anhedonia (MDD ANH+) or with mild
or no anhedonia (MDD ANH-). The primary and key secondary analyses will be conducted in the
adult MDD ANH+ population and will be assessed at the end of Week 6 (Day 43). Participants
with MDD ANH- and elderly participants will not be included in the primary and key secondary
analyses. Criteria defining MDD ANH+ will be described in an addendum to the protocol which
will be blinded to the study sites.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Status: Approved,  Date: 26 January 2024
The proposed design  for enrollment of participants with MDD ANH+  and MDD ANH- will
facilitate the acquisition of efficacy data for the use of aticaprant as adjunctive therapy to the
current SSRI/SNRI antidepressant treatment in improving depression symptoms in both
participant populations (ie, participants with MDD without moderate-to-severe anhedonia and
participants with MDD with moderate-to-severe anhedonia, with the latter being the population of
interest for primary and key secondary analyses). Enrolling participants across the general
spectrum of moderate-to-severe MDD will allow the study to utilize enrichment to help
demonstrate antidepressant effectiveness in the subset of those with MDD ANH+ (see FDA 2019).
An SIQA will assess the validity of the participants’ diagnosis for inclusion in the study. The SIQA
is a tool to facilitate participant selection for MDD clinical studies, with a goal to ensure enrollment
of participants who have symptoms that reflect the current state of illness and that these symptoms
can be reliably measured with appropriate measurement tools, as well as to minimize the placebo
response.
Elderly participants up to 74 years of age, inclusive, will be included in the study enrollment
provided that the initial onset of symptoms of depression was before 55 years of age. The age limit
(74 years, inclusive) and the requirement for first episode of MDD to be prior to age 55 is based
on evidence in the literature that late life onset MDD appears to have a different pathophysiology
than earlier onset MDD and is associated to a greater degree with age related changes in the brain
and to a lesser extent with genetic predisposition to depression  (Covinsky 2014). Furthermore,
antidepressants tend to be less effective in older patients. As the elderly group of MDD patients
was not studied in the Phase 2 study, there exists an uncertainty on the expected clinical
presentation and level of anhedonia severity in this age group. Therefore, participants with MDD
that are 65 to 74 years of age, inclusive, will be included in  the exploratory analysis but not
included in the primary analysis set. The primary and key secondary analyses will be based on the
adult MDD ANH+ population (18 to 64 years of age, inclusive).
Based on the completed Phase 2 study, the treatment duration of 42 days is selected to demonstrate
the treatment effect of aticaprant (primary endpoint).
4.2.2. 
Blinding, Control, Study Phase/Periods, Intervention Groups
Participants will be randomized to receive aticaprant 10 mg or placebo. The study intervention will
be administered orally as 2 film-coated tablets to be administered together, once daily, around the
same time and preferably in the morning.
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active intervention. Randomization will be used to
minimize bias in the assignment of participants to intervention groups, to increase the likelihood
that known and unknown participant attributes (eg, demographic and baseline characteristics) are
evenly balanced across intervention groups, and to enhance the validity of statistical comparisons
across intervention groups. A 1:1 (adjunctive placebo: adjunctive aticaprant 10 mg) randomization
ratio will be used. Blinded intervention will be used to reduce potential bias during data collection
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Status: Approved,  Date: 26 January 2024
and evaluation of clinical endpoints (see Section 6.3 for further details relating to measures to
minimize bias: randomization and blinding).
Criteria defining MDD ANH+ and MDD ANH- subgroups are blinded to the sites and provided
in an addendum to the study protocol.
Conditions to maintain the blind of MADRS raters are specified in Section 8.1.2.1. Activities
employed to ensure independent confirmation of the diagnosis, severity of the depressive episode
and adequacy of the current antidepressant treatment are described in Section 8.1.2.1.
4.2.3. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Written consent may be obtained through various sources (eg, paper or electronic such as
eConsent, eSignature, or digital signature) as determined by regulations as well as study and/or
patient preferences.
The probability of receiving placebo and the concept of random assignment will be explained to
the participant. Only participants who have not adequately responded to their current
antidepressant medication and continue to have moderate-to-severe depression and where a
clinician would consider adjunctive treatment will be enrolled. Current antidepressant medication
(SSRI/SNRI) will need to be continued and remain stable throughout the study and the study
intervention will be added to it. Withdrawal and/or discontinuation symptoms for prohibited
therapies may be challenging for some participants. However, there are a number of strategies
including use of rescue medications that may be used to minimize discomfort to participants. The
duration of the study is short, minimizing the time on adjunctive placebo. Participants in the study
will be monitored very closely with in-person visits and remote contacts during the DB Treatment
Phase. Safety evaluations will include evaluation of suicidal ideation/behavior at each clinic visit
and remote contact. At any point in the study, the participant may withdraw consent, discontinue
study intervention and receive approved adjunctive therapy for depression, or be removed from
the study by the investigator if there are any clinical concerns and provisions for appropriate and
immediate clinical triage as necessary.
The total blood volume to be collected is considered to be within the normal range allowed for this
participant population over this time frame. The approximate blood volume to be collected is
123.5 mL, which will be less than a Red Cross blood donation.
An optional real-world data collection is considered for participants, agreeing via a separate ICF
to the collection and use of their real-world medical data (electronic health record) in the 5 years
prior to and after entry in the study.
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JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 January 2024
For participants who consent to the optional collection of real-world medical data, the sponsor is
committed to protect their data and privacy. Tokenization and matching procedures will be utilized
to allow for those participant’s medical data to be obtained without violation of participant
confidentiality. Participants will be informed that consent to this part of the study is completely
optional and that they can withdraw their consent at any given time. In the event of withdrawal of
consent, the sponsor will remove the token generated and any associated linked real-world data.
Participation in or withdrawal from this optional part of the study will not affect the participation
in the main study (see Section 8.9).
All applicable applications used in this study are General Data Protection Regulation
(GDPR)/Health Insurance Portability and Accountability Act (HIPAA)compliant.
4.2.4. 
Biomarker Sample Collection
The primary  goal of the biomarker analyses is to identify  diagnostic biosignatures from
blood-based biomarker panels that identify participant subgroups that respond differently to
aticaprant. Secondary goals for the biomarker collections are to explore biomarkers reflective of
the mechanism of action of aticaprant or that help to explain interindividual variability in efficacy,
pharmacodynamics, pharmacokinetics, safety, and tolerability.
As MDD with  symptoms of anhedonia may be associated with altered immune/metabolic
activation patterns that are known to interact with the kappa opioid system, blood samples will be
collected to measure biomarkers related to immune system activity, HPA axis activation, and KOR
signaling. Biomarker levels will be combined using multimodal models and the resulting
biosignatures will be evaluated for their utility to identify population subgroups that respond
differently to adjunctive aticaprant treatment. In addition, biomarkers will be explored for their
utility to explain interindividual variability in clinical outcomes and pharmacokinetics. Many of
these biomarkers may be influenced by stage of menstrual cycle in female participants; therefore,
the menstrual cycle will be tracked in premenopausal female participants who are still having their
menses during the study, by the participant diary and participant’s verbal report. Biomarker
samples will be collected under fasting conditions and prior to study intervention administration.
The goal of the pharmacogenomic component is the identification of genetic, epigenetic, and/or
transcription factors that may influence the pharmacokinetics, pharmacodynamics, efficacy,
safety, or tolerability of aticaprant and that are associated with MDD in general and/or specific
symptoms, such as anhedonia. The DNA and RNA collections are optional procedures as detailed
in a separate ICF.
The DNA, RNA, and protein biomarker samples may be used to help address emerging issues and
to enable the development of safer, more effective, and targeted individualized therapies.
4.2.5. 
Pharmacokinetic Assessments
Sparse blood samples will be collected for measurement of the plasma concentrations of aticaprant
and any relevant metabolite(s), if warranted, as indicated in SoA (Section 1.3).
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 January 2024
A population PK analysis using sparse PK data from this study will be performed at the completion
of the study. The purpose of the planned population PK analysis will be to assess and confirm the
PK of aticaprant in the target patient population, and to investigate the potential impact of
covariates. The results of the population PK analysis will be reported separately.
In addition, an optional unscheduled blood sample may be collected for determination of plasma
concentrations of aticaprant in participants who discontinue study intervention for an AESI or SAE
which is related to AESI. This blood sample should be collected as close as to the AESI or
AESI-related SAE occurrence, but preferably within 72 hours of the last study intervention
administration. This sample is not collected in case of discontinuation due to AE, but only for
AESI or AESI-related SAE.
4.3. 
Justification for Dose
The aticaprant 10 mg/day dose selection is based on the results from the completed Phase 2a
Studies FAST-MAS and Study 67953964MDD2001, as well as PK/PD and RO modeling.
Aticaprant administered at 10 mg once daily is predicted to have high kappa occupancy at Cmax
(mean peak occupancy of
%)and at trough levels (mean trough occupancy of
%).
The Phase 1 and Phase 2 program of aticaprant (healthy volunteers and participants with MDD)
included participants up to 73 years of age (inclusive). The data from these studies did not yield
safety and tolerability effects that might be of concern for older adults (ie, no cardiovascular
effects, metabolic effects, or sedation). Considering population PK analysis from these earlier
studies, age was not a significant covariate. Further, aticaprant is not 
 and is
primarily metabolized through CYP
 and CYP
 which may provide rationale not to expect
any age effect on the PK in the elderly up to 74 years, inclusive.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in the SoA for the
last participant in the study. The final data from the study site will be sent to the sponsor (or
designee) after completion of the final participant assessment at that study site, in the time frame
specified in the Clinical Trial Agreement.
Treatment Completion and Study Completion Definition
Participants are considered to have completed the DB Treatment Phase if they have completed the
Day 43 Visit of the DB Treatment Phase (Visit 2.7), including the MADRS assessment at the end
of the 6-week DB Treatment Phase (ie, Day 43 MADRS), and have not discontinued study
intervention early during the DB Treatment Phase.
Participants who have completed the DB Treatment Phase (Day 43) and were compliant to the
study intervention may be eligible to participate in a separate 52-week open-label long-term safety
study 67953964MDD3003. The investigator and the participant will determine, based on efficacy
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and tolerability of the double-blind treatment, whether it is in the best interest of the participant to
continue treatment in the open-label long-term safety study. The decision to enroll in the
67953964MDD3003 study or enter the Follow-up Phase will be documented in the eCRF.
Participants who complete the DB Treatment Phase will be considered to have completed the study
if they roll over to Study 67953964MDD3003 or complete the Follow-up Visit, including the
MADRS and DARS assessments at this visit. If a participant enters the open-label safety study,
the Follow-up Visit (Visit 3.1) will not be conducted.
Participants who discontinue study intervention in DB Treatment Phase will be considered to have
completed the study if they completed the Follow-up Phase (Visit 3.1), including the MADRS and
DARS assessments at this visit.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 30 days before administration of the
study intervention (refer to Section 5.4). Efforts will be made for the inclusion of a diverse study
population in terms of race, gender, and ethnicity.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Age
1. 
Male or female, aged 18 (or the legal age of consent if higher than 18 years of age, in the
jurisdiction in which the study is taking place) to 74 years of age, inclusive.
Type of Participant and Disease Characteristic
2. 
Be medically stable on the basis of physical examination (including a brief neurological
examination), medical history, vital signs (including blood pressure), and 12-lead ECG
performed at screening and baseline. If there are any abnormalities that are not specified
in the inclusion and exclusion criteria, their significance must be determined by the
investigator and recorded in the eCRF and in the participant's source documents and
initialed by the investigator.
3. 
Be medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry panel, hematology, or urinalysis are outside the normal
reference ranges, re-testing of an abnormal laboratory value(s) that may lead to exclusion
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will be allowed once during the Screening Phase. The participant may be included only
if the investigator judges the abnormalities or deviations from normal to be not clinically
significant or to be appropriate and reasonable for the population under study. This
determination must be recorded in the eCRF and in the participant's source documents
and initialed by the investigator.
4. 
Meet DSM-5 diagnostic criteria for recurrent or single episode MDD, without psychotic
features (DSM-5 296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and
confirmed by the SCID-CT. Participants 65 years of age or older must have had the first
onset of depression prior to 55 years of age.
5. 
Criterion modified per Amendment 1
5.1 Criterion modified per Amendment 2
5.2 Have had an inadequate response to at least 1 oral antidepressant treatment (see the
inclusion criterion below), administered at an adequate dose (at or above the minimum
therapeutic dose per MGH ATRQ) and duration (at least 6 weeks) in the current episode
of depression. An inadequate response is defined as <50% reduction in depressive
symptom severity  but with some improvement (>0%) (ie, there may be minimal to
moderate symptomatic improvement since the initiation of treatment, but some of the
initial symptoms are still present, troubling to the participant and affecting behavior and
function), as assessed by the MGH ATRQ. This must apply to the participant's current
antidepressant treatment.
Note: Medical/pharmacy/prescription records, a letter from a treating physician, etc can
be used to verify the adequacy of the current antidepressant trial.
6. 
Criterion modified per Amendment 1
6.1 Criterion modified per Amendment 2
6.2 Is currently receiving and tolerating well any one of the following SSRI or SNRI for
depressive symptoms at screening, in any approved formulation and available in the
participating country/territory: citalopram, duloxetine, escitalopram, fluvoxamine,
fluoxetine, 
milnacipran, 
levomilnacipran, 
paroxetine, 
sertraline, 
venlafaxine,
desvenlafaxine at a stable dose (at or above the minimum therapeutic dose per MGH
ATRQ) for at least 6 weeks. The current antidepressant cannot be the first antidepressant
treatment for the first lifetime episode of depression.
Note: The above SSRI/SNRI needs to be approved for the treatment of MDD according
to the local label of the country/territory where the clinical site is located.
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Note: Medical/pharmacy/prescription records, a letter from a treating physician, etc can
be used to verify the adequacy of the current antidepressant trial. The investigator will
use this information to complete the MGH ATRQ.
Note: Participants using fluvoxamine as background SSRI and have normal renal and
hepatic function may enter the study.
7. 
Have a HDRS-17 total score of 20 or higher at the first and second screening interviews
and must not demonstrate a clinically significant improvement (ie, an improvement of
more than 20% on their HDRS-17 total score) between the first and the second
independent HDRS-17 assessments.
8. 
Participant's current major depressive episode, and antidepressant treatment response in
the current depressive episode, must all be confirmed by the Site Independent
Qualification Assessment.
9. 
Must be an outpatient at screening.
Weight
10. 
Body mass index (BMI) within the range 18 and 40 kg/m2 inclusive
(BMI = weight/height2).
Sex and Contraceptive/Barrier Requirements
11. 
Criterion modified per Amendment 1
11.1 A female participant of childbearing potential must have a negative highly sensitive
serum ( human chorionic gonadotropin [ hCG]) pregnancy test at screening and a
negative urine pregnancy test pre-dose on Day 1 of the Double-blind Treatment Phase
prior to randomization.
12. 
Criterion modified per Amendment 1
12.1 Criterion modified per Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
12.2 A female participant must be (as defined in Appendix 5: Contraceptive and Barrier
Guidance):
a. Not of childbearing potential
b. Of childbearing potential and
o Practicing a highly effective method of contraception (failure rate of <1%
per year when used consistently and correctly) and agrees to remain on a
highly effective method while receiving study intervention and for 1 month
after last dose - the end of relevant systemic exposure. The investigator
should evaluate the potential for contraceptive method failure (eg,
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noncompliance, recently initiated) in relationship to the first dose of study
intervention. Examples of highly effective methods of contraception are
located in Appendix 5: Contraceptive and Barrier Guidance.
13. 
Criterion modified per Amendment 1
13.1 A female participant must agree not to donate eggs (ova, oocytes)or freeze for future
use for the purposes of assisted reproduction during the study and for a period of at least
1 month after receiving the last dose of study intervention.
14. 
During the study and for a minimum of 1 spermatogenesis cycle (defined as
approximately 3 months) after receiving the last dose of study intervention:
A male participant must agree to use a barrier method of contraception (eg, condom
with spermicidal foam/gel/cream/suppository) when engaging in any activity that
allows for passage of ejaculate to another person.
A male participant who is sexually active with a woman who is pregnant must use a
condom.
Male participants should also be advised of the benefit for a female partner to use a highly
effective method of contraception as condom may break or leak.
15. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 1 spermatogenesis cycle (defined as approximately
3 months)after receiving the last dose of study intervention.
Informed Consent
16. 
Must sign an ICF  indicating that the participant understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
Medical Conditions
1. 
Criterion modified per Amendment 1
1.1 Criterion modified per Amendment 2
1.2 Have had in the current depressive episode, no response (treatment failure) to 5 or
more antidepressant treatments including the current SSRI/SNRI (ie, the one presumed
to be continued in the treatment phase) assessed using the MGH ATRQ.
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2. 
Has one or more of the following diagnoses:
A DSM-5 diagnosis (which has been the primary focus of psychiatric treatment
within the past 2 years)of any of the following:
panic disorder
generalized anxiety disorder
social anxiety disorder
specific phobia
Note: These are allowed as secondary diagnoses if MDD is the primary focus of
treatment according to the investigator.
A current (in the past year)DSM-5 diagnosis of:
obsessive-compulsive disorder (OCD)
post-traumatic stress disorder (PTSD)
anorexia nervosa
bulimia nervosa
Note: These disorders need to be under control and stable for at least 1 year for the
participant to be enrolled.
A current or prior (lifetime)DSM-5 diagnosis of:
a psychotic disorder or MDD with psychotic features
bipolar or related disorders (confirmed by the SCID-CT)
intellectual disability (DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2,
315.8, and 319)
autism spectrum disorder
borderline personality disorder
antisocial personality disorder
histrionic personality disorder
narcissistic personality disorders
somatoform disorders
3. 
Has a history or evidence of clinically meaningful noncompliance with current
antidepressant therapy.
4. 
Has a history of moderate-to-severe substance use disorder including alcohol use
disorder according to DSM-5 criteria within 6 months before screening.
5. 
Criterion Modified per Amendment 2
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5.1 Has had in the current episode an inadequate response to adequate course of
intravenous or intranasal ketamine or esketamine, electroconvulsive therapy (ie, at least
7 treatments), vagal nerve stimulation, or deep brain stimulation device.
6. 
Has a current homicidal ideation/intent, per the investigator’s clinical judgment, or has
suicidal ideation with some intent to act within 3 months prior to the start of the
Screening Phase, per the investigator’s clinical judgment or based on the Columbia
Suicide Severity Rating Scale (C-SSRS), corresponding to a response of “Yes” on
Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5
(active suicidal ideation with specific plan and intent), or a history of suicidal behavior
within the past 6 months prior to the start of the Screening Phase. Participants reporting
suicidal ideation with intent to act or suicidal behavior at baseline should be excluded.
7. 
Has cognitive impairment per investigator judgment that would render the informed
consent invalid or limit the ability of the participant to comply with the study
requirements. Participant has neurodegenerative disorder (eg, Alzheimer’s disease,
vascular dementia, Parkinson’s disease with clinical evidence of cognitive impairment)
or evidence of mild cognitive impairment (MCI). Participants aged ≥65 years: has an
MMSE score <25 or <23 for those participants with less than high school equivalent
education.
8. 
Has current, or a history (past 6 months), of seizures.
9. 
Has clinically significant 12-lead ECG abnormalities at the start of the Screening Phase
or on Day 1 of the DB treatment phase, prior to randomization, defined as:
During screening, a QT interval corrected according to Fridericia's formula
(QTcF): 450 msec (males); ≥470 msec (female participants).
Note: if the QTcF is prolonged on the initial 12-lead ECG at a given time point,
the average QTcF of 3 12-lead ECGs, recorded 4 minutes apart, must not be
≥450 msec for males and ≥470 msec for female participants.
On Day 1 (pre-dose), a QT interval corrected according to Fridericia’s formula
(QTcF): ≥450 msec (males) or ≥470 msec (female participants) based on the site-
evaluated ECG; if the QTcF is prolonged on the initial ECG, the average QTcF of
3 ECGs, recorded 4 minutes apart, must not be ≥450 msec for males and ≥470 msec
for female participants.
Evidence of second and third degree atrioventricular (AV) block, complete left
bundle branch block (LBBB), or complete right bundle branch block (RBBB).
Features of new ischemia.
Arrhythmia (except premature atrial contractions [PACs] and premature
ventricular contractions [PVCs]).
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10. 
Participant has a history of additional risk factors for Torsades de Pointes (eg, heart
failure, hypokalemia, family history of Long QT Syndrome).
11. 
Has a history of, or symptoms and signs suggestive of, liver cirrhosis (eg, esophageal
varices, ascites, and increased prothrombin time) OR alanine aminotransferase (ALT)
or aspartate aminotransferase (AST) values ≥3 × the upper limit of normal (ULN) or
total bilirubin >1.5 × the ULN in the Screening Phase.
Repeat of screening test for abnormal ALT and AST is permitted during the
screening period provided per investigator discretion and provided there is an
alternative explanation for the out ofrange value.
For elevations in bilirubin if, in the opinion of the investigator and agreed upon by
the sponsor’s medical officer, the elevation in bilirubin is consistent with Gilbert’s
syndrome, the participant may participate in the study.
12. 
Criterion Modified per Amendment 2
12.1 Has positive test result(s) for alcohol and/or drugs of abuse (eg, opiates [including
methadone], cocaine, amphetamines, methamphetamines, cannabinoids, cannabidiol
[CBD], phencyclidine [PCP], barbiturates, 3,4-Methylenedioxymethamphetamine
[MDMA]) at screening or at baseline.
Note: One retest during screening is allowed at investigator's judgment. Tobacco and
caffeine use are not exclusionary.
Participants who have a positive test result at screening due to prescribed
psychostimulants taken for any indication must discontinue the medication (if
considered clinically appropriate) at least 2 weeks before Day 1 of the DB
Treatment Phase (prior to randomization). The result of the Day 1 (prior to
randomization) test (performed on site)for drugs of abuse must be negative for the
participant to be randomized.
Otherwise, participants who have a positive test result at screening due to
prescribed/over-the-counter opiates or barbiturates may be permitted to continue in
the Screening Phase if the medication is discontinued at least 1 week or 5 half-
lives, whichever is longer, before Day 1 of the DB Treatment Phase (prior to
randomization). The result of the Day 1 (prior to randomization) test (performed
on site)for drugs of abuse must be negative for the participant to be randomized.
Intermittent use of cannabinoids and/or alcohol prior to the start of the Screening
Phase is not exclusionary as long as the participant does not meet the criteria for
substance use disorder. A positive test for cannabinoids and/or alcohol at the start
of the Screening Phase is not exclusionary; however, a positive test (performed on
site)result for either of these on Day 1 of the DB Treatment Phase is exclusionary.
Retesting is not permitted for positive test result(s), except for reasons stated above.
13. 
Has a recent (last 3 months) history of, or current signs and symptoms of:
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Clinically significant or unstable cardiovascular, respiratory, gastrointestinal,
neurologic, hematologic, rheumatologic, immunologic or endocrine disorders.
Uncontrolled Type 1 or Type 2 diabetes mellitus. Note: Participants with Type 1
or Type 2 diabetes mellitus who are controlled (hemoglobin A1c ≤9.0%) may be
eligible to participate if otherwise medically healthy, and if on a stable regimen of
glucose-lowering medications for at least 2 months prior to screening).
14. 
Has current signs/symptoms of hypothyroidism or hyperthyroidism. For participants
with a history of thyroid disease and for participants who, regardless of thyroid history
have the thyroid-stimulating hormone (TSH) value out of range, a free thyroxine (FT4)
test will be conducted. If the FT4 value is abnormal and considered to be clinically
significant (after discussion with the sponsor’s study responsible physician/scientist or
designee) the participant is not eligible.
Participants with a pre-existing history of thyroid disease/disorder who are treated with
thyroid hormones need to be on a stable dosage for 3 months prior to the start of the
Screening Phase. Participants taking thyroid supplementation for antidepressant
purposes are not allowed in the study.
15. 
Has Cushing’s disease, Addison’s disease, primary amenorrhea, or other evidence of
significant medical disorders of the hypothalamic-pituitary-adrenal axis.
16. 
Has severe renal impairment (creatinine clearance <30 mL/min).
17. 
Has significant medical illness, particularly unstable medical problem (to be reviewed
with the sponsor’s medical monitor).
18. 
Has a known history (past 6 months) of peptic ulcer, or history (lifetime) of upper
gastrointestinal bleeding, or known untreated Helicobacter pylori infection, or a
diagnosis of Zollinger-Ellison syndrome (ZES).
19. 
Has a history of malignancy within 5 years before the start of the Screening Phase
(exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ
of the cervix, or malignancy that, in the opinion of the investigator, with concurrence
with the sponsor's medical monitor, is considered cured with minimal risk of
recurrence).
20. 
Has known allergies, hypersensitivity, or intolerance to aticaprantor its excipients (refer
to the IB).
Prior/Concomitant Therapy
21. 
Has taken any prohibited therapies that would not permit dosing on Day 1.
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22. 
Is taking a total daily dose of benzodiazepine greater than the equivalent of 4 mg/day
of lorazepam at the start of the Screening Phase.
23. 
Participants should not take any prohibited medication or food supplements as indicated
in Section 6.8.
Prior/Concurrent Clinical Study Experience
24. 
Ongoing psychological treatments (eg, Cognitive Behavioral Therapy, Interpersonal
Psychotherapy, Psychodynamic Psychotherapy, etc), initiated within 6 weeks prior to
start of screening.
Note: a participant who has been receiving ongoing psychological treatment for a period
of greater than 6 weeks is eligible, if the investigator deems the psychological treatment
to be of stable duration and frequency.
25. 
Has received an investigational intervention (including investigational vaccines) or
used an invasive investigational medical device within  60 days or 10 half-lives,
whichever is longer, before the start of the Screening Phase or has participated in 2 or
more MDD or other psychiatric condition clinical interventional studies (with different
investigational medication) in the previous 1 year before the start of the Screening Phase
or is currently enrolled in an investigational study.
Other Exclusions
26. 
Criterion modified per Amendment 1
26.1 Criterion modified per Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
26.2 Is a female participant who is pregnant, or breastfeeding, or planning to become
pregnant while enrolled in this study or for 1 month  after the last dose of study
intervention.
27. 
Plans to father a child while enrolled in this study or within 3 months after the last dose
of study intervention.
28. 
Has any condition or situation/circumstance for which, in the opinion of the
investigator, participation would not be in the best interest of the participant (eg,
compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments.
Diagnostic Assessments
29. 
Has a diagnosis of acquired immunodeficiency syndrome (AIDS). Human
immunodeficiency virus (HIV) testing is not required for this study.
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Other Exclusions
30. 
Employee of the investigator or study site with direct involvement in the proposed study
or other studies under the direction of that investigator or study site, as well as family
members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening
and/or Day 1 prior to randomization (as applicable). If a participant's clinical status changes
(including any available laboratory results or receipt of additional medical records) after
screening but before the first dose of study intervention is given such that the participant no
longer meets all eligibility criteria, then the participant should be excluded from participation in
the study. Section 5.4 describes options for re-testing. The required source documentation to
support meeting the enrollment criteria are noted in Section 10.3.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
Participants should not take any prohibited medication or food supplements. Refer to
Section 6.8 for details regarding prohibited and restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.3.1. 
Meals and Dietary Restrictions
1. 
The use of limited amounts of alcohol (up to 2 standard drink consumptions daily) will be
allowed but not within 24 hours before any study visit. A standard drink is defined as: a
350-mL glass of 5% alcohol-by-volume (ABV) beer (1.7 units), a 150-mL glass of 12%
ABV wine (2 units), or a 45-mL glass of a 40% ABV (80 proof) spirit (1.7 units).
2. 
Should not consume food or beverages containing grapefruit juice, Seville oranges
(including any orange marmalade), or quinine (eg, tonic water) from 24 hours (72 hours in
the case of grapefruit juice and Seville oranges) before the first dose of study intervention
and throughout the duration of the study until the last dose of study intervention.
5.3.2. 
Activity
1. 
Participants should abstain from strenuous exercise within 48 hours before each blood
collection for clinical laboratory tests. Participants may participate in light recreational
activities during the study (eg, watching television, reading).
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2. 
Participants should be advised not to donate blood during the study and for at least
3 months after completion of the study.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness. When available, the investigator may generate
screening and enrollment logs directly from the interactive web response system (IWRS).
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent.
The sponsor will evaluate and approve/reject requests to rescreen an individual participant on a
case-by-case basis.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Designation 
Product
Investigational Medicinal Product 
Aticaprant (JNJ-67953964)/Placebo
Non-investigational Medicinal 
Product/Auxiliary Medicinal Product
Current SSRI/SNRI antidepressant*
Abbreviations: SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor.
* Current antidepressant therapy must be continued throughout the entire study, at the same dose, every day
without change, and at approximately the same time of the day as prior to entering the study. The following
antidepressants are permitted: citalopram, duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran,
levomilnacipran, paroxetine, sertraline, venlafaxine, and desvenlafaxine. For further information regarding their
use, refer to the relevant local prescribing information.
Study intervention administration must be captured in the source documents and the eCRF.
Aticaprant will be dispensed as film-coated tablets of 10 mg. Placebo will be supplied as matching
tablets.
All participants will receive 2 tablets (1 large tablet and 1 small tablet) to be taken daily,
irrespective of treatment assigned.
The study intervention (aticaprant 10 mg or placebo) will be manufactured and provided under the
responsibility of the sponsor. Refer to the IB for a list of excipients.
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The study intervention will be provided as a double dummy pack type in blister kits (otherwise
described as “container” throughout the document) identified by a study number. The labels will
contain information to meet the applicable regulatory requirements.
During the DB Treatment Phase, all participants must take their assigned study intervention,
supplied as 2 oral film-coated tablets, once daily, around the same time and preferably in the
morning. Participants will take 1 large tablet and 1 small tablet. The first dose will be taken by the
participant at the study site on Day 1 of the DB Treatment Phase after randomization and witnessed
by the investigator or a properly trained designee. Thereafter, study intervention will be taken at
home by the participant for daily self-administration until the next clinical site visit. For clinical
site visits, participants will be asked not to take study intervention in the morningbefore they come
to the site for the visit and the study intervention will be self-administered on-site and witnessed
by the investigator or a properly trained designee. The investigator or designated study personnel
will maintain a log of all study intervention  dispensed and returned. Drug supplies will be
inventoried and accounted for throughout the study. Tablet counts of study intervention will be
performed at each clinical visit during the treatment phase of the study.
If a scheduled dose is missed, participants are advised not to administer 2 doses at a time the next
day. The dose will be skipped. Information about the missing dose should be recorded in
participant diaries and in the eCRF study intervention log.
Study site personnel will instruct participants on how to store the study intervention for at-home
use. A participant diary to capture study intervention use will be provided.
All participants will continue their current SSRI/SNRI antidepressant (the Non-investigational
Medicinal Product) at the same dose without change and taken approximately around the same
time of the day as prior to entering the Screening and DB Treatment Phase. The participant’s use
of their current SSRI/SNRI antidepressant therapy during the study should be captured by the
participant using a medication diary (see Section 6.8.1).
If appropriate, additional details may be provided in a pharmacy manual/study site investigational
product manual that is provided separately and noted in Section 8.
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Description of Interventions
Group/Arm Name 
Group/Arm A  
Group/Arm B
Intervention Name 
Aticaprant/JNJ-67953964  
Placebo
Dose Formulation 
Film-coated tablet 
Matching placebo
Unit Dose Strength(s) 
Available unit dose strength: 10 mg 
Not applicable
Dosage Level(s) and Frequency  
Participants will receive 10 mg aticaprant orally once daily 
in addition to their current antidepressant (SSRI/SNRI) 
therapy which will be continued during the entire study  
Participants will receive matching oral placebo once daily
in addition to their current antidepressant (SSRI/SNRI)
therapy which will be continued during the entire study
Route of Administration 
☒Oral
☐IV infusion
☐IV injection
☐Intramuscular
☐Other
☒Oral
☐IV infusion
☐IV injection
☐Intramuscular
☐Other
Dosing Instructions 
Participants must take 2 (ie, 1 small and 1 large) oral film-
coated tablets once daily, around the same time and
preferably in the morning.
Participants must take 2 (ie, 1 small and 1 large) oral film-
coated tablets once daily, around the same time and
preferably in the morning.
Use 
☒Experimental
☐Background intervention
☐Challenge agent
☐Diagnostic
☐Other
☐Experimental
☒Placebo comparator
☐Active comparator
☐Sham comparator
☐Rescue medication
☐Background intervention
☐Challenge agent
☐Diagnostic
☐Other
Investigational Medicinal Product
(IMP)
☒Yes 
☐No 
☒Yes 
☐No
Non-Investigational Medicinal
Product/Auxiliary Medicinal
Product (NIMP/AxMP)
☐Yes 
☒No 
☐Yes 
☒No
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Status: Approved,  Date: 26 January 2024
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention will be stored in a secure area with restricted access. Tablets must be stored
at controlled room temperatures as indicated on the product specific labeling.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of study intervention to the
participant, and the return of study intervention from the participant (if applicable), must be
documented on the intervention accountability form. Participants must be instructed to return all
original containers, whether empty or containing study intervention. The study intervention
administered to the participant must be documented on the intervention accountability form. All
study intervention will be stored and disposed of according to the sponsor's instructions. Study-site
personnel must not combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and as indicated on the
container label and must be stored at the study site in a limited-access area or in a locked cabinet
under appropriate environmental conditions. Unused study intervention, and study intervention
returned by the participant, must be available for verification by the sponsor's study site monitor
during on-site monitoring visits. The return to the sponsor of unused study intervention, or used
returned study intervention for destruction, will be documented on the intervention return form.
When the study site is an authorized destruction unit and study intervention supplies are destroyed
on-site, this must also be documented on the intervention return form.
Study intervention must be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even  to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study intervention are
provided in the study site investigational product and procedures manual (IP manual).
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of 2 intervention groups in a 1:1 ratio based on a computer-generated randomization schedule
implemented in the IWRS before the study. Separate randomization lists for MDD ANH+ and
MDD ANH- will be generated before the study by, or under the supervision of the sponsor. For
each list, the randomization will be balanced by using randomly permuted blocks and will be
stratified by country/territory and age group (adults [18 to 64 years of age, inclusive], elderly [65
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to 74 years of age, inclusive]). Based on this randomization code, the study intervention will be
packaged and labeled for each participant. The IWRS will assign a unique intervention code, which
will dictate the intervention assignment and matching study intervention kit for the participant.
The requestor must use his or her own user identification and personal identification number when
contacting the IWRS and will then give the relevant participant details to uniquely identify the
participant.
Blinding
Participants will be randomized to receive aticaprant 10 mg or placebo. The study intervention will
be administered orally as 2 film-coated tablets, to be administered together, once daily, around the
same time and preferably in the morning.
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention assignment (ie, study intervention plasma/serum
concentrations, study intervention  preparation/accountability data, intervention  allocation, and
biomarker or other specific laboratory data) will be handled with special care to ensure that the
integrity of the blind is maintained and the potential for bias is minimized. This can include making
special provisions, such as segregating the data in question from view by the investigators, clinical
team, or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind must not be broken until all participants have completed
the study and the database is finalized. The investigator may, in an emergency, determine the
identity of the intervention  by contacting the IWRS. While the responsibility to break the
intervention code in emergency situations resides solely with the investigator, it is recommended
that the investigator contact the sponsor or its designee, if possible, to discuss the particular
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be
informed as soon as possible.
The date and time of unblinding must be documented in the IWRS, and reason for the unblinding
must be documented in the appropriate section of the eCRF, and in the source document. The
documentation received from the IWRS indicating the code break must be retained with the
participant's source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for
the EOT/EW and follow-up assessments as indicated in Section 7.1.
6.4. 
Study Intervention Compliance
Except for on-site clinic visits, the study intervention will be self-administered by participant at
home daily around the same time and preferably in the morning from Day 1 to Day 42 of the DB
Treatment Phase. The first dose will be taken on Day 1 on-site post randomization and will be
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witnessed by the investigator or a responsible designee. At subsequent clinical visits, study
intervention will be self-administered on-site and witnessed by the responsible site staff personnel.
Participants will receive instructions on compliance with the study intervention treatment. During
the course of the study, the investigator or designated study site personnel will be responsible for
providing additional instruction to re-educate any participant to ensure compliance with taking the
study intervention. Participant diary will be provided to capture study intervention use and
reviewed by the investigator or a responsible designee as specified in the SoA (see Section 1.3).
The number of study intervention tablets dispensed for self-administration by participants at home
will be recorded and compared with the number returned during postbaseline visits. Participants
with repetitive noncompliance to the study intervention  in the DB Treatment Phase (ie, have
missed either 4 or more consecutive doses of study intervention or a total of 8 or more doses during
the DB Treatment Phase) may be withdrawn from study intervention (see Section 7.1). Missing
study intervention doses due to temporary interruption (eg, adverse event per Section 7.1.3 or other
clinically relevant reason)will not be considered noncompliance.
The investigator or designated study site personnel will maintain a log of all study intervention
dispensed and returned. Drug supplies for each participant will be inventoried and accounted for
throughout the study. If appropriate, additional details may be provided in a site investigational
product manual that is provided separately and noted in Section 8.
6.5. 
Dose Modification
This is a fixed dose study of 10 mg aticaprant or placebo. No dose modifications in study
intervention are permitted during the DB Treatment Phase.
6.6. 
Continued Access to Study Intervention After the End of the Study
Participants who have completed the DB  Treatment Phase may be eligible to participate in a
separate 52-week open-label long-term safety study 67953964MDD3003. The investigator and the
participant will determine, based on efficacy and tolerability of the DB treatment, whether it is in
the best interest of the participant to continue treatment in the open-label study. Please refer to the
67953964MDD3003 protocol for full details and criteria for rolling over to this open-label study.
Participants who receive at least 1 dose of study intervention in the DB Treatment Phase and are
not enrolling in the open-label long-term safety study 67953964MDD3003 will proceed to the
Follow-up Phase. The study intervention will not be administered during the Follow-up Phase.
Further clinical/standard-of-care for the treatment of depression will be arranged by the study
investigator and/or the participant’s treating physician.
6.7. 
Treatment of Overdose
For this study, any dose of aticaprant greater than 6 tablets (3 small and 3 large) within a 24-hour
time period will be considered an overdose. The sponsor does not recommend specific treatment
for an overdose.
In the event of an overdose, the investigator or treating physician should:
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Contact the medical monitor immediately.
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention must be interrupted.
Closely monitor the participant for AE/SAE and laboratory abnormalities until aticaprant can
no longer be detected systemically (at least 2 days).
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose of study
intervention if requested by the medical monitor (determined on a case-by-case basis).
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Overdose should be reported in the eCRF as an AE.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the medical monitor based on the clinical evaluation of the participant.
6.8. 
Concomitant Therapy
Prestudy non-antidepressant therapies administered for up to 30 days before the start of the
Screening Phase must be recorded at the start of this phase. Ongoing (chronic or occasional)
administration and known prior (past 6 months) use of proton pump inhibitors (PPIs), H2 blockers
or other gastroprotective agents, nonsteroidal anti-inflammatory drugs (NSAID), or aspirin, must
be recorded (eg, dose, duration, reason) under Concomitant Therapies in the eCRF.
All antidepressant treatment(s), taken during the current depressive episode (ie, including those
taken more than 30 days prior to the start of the Screening Phase) will be recorded at the start of
the Screening Phase. This includes non-pharmacological treatments (eg, psychotherapy,
transcranial magnetic stimulation [TMS], etc). Antidepressant pharmacological treatments which
are not listed on the MGH ATRQ  but were used, or currently being used, as antidepressant
treatment in the current depressive episode must be recorded in the ‘Concomitant Therapy’ eCRF.
Concomitant therapies must be recorded throughout the study, beginning with signing of the ICF
and continuing up to the last study visit. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
Modification of an effective pre-existing therapy should not be made for the explicit purpose of
entering a participant into the study. Information on concomitant therapies should also be obtained
beyond this time only in conjunction with new or worsening AEs until resolution of the event.
Participants should continue to take their permitted concomitant medications at their regular
schedule; however, restrictions as outlined in Section 6.8.2 and Section 10.7 should be taken into
account. Participants taking antidepressant medications which are not listed on the MGH ATRQ
(for a complete list of antidepressant medications, please refer to Section 10.7 for a list of
medications used for the treatment of depression to be discontinued during the Screening Phase)
at entry will have these medications tapered (if applicable) and discontinued during this phase, per
the local prescribing information or clinical judgment. Additionally, any medication that is listed
on the MGH ATRQ and taken in addition to the current SSRI or SNRI which will be continued in
the study treatment phase including medications taken  for reasons other than depression (eg,
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insomnia or anxiety) should be continued during the Screening Phase but must be discontinued
before the start of the DB Treatment Phase.
Tapering and discontinuation of prohibited therapies should be initiated after completion of the
second HDRS-17 assessment (see Section 1.3) and the SIQA and confirmation these were passed.
Eligible participants who do not require a tapered discontinuation of their prohibited treatment(s)
can proceed to the baseline randomization visit.
This study allows the use of locally approved (including emergency use-authorized [or
country/territory-specific equivalent emergency use approved]) COVID-19 vaccines. For
participants who receive an approved or authorized vaccine, it is recommended that this occurs at
least 5 days prior to the start of dosing, or once randomized at least 5 days prior to the next
scheduled visit. If any vaccines (COVID-19 or other vaccines, eg, influenza) are administered,
these should be recorded in the source documents and entered in the eCRF.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as psychotherapy electrical stimulation,
acupuncture, special diets, and exercise regimens) different from the study intervention must be
recorded in the eCRF. Modification of an effective pre-existing therapy should not be made for
the explicit purpose of entering a participant into the study, unless permitted by protocol.
6.8.1. 
Current (SSRI/SNRI) Antidepressant Therapy
Throughout the study, all participants will need to continue their currentSSRI/SNRI antidepressant
(at the same dose without change and taken approximately around the same time of the day as
prior to entering the study) on which they have had inadequate response at the time of screening.
All participants will continue their current antidepressant (SSRI/SNRI) therapy during the
Screening and DB Treatment Phase. The following antidepressants are permitted: citalopram,
duloxetine, escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine,
sertraline, venlafaxine, and desvenlafaxine. Participants will only continue one of these allowed
antidepressants at an adequate and tolerated dose during the study. No changes in current
antidepressant or dose are permitted from Screening until the end of the DB Treatment Phase.
Participants will receive instructions on compliance with their current oral antidepressant treatment
(SSRI/SNRI). During the course of the study, the investigator or designated study-site personnel
will be responsible for providing additional instructions to re-educate any participant to ensure
compliance with taking the current oral antidepressant (SSRI/SNRI). During the screening phase,
compliance to the current antidepressant treatment must be confirmed by documented records (eg,
medical/pharmacy/prescription record, a letter from a treating physician, etc). During the DB
Treatment Phase, the compliance to the SSRI or SNRI (the one that is continued in this phase) will
be assessed by documented records (medical/pharmacy/prescription records, pill counts, etc). In
the absence of other options to assess compliance, blood or urine levels can be used by the site to
evaluate the adherence to the antidepressant treatment. A participant’s diary will be provided to
capture the current oral antidepressant (SSRI/SNRI) use (see Section 1.3).
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The current antidepressant will not be provided by the sponsor. Participants or their insurance will
be responsible for the cost of the SSRI/SNRI; the sponsor will not be responsible for the cost unless
otherwise specified by local regulations. If during the study, the participant can no longer provide
for the SSRI/SNRI, this issue will need to be discussed with the sponsor’s medical monitor.
6.8.2. 
Prohibited Therapies
A list of prohibited concomitant therapies is provided in Section 10.7. This list is not all-inclusive;
if necessary, please contact the medical monitor for any questions regarding a medication(s).
Please refer to the local prescribing information of the participant’s non-study medications for
information regarding prohibited concomitant medications.
Except where specifically noted, the prohibited medications listed in Section 10.7 are prohibited
from 1 week (or 5 half-lives, whichever is longer) prior to the first dose of study intervention until
after the last dose of study intervention.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
Refer to Section 5.1 (Inclusion Criteria) and Section 5.2 (Exclusion Criteria) for information
regarding contraception requirements and to Section 5.3 (Lifestyle Considerations) for additional
information on prohibition and restrictions.
In addition:
Electroconvulsive therapy (ECT), deep brain stimulation (DBS), TMS, and vagus nerve
stimulation (VNS) are prohibited from study entry through the end of the DB Treatment
Phase.
Participants taking benzodiazepines and/or permitted non-benzodiazepine sleep medications
(eg, zolpidem, zaleplon) during the Screening Phase can continue these medications during
the DB Treatment Phase. No dose increases beyond the equivalent of 4 mg/day of lorazepam
or start of new benzodiazepine medications are permitted during the DB  Treatment Phase.
Benzodiazepines and non-benzodiazepine sleeping medication (eg, zolpidem, zaleplon,
eszopiclone, and ramelteon) are prohibited within 12 hours prior to cognition testing
(Revere.D).
A positive urine drug test for use of PCP or cocaine from Day 1 of the DB Treatment Phase
through the final visit in the DB Treatment Phase will lead to discontinuation from the study
(see Section 7).
Participants who have been receiving ongoing psychological treatment (eg, Cognitive
Behavioral Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy, etc) for a
period of greater than 6 weeks prior to start of screening can continue receiving the
psychotherapy. Start of new psychotherapy or change in existing therapy is not allowed from
the start of the Screening Phase through to the final visit in the DB Treatment Phase.
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention or withdraws from the study before the end of the
DB Treatment Phase, the early withdrawal assessments should be obtained.
All participants who prematurely discontinue study intervention during the DB Treatment Phase
will have an EOT/EW Visit (Visit 2.7 in the SoA, see Section 1.3) and a Follow-up Phase (Visit 3.1
in the SoA) performed.
7.1. 
Discontinuation of Study Intervention
A participant will not be automatically withdrawn from the study if he or she has to discontinue
study intervention before the end of the DB Treatment Phase.
A participant’s study intervention will be discontinued for any of the following reasons:
Lack of Efficacy, per investigator’s judgment.
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention, including, but not limited to:
Signals indicative of acute suicidal ideation with a clear plan or intent at any time during
the study; the participant should be referred to appropriate medical/psychiatric care.
AST and/or ALT >5 x ULN (confirmed by repeat testing).
AST and/or ALT≥3 x ULN and total bilirubin ≥2 x ULN (confirmed by repeat testing).
The participant becomes pregnant. Refer to Section 10.5.
Major protocol deviation (to be assessed on a case-by-case basis).
Study intervention blind is broken.
Lost to follow-up.
Positive urine drug test for PCP or cocaine at any time point during the study.
When a participant withdraws, the reason for withdrawal is to be documented in the eCRF and in
the source document.
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant.
7.1.1. 
Liver Chemistry Stopping Criteria
Stopping of study intervention for abnormal liver tests is required by the investigator when either
a participant meets ALT or AST elevations >5 x ULN at least twice over a 2-week period, AST
and/or ALT ≥3 x ULN and total bilirubin ≥2 x ULN (confirmed by repeat testing), or one of the
conditions outlined in Section 10.6, or in the presence of abnormal liver chemistries not meeting
protocol-specified stopping rules if the investigator believes that it is in best interest of the
participant.
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7.1.2. 
QTc Stopping Criteria
If a clinically significant finding is identified (including, but not limited to changes from baseline)
in QT interval corrected using Fridericia’s formula (QTcF) after enrollment, the investigator or
qualified designee will determine if the participant can continue in the study and if any change in
participant management is needed. This review of the ECG printed at the time of collection must
be documented. Any new clinically relevant finding must be reported as an AE. The QTc stopping
criteria apply only to the DB Treatment Phase and not at Screening or Baseline.
A participant who meets either of the following criteria (after baseline, Day 1, pre-randomization)
based on the average of triplicate ECG readings will be withdrawn from study intervention:
QTcF change from baseline is ≥60 msec AND QTcF >480 msec
OR
QTcF >500 msec.
7.1.3. 
Temporary Interruption, Restart or Rechallenge
The following guidance should be considered during the study treatment phase if a participant
reports moderate/severe 
 lasting more than
3 days and with no potential alternative causes according to clinical judgment:
The oral study intervention should be interrupted.
If the symptoms resolve with the interruption, treatment may be restarted.
If the symptoms worsen or do not resolve with the interruption ofthe oral study intervention,
the participant should be referred to a
 other relevant specialist, or primary
care physician for a follow-up assessment. After the assessment, if recommended by the
referring physician, and considered appropriate according to the clinical judgment of the
investigator, the participant may continue with dosing.
If moderate/severe 
 re-occur with
rechallenge, consider treatment discontinuation and refer to a 
 other
specialist or primary care physician for further follow-up assessments.
7.2. 
Participant Discontinuation/Withdrawal from the Study
A participant will be withdrawn from the study for any of the following reasons:
Lost to follow-up,
Major Protocol Deviation (to be assessed on a case-by-case basis),
Withdrawal of consent (Note: “Withdrawal of Consent” should only be selected as a reason
for withdrawal if the participant does not agree to any further study assessments or procedures.
If the participant is agreeable to participating in the EOT/EW Visit and the Follow-up Phase,
another reason for withdrawal should be selected),
Positive urine drug test for PCP or cocaine at any time point during the study,
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Death.
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document.
Any participant who withdraws after receiving the study intervention will have an early withdrawal
evaluation.
Withdrawal of Consent
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent, then no additional assessments are allowed unless the participant agrees
to take part in the EOT/EW Visit. A participant declining to return for scheduled visits does not
necessarily constitute withdrawal of consent. Alternate follow-up mechanisms that the participant
agreed to when signing the consent form apply as local regulations permit.
Every effort will be made in the study to ensure withdrawal of consent is not selected as a reason
for discontinuation when in fact the participant withdrew for an identifiable reason (eg, due to an
AE or withdrew due to lack of efficacy). Participants who wish to withdraw from the study should
be asked if they are agreeable to continue to an early withdrawal visit (if withdrawing from the
DB Treatment Phase) and the Follow-up Phase, or to be contacted to collect follow-up information.
Participants who are not agreeable to follow-up contact will be withdrawn from the study as
“withdrawal of consent.” Participants who no longer wish to take study intervention but agree to
provide information will be withdrawn from the DB Treatment Phase with the reason noted as
“Other” and will specify the reason why. For a participant who does “withdrawal of consent,” it is
recommended that the participant withdraw consent in writing; if he/she refuses or is physically
unavailable, the study site should document and sign the reason for the participant’s failure to
withdraw consent in writing and maintain it with the source records. The investigator will be
responsible for making all required notifications to the Institutional Review Board (IRB) or
Independent Ethics Committee (IEC).
When a participant withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Participants who withdraw will not be
replaced.
Managing Missing Data
For any participant who has not completed the DB Treatment Phase (Day 43 Visit or at least
Day 43 MADRS assessment), an EOT/EW Visit should be conducted as soon as possible,
preferably within one day of the last dose of study intervention.
If a participant discontinues from the study in the DB Treatment Phase (ie, prior to completion of
the Day 43 visit), an EOT/EW Visit (Visit 2.7) should be conducted as soon as possible, preferably
the day after the last dose of study intervention, and within 1 week of the date of discontinuation,
followed by the Follow-up Phase (Visit 3.1). Participants who prematurely discontinue study
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intervention for any reason before completion of the DB Treatment Phase will not be considered
to have completed the DB Treatment Phase of the study.
Participants that discontinue study intervention early (ie, prior to completion of the Day 43 Visit)
or who are non-compliant to the study intervention (ie, have missed either 4 or more consecutive
doses of study intervention or a total of 8 or more doses during the DB Treatment Phase; see
Section 6.4) will not be eligible to participate in the open-label study.
Missing data in clinical trials can lead to problems that undermine the scientific credibility of
causal conclusions. The most common reason for missing data is participants who discontinue the
assigned study intervention because of AEs, lack of tolerability, lack of efficacy, or inconvenience.
To reduce missing data in this study, if a participant discontinues the DB study intervention for
reasons other than withdrawal of consent, he/she will be expected to complete the Follow-up Phase
(Visit 3.1).
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Optional Research Samples While Remaining in the Main Study
The participant may withdraw consent for optional research samples while remaining in the study.
In such a case, the optional research samples will be destroyed. The sample destruction process
will proceed as described above.
Withdrawal From the Use of Genetic Research Samples
A participant who withdraws their consent from the use of pharmacogenomics and epigenetic
(DNA, RNA) samples obtained in the study will have the following options regarding the optional
research sample:
The collected samples will be retained and used in accordance with the participant's original
separate informed consent for optional research samples.
The participant may withdraw consent for optional research samples, in which case the
samples will be destroyed, and no further testing will take place. To initiate the sample
destruction process, the investigator must notify the sponsor study site contact of withdrawal
of consent for the optional research samples and to request sample destruction. The sponsor
study site contact will, in turn, contact the biomarker representative to execute sample
destruction. If requested, the investigator will receive written confirmation from the sponsor
that the samples have been destroyed.
Details should be provided in a separate ICF for optional research samples.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Section 10.3.5,
Long-term Retention of Samples for Additional Future Research). In such a case, samples will be
destroyed after they are no longer needed for the clinical study. Details of the sample retention for
research are presented in the main ICF and in the separate ICF for optional research samples.
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7.3. 
Lost to Follow-up
To ensure access to participants during follow-up, the study sites should attempt to obtain both
primary and secondary telephone contact numbers (eg, home, work, and mobile phone numbers),
as well as other contact information (eg, email addresses) from participants before randomization.
In addition, the study site should emphasize the importance of follow-up information to the
participant before randomization. The measures taken to follow-up must be documented in the
eCRF.
A participant will be considered lost to follow-up if the participant repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study  site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant where possible (3 telephone calls,
emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA(Section 1.3) summarizes the frequency and timing ofefficacy, safety, laboratory, clinical
pharmacology, pharmacogenomics and epigenetic, and biomarker, measurements applicable to
this study.
Order of Assessments
All MADRS assessments will be performed by qualified site-based raters using videoconferencing
which provides opportunity to schedule and complete the MADRS assessment before or after the
on-site visit but respecting the visit window. To reduce the time spent by a participant on-site
during the clinical visit, sites are recommended for clinical visits in the study treatment period with
several procedures to consider scheduling and conducting the MADRS assessment (with
videoconferencing) outside of the on-site visit.
Patient-reported outcome (PRO) assessments should be completed by participants in the order
stated in the SoA and in a language in which the participant is fluent and literate. Study personnel
will instruct participants how to self-complete the PRO assessment (see Section 10.8) and further
details are provided in a separate manual provided to the site (see below in Study-Specific
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Materials). When possible, PRO assessments that have not been completed at home prior to the
study visit but are conducted when the participant is on-site, together with the on-site PRO
assessments, should be completed before any tests, procedures, or other consultations to prevent
influencing participant perceptions. However, during site visits with fasting blood sampling, this
may not be possible and for these visits it is recommended that procedures should be performed in
the following sequence:
Blood and urine collection (when in fasted condition), dosing, breakfast, PROs, interview with
site-based rater (SIGMA via videoconference, if not completed before the actual visit, CGI-S),
C-SSRS, and safety assessments. Blood collections for PK and PD assessments should be kept
as close to the specified time as possible.
Twelve-lead ECG readings will be performed both pre-dose and post-dose at Visit 2.1
(Day 1). Additional 12-lead ECG readings will be taken 1 to 4 hours post-dose at Visit 2.5
(Day 29) and Visit 2.7 (EOT/EW). If blood sampling or vital sign measurement is scheduled
for the same time point as 12-lead ECG recording, the procedures are recommended to be
performed in the following order: 12-lead ECG, vital signs, blood draw.
Additional serum (by central laboratory) 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 participation in the study. Repeat or unscheduled
samples may be taken for safety reasons or for technical issues with the samples.
The total blood volume for the study is approximately 123.5 mL (21.0 mL for safety, 24.0 mL for
pharmacokinetics, 8.0 mL for antidepressant compliance, 2.0 mL for pharmacogenomics and
epigenetics, 10.0 mL for RNA samples and 60.0 mL for biomarkers).
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 150.0 mL.
The total blood volume to be collected from each participant will be approximately 123.5 mL.
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Volume of Blood to be Collected from Each Participant
Type of Sample 
Volume per 
Sample (mL) 
No. of Samples 
per Participant 
Approximate
Total Volume
of Blood (mL)[a]
Safety (including screening and post-intervention
assessments)
- Hematology and serum chemistry[b] 
4.5 
3 
13.5
- TSH/FT4 
-- Lipid Panel 
2.5 
2.5 
1 
1 
2.5
2.5
Efficacy
Pharmacokinetic samples 
4.0 
6 
24.0
Antidepressant compliance 
2.0 
4 
8.0
Biomarker samples (plasma and serum) 
20.0 
3 
60.0
RNA samples[c] 
5.0 
2 
10.0
DNA sample[c] 
3.0 
1 
3.0
Approximate Total[d] 
43.5 
21 
123.5
Abbreviations: DNA=deoxyribonucleic acid; FT4=free thyroxine; HbA1c=Hemoglobin A1c; RNA=ribonucleic
acid; TSH=thyroid-stimulating hormone; β-hCG=beta human chorionic gonadotropin.
a. Calculated as number of samples multiplied by amount of blood per sample.
b. HbA1c is taken with hematology if at the same visit.
      Serum β-hCG pregnancy test at Visit 1.1 is taken with serum chemistry.
      Lipid testing is taken with serum chemistry at visit 1.1, 2.1 and 2.7.
c. Blood samples will be collected only from participants who have consented to provide an optional DNA and
RNA sample[s] for research.
d. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.
Note: An indwelling intravenous cannula may be used for blood sample collection.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
Refer to the SoA in Section 1.3 for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the Laboratory Manual.
Study-Specific Materials
The investigator will be provided with the following supplies:
IB for aticaprant
Data Science Materials
Investigational Product (IP) Binder, including the IP Procedures Manual
Laboratory manual and materials
Guidance on the recommended order of study procedures
MGH ATRQ Guidance Document
12-lead ECG equipment and associated materials (eg, manual)
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Rater qualifications/requirements for select clinician-administered assessments
Clinician-administered and patient-reported outcome assessments:
– Paper versions, as applicable
– Electronic devices and associated materials
Study guide for Participant Experience Interview and associated Participant Interview Manual
(for sites in the Czech Republic, Spain, and USA only). Interviews will be conducted by a
third-party vendor.
Procedural documents for SIQA
Procedural documents for independent, central rater and site-based rater interviews
eCRF Completion Guidelines
Sample ICF
IWRS Manual
Participant recruitment materials
Participant diaries
Engage: A Smartphone Application used for video and audio teleconferencing
The Engage application does not place cookies on the participant’s device nor requires access
to personal or GPS data. The application uses the camera and microphone only during an
active call and it does not use the device’s inbuilt possibilities for autofill, photo, or GPS. The
application does use the inbuilt possibilities for video capabilities. The application  has no
access to device storage, photos, videos or other data on the device. All audio/video is captured
on the vendor’s conduit server only.
This list is not all-inclusive.
8.1. 
Assessments
The following assessments will be performed at the timepoints indicated in the SoA (Section 1.3).
To minimize the risk of unblinding the treatment assignment, different site raters will perform
efficacy and safety assessments; clinicians who perform the MADRS assessments will not be
involved in assessing AEs.
8.1.1. 
Screening Assessments
The following screening assessments will be administered by independent remote raters:
SIQA
HDRS-17
The following assessments will be performed by appropriately trained and certified investigators
or designees:
SCID-CT
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MGH ATRQ
MMSE (safety assessment to be performed in participants of 65 to 74 years of age, inclusive)
8.1.1.1. 
17-item Hamilton Depression Rating Scale (HDRS-17)
8.1.1.2. 
Massachusetts General Hospital Antidepressant Treatment Response
Questionnaire (MGH ATRQ)
8.1.1.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders –Clinical
Trials Version (SCID-CT)
8.1.1.4. 
Site Independent Qualification Assessment (SIQA)
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8.1.2. 
Efficacy Assessments
The following efficacy assessments will be performed:
MADRS (performed using the Structured Interview Guide for the MADRS [SIGMA])
CGI-S
RLT (to be performed in English-speaking countries/territories).
The following efficacy assessments are PROs and will be completed by the participants:
SHAPS
DARS
PGI-S (anhedonia)
PHQ-9
PGI-S (depression)
PROMIS-APS 8a
QLDS
EQ-5D-5L
GAD-7
PGI-C (anhedonia)
WPAI: D
TSQM-9
All PRO instruments will be provided in the local language in accordance with local guidelines.
All PRO instruments will be available for regulators and for IRB/IEC submissions and will be
provided separately in a companion manual with the instruments that will be submitted with the
protocol.
The PRO and AE data will not be reconciled with each other.
8.1.2.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS)
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8.1.2.2. 
Snaith-Hamilton Pleasure Scale (SHAPS)
8.1.2.3. 
Dimensional Anhedonia Rating Scale (DARS)
8.1.2.4. 
Clinical Global Impression-Severity (CGI-S)
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8.1.2.5. 
Patient Global Impression of Severity (PGI-S)
8.1.2.6. 
Patient Global Impression of Change (PGI-C)
8.1.2.7. 
Patient Health Questionnaire, 9-item (PHQ-9)
8.1.2.8. 
PROMIS Short Form v2.0 –Ability to Participate in Social Roles and
Activities –8a (PROMIS-APS 8a)
8.1.2.9. 
Generalized Anxiety Disorder 7-item Scale (GAD-7)
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8.1.2.10. 
Quality of Life in Depression Scale (QLDS)
8.1.2.11. 
European Quality of Life, 5 Dimension, 5-Level (EQ-5D-5L)
Questionnaire
8.1.2.12. 
Work Productivity and Activity Impairment: Depression (WPAI:D)
8.1.2.13. 
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
8.2. 
Safety Assessments
An IDMC will be commissioned for this study to periodically review safety data.
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Details regarding the IDMC are provided in Section 10.3.6, Committees Structure.
Physical examination, body weight, BMI, vital signs (including blood pressure, pulse/heart rate,
and temperature measurements), 12-lead ECG, clinical laboratory tests (including hematology,
serum chemistry, and urinalysis), pregnancy testing (for female participants of childbearing
potential) will be performed throughout the study to monitor participant safety.
Additional blood and urine samples may be taken, or vital signs and 12-lead ECGs recorded at the
discretion of the investigators as needed.
Menstrual cycles will be tracked in premenopausal female participants who are still having their
menses during the study, using a participant diary and participant’s verbal report.
Adverse events (AEs), including TEAEs will be evaluated throughout the course of the study.
Clinically relevant TEAEs of special interest will be examined separately and grouped in the
following categories as defined by the Standardized Medical Dictionary for Regulatory Activities
(MedDRA) (version 23.0, or above if applicable).
Adverse events will be reported and followed by the investigator as specified in Section 8.3 and
Section 10.4.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
section of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
Narrative descriptions will be provided for deaths, participants with serious adverse events, and
participants who discontinued study intervention due to an adverse event.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the SoA (Section 1.3).
8.2.1. 
Physical Examinations
The study investigator, or other authorized and appropriately qualified designee, will perform the
physical examinations that will include assessment of sensation, level of alertness, ataxia, tremor,
and other routine components of a brief neurological examination. Height will be measured at
screening only. Body weight will be measured at screening and throughout the study according to
the SoA (see Section 1.3).
Body weight should be measured using a calibrated scale at each indicated visit as outlined in the
SoA (see Section 1.3). Participants should be weighed at approximately the same time of day on
the same scale, wearing lightweight clothing without shoes; they will be instructed to empty their
bladders before being weighed.
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8.2.2. 
Vital Signs
Blood pressure and pulse/heart rate measurements will be assessed with the participant in a sitting
position using a completely automated device. Manual techniques will be used only if an
automated device is not available. Sitting blood pressure and pulse/heart rate measurements should
be preceded by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell
phones).
In addition, oral or tympanic temperature will be measured. In the places where oral or tympanic
temperature are not standard practice, axillary temperature can be used. The same temperature
measure should be used throughout the study.
8.2.3. 
Electrocardiograms
Twelve-lead ECGs, intended for safety monitoring, will be recorded in a supine position so that
the different ECG intervals (RR, PR, QRS, QT) can be measured. The 12-lead ECG will be
recorded at Screening and Baseline (Day 1, pre-randomization) until 4 regular consecutive
complexes are available in good readable quality.
Notes:
During screening, ifQTcF is prolonged on the initial 12-lead ECG (ie, ≥450 msec [males] or
≥470 msec [females]), the average QTcF of three 12-lead ECGs, recorded 4 minutes apart,
must not be ≥450 msec for male participants and ≥470 msec for female participants.
At Visit 2.1 (Day 1), if QTcF is prolonged based on a site-evaluated ECG, a total of three
12-lead ECGs should be obtained at least 4 minutes apart. The average QTcF of the three 12-
lead ECGs will then be used to determine the participant’s eligibility.
During the DB Treatment Phase, if a clinically significant finding is identified in QTcF, the
average QTcF of three 12-lead ECGs, recorded 4 minutes apart, will be used to assess QTc
stopping criteria (see Section 7.1.2, QTc Stopping Criteria).
During the collection of ECGs and vital signs, participants should be in a quiet setting without
distractions (eg, television, cell phones). Participants should rest in a supine position for at least
5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood
sampling or vital sign measurement is scheduled for the same time point as ECG recording, the
procedures should be performed in the following order: 12-lead ECG(s), vital signs, blood draw.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Section 10.2. The investigator must review the laboratory results,
document this review, and record any clinically relevant changes occurring during the study in the
AE section of the CRF. The laboratory reports must be filed with the source documents.
Clinical laboratory assessments, including TSH  (all participants, at screening only), follicle
stimulating hormone (FSH) (female participants only, at screening only if required for
documentation that a female participant is not of childbearing potential, see Inclusion
Criterion 12), FT4, hematology, serum chemistry, HbA1c, lipid panel, and urinalysis that should
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be performed at approximately the same time under fasting conditions, except possibly at the
screening visit. The clinical laboratory assessments, ECGs and vital signs should be done first and
then food or coffee provided before PROs and clinician-rated observations are carried out.
8.2.5. 
Pregnancy Testing
For female participants of childbearing potential, a serum pregnancy test must be performed at
screening, and urine pregnancy tests must be performed as indicated in the SoA (see Section 1.3)
to establish absence of pregnancy. Additional serum and urine pregnancy tests may be conducted
as needed per the investigator’s judgment.
8.2.6. 
Columbia Suicidality Severity Rating Scale (C-SSRS)
8.2.7. 
Arizona Sexual Experiences Scale (ASEX)
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8.2.8. 
Cognitive Test Battery (Revere.D)
8.2.9. 
Mini Mental State Examination (MMSE) - Screening Only
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8.2.10. 
Menstrual Cycle Tracking
Menstrual cycle tracking (start date of last menstrual period) will be documented at the study visits
specified in the SoA (Section 1.3) only for female participants with a menstrual cycle.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and PQCs, from clinical studies are crucial for the protection of participants, investigators, and the
sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
Standard Operating Procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of safety information; all clinical studies conducted by the sponsor or its
affiliates will be conducted in accordance with those procedures.
Adverse events, including AESIs, will be reported by the participant (or, when appropriate, by a
caregiver, surrogate, or the participant's legally acceptable representative) for the duration of the
study. Further details on AEs, SAEs, and PQCs can be found in Section 10.4.
This study allows the use of locally approved (including emergency use-authorized [or
country/territory-specific equivalent emergency use approved]) COVID-19 vaccines. All AEs,
including those following vaccination, should be included in the source and entered in the eCRF.
See Section 10.9 for further details regarding COVID-19.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs, including AESI and special reporting situations, whether serious or non-serious, will be
reported from the time a signed and dated ICF is obtained until completion of the participant's last
study-related procedure, which may include contact for follow-up of safety. Serious adverse
events, including those spontaneously reported to the investigator within 30 days after the last dose
of study intervention, must be reported using the Serious Adverse Event Form. The sponsor will
evaluate any safety information spontaneously reported by an investigator beyond the time frame
specified in the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study site personnel immediately, but no later than 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
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Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician
from the study site, and transmitted to the sponsor immediately but no later than within 24 hours.
The initial and follow-up reports of an SAE should be transmitted electronically or by facsimile
(fax). Telephone reporting should be the exception and the reporter should be asked to complete
the appropriate form(s) first.
A possible Hy’s Law case is defined by the occurrence of ALT/AST ≥3 x ULN, ALP <2 x ULN
together with Tbili ≥2 x ULN or international normalized ratio (INR) >1.5 (if measured). Any
possible Hy’s Law case is considered an important medical event and must be reported as an SAE
to the sponsor in an expedited manner, using the SAE form, even before all other possible causes
of liver injury have been excluded.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
Solicited Adverse Events
Solicited AEs are predefined local and systemic events for which the participant is specifically
questioned during the study (see Section 8).
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned during the
study visits.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
product quality complaint (PQC)as fully as possible. This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.
Adverse events and the special reporting situation of pregnancy will be followed by the
investigator as specified in Section 10.4.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported to
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regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded
SUSAR summary, unless otherwise specified.
An anticipated event is an AE that commonly occurs in the study population independent of
exposure to the drug under investigation. For the purposes of this study the following SAEs will
be considered anticipated events:
Suicidal thinking, ideation, and behavior
Sleep changes, difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, and
reduced energy
Difficulty in sexual desire, performance, or satisfaction
Reduced appetite and weight changes (loss or increase)
Activation or hypomania/mania
Irritability, anger, and impulsive behavior
Agitation, tension, panic attacks, and phobia
Depression
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the intervention group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries/territories in which the studies are conducted.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. Any participant who becomes
pregnant during the study must be promptly discontinued from further study intervention.
Because the effect of the study intervention on sperm is unknown, pregnancies in partners of male
participants included in the study will be reported as noted above.
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Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of male participant and his partner, and
any postnatal sequelae in the infant will be required.
8.3.6. 
Adverse Events of Special Interest
The following AEs are considered to be of special interest in this study:
Investigators are instructed to inquire about the occurrence of such events during the collection of
AEs at each visit. When reported, investigators will be required to complete additional eCRF pages
for the AESI. At a minimum, a description of the event (including any known precipitating
circumstances), the time relative to dose administration, the duration, concomitant treatment, and
outcome of the event will be reported. See Section 10.4.3.1 for guidance on assessing the severity
of AESI.
Note: If the event meets the seriousness criteria (see Section 10.4.1), the Serious Adverse Event
Form must also be completed according to the SAEs reporting timeline, ie, within 24 hours of
having become aware of the event, even if all details are not available (see Section 10.4.5).a
8.4. 
Digital Biomarker Assessments
Objective behavior and physical measurements will only be administered where applicable and/or
permitted per local regulations.
Objective behavior and physical measurements, including Speech/Facial Digital Biomarker and
Passive Behavior Sensing using a smartphone application software, will be performed as optional
assessments. In addition, the RLT will be performed as an objective assessment (as a sub-study)
of the ability to modulate behavior as a function of prior reinforcement.
8.4.1. 
Speech/Facial Digital Biomarker Analysis (Optional)
Studies have supported the view that vocal acoustic properties in speech may serve as digital
biomarkers for depression severity and treatment response (Mundt 2007; Mundt 2012). In this
study, the MADRS physician-patient interview may be recorded for data quality monitoring. To
reduce participant burden, consent will be obtained to use the same speech/video samples for
exploratory analysis of acoustic and linguistic properties, and facial emotional characteristics. For
the linguistic analysis, the speech sample may also undergo analysis of lexicosyntactic variables
for the types of words used and sentence complexity, and analysis of semantic measures to quantify
information content. Semantic measures, such as semantic coherence (ie, how well he or she stayed
a 
The intention is to collect PK sample around the time of occurrence of these events (see Section 1.3, SoA).
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on topic) and syntactic structure (eg, phrase length and use of determiner words that link the
phrases)have been associated with the onset of psychosis in high-risk participants (Bedi 2015).
8.4.2. 
Passive Behavior Sensing Using a Smartphone Application Software
(Optional)
In this optional study component, participants will carry their smartphone on their person during
routine daily activity. A smartphone app will run continuously in the background, sensing and
collecting data from which to infer the status of participants’ activity and behavior, including the
following:
Number of steps taken, and physical activities undertaken.
Time spent in specific locations (eg, the home, workplace) and distance traveled.
Technology use pattern such as screen unlocks and on/off time and battery charging state.
Inferred sleep duration and wake/sleep cycles.
Using the accelerometer, the app generates and stores physical activity status (ie, active vs
sedentary) based on movement detected. For privacy protection, location data will be obfuscated
so that GPS coordinates are unknown. Smartphones will not be provided to participants for
participation in this optional study component. Rather, if the participant has his/her own
smartphone, he/she is eligible to participate in this component of the study. No data collected will
be displayed for the study participant.
8.4.3. 
Reward Learning Task (RLT)
The RLT provides an objective assessment of the ability to modulate behavior as a function of
prior reinforcement. The RLT is a computerized signal detection task to measure the sensitivity to
reward in children with attention-deficit hyperactivity disorder (ADHD) (Tripp 1999). It was
further contextualized as an objective measure for anhedonia (Pizzagalli 2005).
This task measures the participant’s ability to modulate behavior in response to rewards
(Pizzagalli 2005). In each trial, the participant is asked to identify which type of image, out of 2
groups of similar images (Group A stimuli and Group B stimuli), is displayed. Critically, the
difference between the 2 sets of images is small and the correct responses of 1 type are followed
by rewards 3 times more frequently than correct responses of the other type. The participant is
specifically instructed that not all correct responses will be rewarded, and the goal is to maximize
reward. One key measure is response bias, a measure of the degree to which the participant
preferentially chooses the response that is more frequently rewarded. Other measures include
reaction time and discriminability, a measure of the participant’s ability to discriminate between
the 2 sets of images, learning rate, and reward sensitivity.
8.5. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of aticaprant. Plasma collected for PK may
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
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after the study period. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
8.5.1. 
Evaluations
Venous blood samples of approximately 4 mL for the determination of plasma concentrations of
aticaprant and any relevant metabolite(s)(if warranted) will be collected from participants per the
SoA (see Section 1.3).
The exact dates and times of PK blood sample collection must be recorded, along with all
concomitant medications (dose, drug, start and stop date). Study intervention dosing time on the
day before each PK sample collection will be accurately recorded by exact dosing date and time
by the participant in the participant diary. In addition, in participants who have ongoing AESI, or
AESI related to an SAE leading to discontinuation, every effort will be made to collect additional
unscheduled PK sample (This blood sample should be collected as close as possible to the AESI
or AESI-related SAE occurrence, but preferably within 72 hours of the last study intervention
administration).
Venous blood samples will be collected for the analysis of aticaprant. Samples collected for
analyses of aticaprant plasma concentration may additionally be used to evaluate safety or efficacy
aspects that address concerns arising during or after the study period. Genetic analyses will not be
performed on these plasma samples. Participant confidentiality will be maintained. Additional
information about the collection, handling, and shipment of biological samples can be found in the
Laboratory Manual.
During the DB phase, blood samples for PK will be collected from all participants, including
placebo-treated participants, but samples from placebo-treated participants will not be analyzed
for PK. These samples will be stored and may be analyzed if needed (eg, suspicion of an incorrect
treatment assignment).
8.5.2. 
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of aticaprant (and any relevant
metabolite(s), if warranted)using a validated, specific, and sensitive liquid chromatography/mass
spectrometry/mass spectrometry (LC-MS/MS) method by or under the supervision of the sponsor.
In addition, plasma PK samples may be stored for future analysis of the metabolite profile.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Plasma concentration-time data will be displayed by visit date and time for aticaprant.
The plasma concentration-time data of aticaprant will be analyzed using population PK modeling.
Typical population values of basic PK parameters (eg, aticaprant clearance, distribution volume)
will be estimated together with the inter-individual variability. Effects of participant
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demographics, laboratory parameter values, and other covariates on the PK of aticaprant will be
explored. The results of the population PK analyses will be reported separately.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between MADRS total score (and possibly selected AEs as additional PD
parameters) and PK metrics of aticaprant may be evaluated. If there is any visual trend in graphical
analysis, suitable models will be applied to describe the exposure-effect relationships. The results
of the exposure-response evaluations will be presented in a separate report.
8.6. 
Biomarkers
Blood samples will be collected during the DB Treatment Phase: (a) to evaluate diagnostic
biomarker signatures predictive of enhanced clinical improvement to aticaprant; (b) to explore
biomarkers that help to explain interindividual variability in efficacy, pharmacokinetics,
pharmacodynamics, safety and tolerability of adjunctive aticaprant, or that may be associated with
MDD in general and/or specific symptoms, such as anhedonia.
Biomarkers may be added or deleted based on scientific information ortechnical innovations under
the condition that the total volume of blood collected will not be increased.
To avoid interference caused by lipid content in the morning blood specimens collected for
biomarker evaluation, biomarker samples will be collected under fasting conditions and prior to
study intervention administration.
Menstrual cycle will be tracked in premenopausal female participants who are still having their
menses during the study as indicated in the SoA (see Section 1.3).
8.7. 
Immunogenicity Assessments
Not applicable.
8.8. 
Pharmacogenomic and Epigenetic (DNA, RNA) Assessments
Participation of pharmacogenomic blood sample collection is optional. Participants must sign a
separate ICF if they  agree to participate in the optional DNA and RNA sample collection for
research (where local regulations permit). Refusal to give consent for the optional DNAand RNA
research samples does not exclude a participant from the study.
With participant’s consent, blood sample collection per the SoA (see Section 1.3) will be
performed to allow for the potential identification of genetic (DNA and RNA), epigenetic factors
and transcriptional 
changes that 
may 
influence 
the 
efficacy, 
pharmacokinetics,
pharmacodynamics, safety and tolerability of adjunctive aticaprant, or that may be associated with
MDD in general and/or specific symptoms, such as anhedonia.
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8.9. 
Participant Medical Information Prior to, During and After the Study
(Optional Real-world DataCollection)
Tokenization (US only) enables linkage of clinical trial data with real-world evidence (RWE) data,
which allows for the correlation of patient characteristics at baseline with long-term clinical
outcomes (eg, psychiatric hospitalization) available from RWE data. For participants who have
provided consent for the optional substudies, medical data (electronic health records, claims and
laboratory data from other care settings) from 5 years prior to study enrollment until 5 years after
study completion may be accessed utilizing tokenization and matching procedures (ie, the
generation of anonymous identifiers or “tokens” [hashed and encrypted combinations of
identifying elements] to allow linking of participant data from different sources without
compromising the participant’s confidentiality). Data collection is optional. These data may be
used for exploratory analyses to enhance our understanding of the impact of prior medical history
on the response to the study intervention on efficacy and duration of efficacy as well as AEs that
may occur during and after completion of the study. The analyses will be described in detail in a
dedicated analysis plan.
8.10. Ongoing Participant Review
AEs and concomitant medication will be recorded at each visit, including the remote contact visit.
The participant will also maintain a diary for current antidepressant use, which will be reviewed
by the site at each clinical visit.
8.11. Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this study.
8.12. Participant Experience Interview (Optional)
An optional Participant Experience Interview will be conducted as a sub-study. The sub-study is
optional and choosing not to participate in the interview will not impact the participant’s
involvement in any other aspects of the main study. Participants randomized in the main study
who have provided the sub-study specific separate informed consent may participate in the
Participant Experience Interview. The opportunity to provide informed consent to participate in
this sub-study may be offered anytime during the DB Treatment Phase following the first dose of
study intervention, but no later than Visit 2.7. The opportunity to consent may be offered after the
collection of PRO assessments for the visit.
The Participant Experience Interview will be conducted by a third-party vendor using interviewers
trained in qualitative semi-structured interviewing. The objectives of this interview study are to
better understand the participant’s experience of depression and anhedonia, including validation
and interpretation of the DARS. This interview will be scheduled within approximately 7 days of
the participant’s scheduled Visit 2.7.
The interview will be conducted via telephone in the local language in accordance with local
guidelines and will last approximately 60 minutes. The interview will follow a semi structured
interview guide using open-ended questions to guide discussion without leading. The interview
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will be audio recorded, transcribed, and analyzed. Only de-identified transcripts will be sent to the
sponsor.
Further details can be found in the separate study guide for the Participant Experience Interview
and associated Participant Interview Manual. The results from the Participant Experience
Interviews will be analyzed and presented separately from the main study.
9. 
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
This study is designed to show that the treatment effect in improving depressive symptoms (as
measured by change from baseline on Day 43 in MADRS total score) of aticaprant 10 mg as an
adjunctive MDD treatment is superior to placebo in adult participants with MDD ANH+.
If µT is the mean change in MADRS total score for the aticaprant 10 mg group and µP is the mean
change in MADRS total score for the placebo group, then the hypothesis can be written as follows:
H0: µT –µP ≥0 vs
H1: µT –µP <0
Superiority can be concluded if the 2-sided p-value for the testing of the hypothesis above is less
than 0.05 (2-sided) and the direction is consistent with the alternative hypothesis.
9.2. 
Sample Size Determination
Approximately 538 participants, including adult (18 to 64 years of age, inclusive) and elderly
(65 to 74 years of age, inclusive) will be enrolled in this study.
Participants entering the DB Treatment Phase will be randomized in a 1:1 ratio to receive
adjunctive aticaprant 10 mg or adjunctive placebo. A minimum of 324 adult participants with
MDD ANH+ and approximately 106 adult participants with MDD ANH- will be enrolled.
Assuming an effect size of 0.4 for the change in MADRS total score, and a 1-sided significance
level of 0.025 (equivalently, 2-sided 0.05), this sample size of 324 adult participants with MDD
ANH+ will provide approximately 90% power for the comparison between aticaprant 10 mg and
placebo for the primary efficacy endpoint (in adult participants with MDD ANH+), accounting for
a dropout rate of approximately 15%.
The effect size used in the sample size calculation was based on the results of
Study 67953964MDD2001 where the effect size was 0.45 (mean difference between treatment
groups of -4.1 and a pooled standard deviation of 8.98) for the change from baseline to Day 43 in
MADRS total score for the relevant study population, and clinical judgment. Given that
67953964MDD2001 was a Phase 2 study, the sample size for the primary efficacy analysis for this
Phase 3 study was determined using a smaller effect size of 0.4 to allow for greater variability that
can be expected for a global study that is larger in scope.
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It is expected that approximately 108 elderly participants (65 to 74 years of age, inclusive) will be
enrolled in the study. This subset of participants will be analyzed as an exploratory evaluation and
will not be included in the primary analysis set.
9.3. 
Participant Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Analysis Sets 
Description
All Participants 
All participants who sign the ICF
Randomized 
All participants who were randomized in the study
Full Analysis Set 
(FAS_ANH+) 
All adult randomized participants with MDD ANH+ who take at least 1 dose of study
intervention
Safety  
All randomized participants (adults and elderly) who take at least 1 dose of study intervention
The analyses of primary and key secondary endpoints will be based on the FAS_ANH+. The
analyses of other efficacy endpoints and the corresponding analysis sets will be specified in the
Statistical Analysis Plan.
The safety analyses will be based on the safety analysis set.
9.4. 
Statistical Analyses
Statistical analysis will be performed by the sponsor or under the authority of the sponsor. A
general description of the statistical methods to be used to analyze the efficacy and safety data is
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).
The SAP will be finalized prior to the database lock and will include a more technical and detailed
description of the statistical analyses described in this section. This section is a summary of the
planned statistical analyses of the most important endpoints including primary and key secondary
endpoints.
9.4.1. 
General Considerations
The assessment of primary and secondary (key and other) endpoints will be conducted on the
FAS_ANH+, which includes randomized adult (not elderly) participants with MDD ANH+ who
took at least 1 dose of study intervention.
The primary efficacy endpoint is the change in MADRS total score from baseline to Day 43 in
adult participants with MDD ANH+. The key secondary endpoint is the change in DARS total
score from baseline to Day 43 in this group of study participants.
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9.4.2. 
Efficacy Analysis
9.4.2.1. 
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the change from baseline in MADRS total score at Day 43 in
FAS_ANH+.
Primary Estimand: This estimand is defined to address the primary objective when the study
intervention is taken as directed. This estimand has the following components:
Study intervention:
Experimental: Aticaprant 10 mg as an adjunctive treatment to SSRI or SNRI
Control: Placebo as an adjunctive treatment to SSRI or SNRI
Population: Adult participants (18 to 64 years of age, inclusive) with MDD ANH+ who have had
an inadequate response to current antidepressant therapy with an SSRI/SNRI, as reflected by the
inclusion/exclusion criteria.
Endpoint: Change in MADRS total score from baseline to Day 43.
Intercurrent events: The following intercurrent events will be managed using a hypothetical
strategy (ie, as if the intercurrent event did not occur):
Discontinuation of study intervention only,
Discontinuation of both study intervention and current antidepressant,
Switch of study intervention only (ie, initiation of another antidepressant after discontinuation
of study intervention),
Switch of current antidepressant therapy only,
Switch of study intervention and current antidepressant therapy.
Summary measure: Difference in treatment means.
Primary analysis: Change from baseline in MADRS total score will be analyzed by MMRM based
on observed case. The fixed terms included in the model will be intervention group (aticaprant
10 mg and placebo), country/territory, time, and time-by intervention interaction, and the baseline
MADRS total score as a covariate. The within-subject covariance between visits will be estimated
via an unstructured variance-covariance matrix. In case of convergence problems, alternative
variance-covariance structures will be tried in the following order, with the first structure that
converges being used in the analysis: heterogeneous Toeplitz, standard Toeplitz, and AR(1) with
separate subject random effect. The Kenward-Roger method will be used for approximating the
denominator degrees of freedom. Comparison between aticaprant 10 mg and placebo at Day 43
will be performed using the appropriate contrast. Difference in least square means and 2-sided
95% confidence intervals (CI) will be presented.
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Sensitivity analysis: Delta adjustment tipping point will be conducted as a sensitivity analysis.
Justification of MMRM: The discontinuation rates observed in the Phase 2a Study
67953964MDD2001 were less than 5% in the 2 treatment arms (4.8% in aticaprant 10 mg, and
2.4% in placebo). There was no apparent pattern of trajectories of MADRS change from baseline
among participants who completed the study compared with participants who discontinued study
intervention within each intervention group. Additionally, there was no specific pattern of
trajectories MADRS change from baseline for each dropout reason. Based on these observations,
it is considered reasonable to assume missing at random (MAR) as the missingness mechanism.
MAR assumption cannot be tested vs MNAR using observed data, however, simulation findings
(Siddiqui 2009) indicate that in the presence of a mixture of the 3 missing mechanisms (missing
completely at random [MCAR], MAR, missing not at random [MNAR])with differential dropout
rates between treatment groups, the MMRM approach is able to re-estimate the true treatment
difference consistently with a negligible bias and control Type I error rate. Therefore, the primary
analysis in this Phase 3 study will be MMRM, with sensitivity analysis using the tipping point
method to stress test the efficacy findings under MNAR assumption.
Any supplementary estimands that are identified will be described in the SAP.
9.4.3. 
Secondary Endpoint(s)
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the change from baseline to Day 43 in DARS total score
in participants belonging to FAS_ANH+.
The same estimand as described above (except the endpoint component) and corresponding
analyses as for the primary endpoint will be used for the key secondary endpoint.
Testing Procedure for Primary and Key Secondary Endpoints
A fixed sequence testing procedure will be applied to control the family-wise error rate (FWER)
at 2-sided 0.05 level accounting for multiplicity due to the primary (MADRS total score) and the
key secondary efficacy endpoints (DARS total score). The testing procedure will first test the
primary endpoint at 2-sided 0.05 level. If the hypothesis corresponding to the primary endpoint is
rejected, then the key secondary endpoint will be tested at 2-sided 0.05 level; if the hypothesis
corresponding to the primary endpoint is not rejected, then the testing procedure will stop.
Other Secondary and Exploratory Efficacy Endpoints
The definitions and analyses for the other (secondary and exploratory) efficacy endpoints and
study populations (adult participants with MDD ANH+, adult participants with MDD ANH-, and
all participants MDD ANH+/-) will be described in the SAP. To evaluate the consistency of
efficacy in subgroups of participants, the analysis of primary and key secondary endpoints will be
performed by intrinsic (baseline demographics) and extrinsic (baseline disease characteristics,
medical history, baseline medications, etc) factors.
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9.4.4. 
Safety Analyses
Safety analyses will be based on the safety analysis set, which consists of all randomized
participants (adults and elderly) who take at least 1 dose of study intervention.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
MedDRA. All reported treatment-emergent AEs, ie, AEs with onset during the DB Treatment
Phase, or AEs that are a consequence of a pre-existing condition that has worsened since baseline,
will be included in the analysis. For each treatment-emergent AE, and AESI (see Section 8.3.6),
the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by study intervention. Serious adverse events (SAEs) will be summarized separately.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe AE
or an SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test and study intervention. Markedly
abnormal ranges (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point.
The proportion of participants with markedly abnormal results will be presented for each analyte
and study intervention group.
A listing of participants with any markedly abnormal laboratory results will also be provided.
Electrocardiogram
The effects on ECG measurements (heart rate, PR interval, QT interval, and QTc interval) will be
evaluated using descriptive statistics and frequency tabulations. QTc intervals will be calculated
using the Bazett and Fridericia correction methods and summarized accordingly (Bazett 1920).
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval higher than pre-specified
levels will be summarized, as will the percentage of participants with QTc interval increases from
baseline >30 milliseconds or >60 milliseconds.
A listing of participants with abnormal ECG findings will be presented. ECG data will be
summarized by each parameter and study intervention group. Proportion of participants with
abnormal ECG will be presented.
Vital Signs
Descriptive statistics of pulse, sitting blood pressure (systolic and diastolic), and body temperature
for observed values will be provided and changes from baseline will be summarized at each
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scheduled time point by study intervention group. Changes in body weight and BMI will be
summarized descriptively.
ASEX
Sexual dysfunction (ASEX) data will be summarized descriptively at each scheduled timepoint by
treatment group.
C-SSRS
Suicide-related thoughts and behaviors based on the C-SSRS will be tabulated by study
intervention.
Cognitive Function
Results from cognitive function assessment will be tabulated by study intervention.
9.4.5. 
Other Analyses
9.4.5.1. 
Benefit-Risk Analyses
Benefit-risk assessment for aticaprant 10 mg versus placebo as adjunctive therapy to an
antidepressant (SSRI or SNRI) in participants with MDD with or without moderate-to-severe
anhedonia (MDD ANH+ or MDD ANH-, respectively) will be assessed using a structured
framework approach. Benefits in the assessment will include endpoints for symptoms of
depression (eg, change from baseline to Day 43 in the MADRS total score) and anhedonia (eg,
change from baseline to Day 43 in DARS total score). Assessment of risk will include clinically
meaningful AEs, including treatment-emergent AEs and AESIs.
The benefit-risk assessment will be evaluated based on the between treatment differences (eg, risk
difference 
or 
excess 
number 
of 
events) 
for 
efficacy 
and 
safety 
endpoints.
Kaplan-Meier-Product-Limit estimates may also be used to display and evaluate benefits and risks
over time. To compare efficacy and safety endpoints in similar units (proportions to proportions,
or rates to rates), endpoints will be assessed as the proportions or rates of participants exhibiting
each measure. Benefit-risk results will be depicted with effects tables and with other visual
representations (eg, forest plots).
9.4.5.2. 
Pharmacokinetic Analyses
Blood samples will be collected for determination of plasma concentrations of aticaprant as
indicated in the SoA (Section 1.3).
A population-based pharmacokinetic (PK) analysis using PK data from previous studies of
aticaprant Phase 1 and Phase 2a studies will be performed and post hoc Bayesian estimates of
aticaprant PK parameters will be derived. Available covariates will be included in the model as
necessary.
The results of the population PK and PK-PD analysis will be reported separately, as appropriate.
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9.4.5.3. 
Biomarker Analyses
Biomarker Analyses
Laboratory data of biomarker levels at baseline will be combined in multivariate models
(biosignatures) that will be identifiedin a training setbased on 2 key criteria: Their utility to predict
treatment outcomes of aticaprant over placebo as measured by i) change in MADRS from baseline
at the end of the DB Treatment Phase, and ii) their prevalence in the adult study MDD population
that took at least 1 dose of study intervention and were randomized to receive aticaprant or placebo.
The final biosignature will then be confirmed in a test set. The details of the analysis will be
described in a separate analysis plan.
Digital Biomarker Analyses
Accuracy, reaction time, and response bias for each block, learning rate, and reward sensitivity
will be derived from the data collected from RLT. De-identified speech/video features during
participant interviews may be extracted. Individual features measured at baseline and multivariate
models will be assessed for their ability to predict treatment outcome of aticaprant over placebo as
measured by change in MADRS from baseline at the end of the DB Treatment Phase. Change of
exploratory digital endpoint (for example, response bias from block 1 to block 2 or from block 1
to block 3, learning rate, and reward sensitivity) will also be assessed in the aticaprant arm
compared to placebo.
Passive behavior sensing features will be evaluated for change from baseline/screening by
treatment arm.
Exploratory analysis correlating RLT metrics, the speech/video features, and passive behavior
sensing features with clinical characteristics of depression symptoms and biomarker measures will
be performed as well.
9.4.5.4. 
Immunogenicity Analyses
Not applicable.
9.4.5.5. 
Exploratory Biomarker Analyses
The exploratory RNA, serum, plasma biomarkers will be tabulated by treatment and summary
statistics will be calculated. Post-treatment changes in exploratory biomarkers will be summarized
by treatment group. Associations between baseline biomarker levels and clinical endpoints, such
as change in MADRS, may be explored. Results maybe presented in a separate Biomarker Report.
9.4.5.6. 
Pharmacokinetic/Pharmacodynamic Analyses
A population-based PK analysis using PK data from previous studies of aticaprant Phase 1 and
Phase 2a studies will be performed and post hoc Bayesian estimates of aticaprant PK parameters
will be derived. Available covariates will be included in the model as necessary.
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The relationship between MADRS total score (and possibly selected AEs) and PK metrics of
aticaprant may be evaluated. Based on any visual trend in graphical analysis, suitable models will
be applied to describe the PK/PD relationships between PK and efficacy or safety.
The results of the both the population PK and PK-PD analyses will be performed and reported
separately, as appropriate.
9.4.5.7. 
Pharmacogenomic Analyses
A composite genotype may be derived from the raw genotyping data for the analyzed genes, as
appropriate. Specific analyses will include, but are not limited to, interrogation of single nucleotide
polymorphisms in whole blood DNA at discrete loci implicated in mood. The relationship between
genetic subgroups and pharmacokinetic endpoints may be examined through descriptive statistics
or graphically. Transcriptional changes may be analyzed in correlation to clinical outcomes.
DNA and RNA samples will be used for research related to aticaprant and depression. They may
also be used to develop tests/assays related to aticaprant. Pharmacogenomic research may consist
of the analysis of one or more candidate genes or of the analysis of genetic markers throughout the
genome (as appropriate) in relation to aticaprant or clinical endpoints.
Results will be presented in a separate report.
9.5. 
Interim Analysis
A blinded interim analysis will be performed to evaluate the measurement properties of the DARS,
and to determine meaningful change threshold (MCT) (or range of thresholds) in the DARS total
score using anchor-based approaches along with distribution-based analyses. The interim analysis
will be conducted when approximately 200 adult MDD participants, regardless of anhedonia
status, have completed the DB Treatment Phase of the study. Details of the analysis will be
described in a separate analysis plan.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
ABV  
alcohol-by-volume
ADL 
activities of daily living
AE 
adverse event
AESI 
adverse event of special interest
ALT  
alanine aminotransferase
ANH+  
with moderate-to-severe anhedonia
ANH- 
without moderate-to-severe anhedonia
AP  
alkaline phosphatase
API 
active pharmaceutical ingredient
ASEX  
Arizona Sexual Experiences Scale
AST  
aspartate aminotransferase
AUC  
area under the concentration-time curve
BMI 
body mass index
CGI-S 
Clinical Global Impression - Severity
CI 
confidence interval
COA  
clinical outcome assessment (paper or electronic as appropriate for this study)
CRF  
case report form(s) (paper or electronic as appropriate for this study)
C-SSRS  
Columbia Suicidality Severity Rating Scale
CSR  
clinical study report
CV  
coefficient of variation
CYP  
cytochrome P450
DARS  
Dimensional Anhedonia Rating Scale
DB  
double-blind
DMC  
Data Monitoring Committee
DNA  
deoxyribonucleic acid
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-5th edition
DOR  
delta opioid receptor
ECG  
electrocardiogram
eDC  
electronic data capture
EOT  
end-of-treatment
EQ-5D-5L 
EuroQol-5 Dimension-5 Level
EQ-VAS  
EQ visual analogue scale
EW  
Early Withdrawal
FAS  
full analysis set
FDA  
Food and Drug Administration
FOIA  
Freedom ofInformation Act
FSH  
follicle stimulating hormone
FT4 
free thyroxine
GAD-7 
Generalized Anxiety Disorder 7-item Scale
GCP  
Good Clinical Practice
GDPR  
General Data Protection Regulation
HbA1c 
glycated hemoglobin
HBsAg 
hepatitis B surface antigen
HDRS-17 
17-item Hamilton Depression Rating Scale
HIPAA 
Health Insurance Portability and Accountability Act
HIV  
human immunodeficiency virus
ICF  
informed consent form
ICH  
International Council for Harmonisation
IDFU  
Investigational directions for use
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IMP  
Investigational Medicinal Product
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IRB  
Institutional Review Board
IWRS  
interactive web response system
KOR  
kappa opioid receptor
LC-MS/MS  
liquid chromatography/mass spectrometry/mass spectrometry
MADRS  
Montgomery-Åsberg Depression Rating Scale
MDD  
major depressive disorder
MDD ANH+  
MDD with moderate-to-severe anhedonia (ANH+)
MDD ANH- 
MDD without moderate-to-severe anhedonia (ANH-)
MedDRA  
Medical Dictionary for Regulatory Activities
MGH ATRQ  
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
MMRM  
mixed model for repeated measures
MMSE 
Mini Mental State Examination
MOR  
mu opioid receptor
NIMP  
Non-Investigational Medicinal Product
PCP  
phencyclidine
PD 
pharmacodynamic(s)
PGI-C 
Patient Global Impression of Change
PGI-S 
Patient Global Impression ofSeverity
PHQ-9 
Patient Health Questionnaire, 9-item
PK 
pharmacokinetic(s)
PQC  
Product Quality Complaint
PRO  
Patient-Reported Outcome(s) (paper or electronic as appropriate for this study)
PROMIS  
Patient-Reported Outcomes Measurement Information System
PROMIS-APS 8a 
PROMIS Short Form v2.0 - Ability to Participate in Social Roles and Activities - 8a
QLDS  
Quality of Life in Depression Scale
QTc 
Corrected QT
QTcF  
Corrected QT interval by Fridericia
RLT  
Reward Learning Task
RNA  
ribonucleic acid
SAE  
serious adverse event
SAP  
Statistical Analysis Plan
SCID-CT  
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical Trials version
SHAPS  
Snaith-Hamilton Pleasure Scale
SIGH-D 
Structured Interview Guide for the Hamilton Depression Scale
SIGMA  
Structured Interview Guide for the MADRS
SIQA  
Site Independent Qualification Assessment
SNRI 
serotonin-norepinephrine reuptake inhibitor
SoA  
Schedule of Activities
SSRI 
selective serotonin reuptake inhibitor
SUSAR  
suspected unexpected serious adverse reaction
t1/2 
half-life
TEAE  
treatment-emergent adverse event
tmax  
time to maximum drug concentration
TSH  
thyroid-stimulating hormone
TSQM-9 
Treatment Satisfaction Questionnaire for Medication
ULN  
upper limit of normal
USA  
United States of America
WHO  
World Health Organization
WPAI:D 
Work Productivity and Activity Impairment: Depression
Definitions of Terms
Electronic source
system
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation
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PRO  
A measurement based on a report that comes directly from the patient about the status of
the patient’s health condition without interpretation of the patient’s response by a clinician
or anyone else
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on GCP, and applicable regulatory and country/territory-specific
requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact must be made before implementing any departure from the protocol. In all
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cases, contact with the sponsor must be made as soon as possible to discuss the situation and agree
on an appropriate course of action. The data recorded in the CRF and source documents will reflect
any departure from the protocol, and the source documents will describe this departure and the
circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
Protocol and amendment(s), if any, signed and dated by the principal investigator.
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
Regulatory authority approval or notification, if applicable.
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.
Documentation of investigator qualifications (eg, curriculum vitae).
Completed investigator financial disclosure form from the principal investigator, where
required.
Signed and dated Clinical Trial Agreement, which includes the financial agreement.
Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first
participant:
Completed investigator financial disclosure forms from all sub-investigators.
Documentation of sub-investigator qualifications (eg, curriculum vitae).
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable.
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Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the
Independent Ethics Committee or Institutional Review Board (IEC/IRB) with current and
complete copies of the following documents (as required by local regulations):
Final protocol and, if applicable, amendments
Sponsor-approved ICF (and any other written materials to be provided to the participants)
IB (or equivalent information) and amendments/addenda
Sponsor-approved participant recruiting materials
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this
optional research component.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
Revision(s) to ICF and any other written materials to be provided to participants
If applicable, new or revised participant recruiting materials approved by the sponsor
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
New edition(s) of the IB and amendments/addenda
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Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
New information that may adversely affect the safety of the participants or the conduct of the
study
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
Report of deaths of participants under the investigator's care
Notification if a new investigator is responsible for the study at the site
Development Safety Update Report and Line Listings, where applicable
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 4.2.3.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.3.
10.3.2. 
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above)for details on financial disclosure.
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10.3.3. 
Informed Consent Process
Each participant must give consent according to local requirements after the nature of the study
has been fully explained. Study sites may be asked by the sponsor to obtain informed consent using
a validated electronic system instead of a paper-based process. The ICF(s) must be signed before
performance of any study-related activity. The ICF(s) that is/are used must be approved by both
the sponsor and by the reviewing IEC/IRB and be in a language that the participant can read and
understand. The informed consent must be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor personnel without
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or
regulations. By signing the ICF the participant is authorizing such access. It also denotes that the
participant agrees to allow his or her study physician to recontact the participant for the purpose
of obtaining consent for additional safety evaluations, and subsequent disease-related treatments,
if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent must be appropriately recorded by
means of the participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
Participants who are rescreened are required to sign a new ICF.
Participants will be asked for consent to provide optional samples for research (where local
regulations permit). After informed consent for the study is appropriately obtained, the participant
will be asked to sign and personally date a separate ICF indicating agreement to participate in the
optional research component. Refusal to participate in the optional research will not result in
ineligibility for the study. A copy of this signed ICF will be given to the participant.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
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These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes information about, and where
required per applicable regulations, explicit consent for the processing of personal data and for the
investigator/institution to allow direct access to his or her original medical records (source
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection.
The informed consent also provides information to address the lawful transfer of the data to other
entities and to other countries/territories.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete or make requests
concerning his or her personal data in accordance with applicable data protection law. Reasonable
steps will be taken to respond to such a request, taking into consideration the nature of the request,
the conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory biomarkerand PKresearch is notconducted under standards appropriate for the return
of data to participants. In addition, the sponsor cannot make decisions as to the significance of any
findings resulting from exploratory research. Therefore, exploratory research data will not be
returned to participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. The start of the storage period is defined as the completion date of the
clinical study report (CSR). Samples will only be used to understand depression and disorders with
depressive symptoms, and/or the use of aticaprant as adjunctive therapy, to understand differential
intervention responders, and to develop tests/assays related to aticaprant. The research may begin
at any time during the study or during the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1).
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10.3.6. 
Committees Structure
An IDMC will be commissioned for this study to periodically review safety data. The IDMC will
consist of at least 1 medical expert in the relevant therapeutic area and at least 1 statistician. The
IDMC responsibilities, authorities, and procedures will be documented in its charter.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding aticaprant or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including pharmacogenomic or biomarker research data,
generated as a result of this study, are considered confidential and remain the sole property of the
sponsor. The investigator agrees to maintain this information in confidence and use this
information only to accomplish the goals of this study and will not use it for other purposes without
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofaticaprant, and thus may be disclosed as
required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of
pharmacogenomic or biomarker analyses performed after the Clinical Study Report has been
issued will be reported in a separate report and will not require a revision of the Clinical Study
Report.
Study participant identifiers will not be used in the publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
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not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. The
disclosure of the study results will be performed after the end of study in order to ensure the
statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory  into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor may review the electronic CRF (eCRF)for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study database they will
be verified for accuracy and consistency with other data sources.
10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in the eCRF. All eCRF entries, corrections,
and alterations must be made by the investigator or authorized study site personnel. The
investigator must verify that all data entries in the eCRF are accurate and correct.
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The study data will be transcribed by study site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Data must be entered into the eCRF in English. The eCRF must be completed as soon as possible
after a participant visit and the forms must be available for review at the next scheduled monitoring
visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable.
The author of an entry in the source documents must be identifiable. Given that PROs are reports
of a patient's health condition that come directly from the patient, without interpretation by a
clinician or anyone else, the responses to PRO measures entered by study participants into source
records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data:
Race
History of all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of
e-cigarettes), cigars, chewing tobacco, patch, gum, etc
Blood pressure and pulse/heart rate
Height and weight
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The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Referral letter from treating physician or
Complete history of medical notes at the site
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol-required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An electronic (eSource)system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. These data are electronically
extracted for use by the sponsor. If eSource is utilized, references made to the eCRF in the protocol
include the eSource system but information collected through eSource may not be limited to that
found in the eCRF. Data in this system may be considered source documentation. Centralized
and/or remote data will be identified as source from the vendor and the collected information used
(eg, questionnaires, scales, or other tools) will be considered as source and maintained centrally
by the vendor(s). In these cases, original entries will be made electronically via a tablet or other
device. The data (ie, clinical study-specific data fields as determined by the protocol) will not be
maintained in a hospital or clinic record as source documentation. The site’s data will be made
available to the site via a portal for review and will also be provided as a final data transfer at the
end of the study.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques, including central, remote, or on-site
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor may  compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study site personnel and are accessible for verification by the
sponsor study site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
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meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12. 
On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study site personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator must immediately notify the sponsor if he or she has been
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP E6 (Section 8 Essential Documents for the Conduct of a
Clinical Trial) and all study documents as specified by the applicable regulatory requirement(s).
The investigator/institution will take measures to prevent accidental or premature destruction of
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first participant screened is considered the first act of recruitment and it becomes the study
start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor’s procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development
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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Council for
Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is a suspected transmission of any infectious agent via a medicinal product
Is Medically Important*
*Medical and scientific judgment must be exercised in deciding whether expedited reporting
is also 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 intervention to prevent one of the other outcomes listed in the
definition above. These should usually be considered serious.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study intervention and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For aticaprant, the expectedness of an AE will be determined by
whether or not it is listed in the IB. For background selective serotonin reuptake inhibitor (SSRI)
or serotonin-norepinephrine reuptake inhibitor (SNRI) treatment that is required to be continued
along with the study intervention and with a marketing authorization, the expectedness of an AE
will be determined by whether or not it is listed in the applicable product information sheet (eg,
package insert/summary of product characteristics).
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention  is assessed by the Investigator. The following
selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term “reasonable causal relationship” means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator must use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
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10.4.3.1. 
Guidance for Assessing Severity of Adverse Events of Special
Interest
The following guidance is provided as a recommendation to consider when assessing the severity
of 
 and
 in the aticaprant studies:
 
 
 
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
Overdose of a sponsor study intervention
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Suspected abuse/misuse of a sponsor study intervention
Accidental or occupational exposure to a sponsor study intervention
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
Exposure to a sponsor study intervention from breastfeeding
Reporting of participant pregnancy or participant partner(s) pregnancy
Special reporting situations must be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the SAE page of the eCRF.
10.4.5. 
Procedures
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory
infection”). Investigators must record in the CRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a “wallet (study) card” and instructed to carry this card with them for the duration
of the study indicating the following:
Study number
Statement, in the local language(s), that the participant is participating in a clinical study
Investigator’s name and 24-hour contact telephone number
Local sponsor’s name and 24-hour contact telephone number (for medical personnel only)
Site number
Participant number
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon  the
participant’s discontinuation from the study, must be followed until any of the following occurs:
The event resolves
The event stabilizes
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The event returns to baseline, if a baseline value/status is available
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.
The cause of death of a participant in a study within 30 days of the last dose of study intervention,
whether or not the event is expected or associated with the study intervention, is considered an
SAE.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician
from the study site, and transmitted to the sponsor immediately but no later than within 24 hours.
The initial and follow-up reports of an SAE should be transmitted electronically or by facsimile
(fax). Telephone reporting should be the exception and the reporter should be asked to complete
the appropriate form(s) first.
10.4.6. 
Product Quality Complaint Handling
Definition
A PQC  is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
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Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
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10.5. Appendix 5: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section  5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.4, Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
Definitions
Female Participant of Childbearing Potential
A female participant is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
Female Participant Not of Childbearing Potential
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in female participants
not using hormonal contraception or hormonal replacement therapy (HRT), however in the
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
If there is a question about menopausal status in female participants on HRT, the female
participant will be required to use one of the non-estrogen-containing hormonal highly
effective contraceptive methods if she wishes to continue HRT during the study.
permanently sterile (for the purpose of this study)
Permanent sterilization methods include hysterectomy, or bilateral salpingectomy, or
bilateral oophorectomy.
Has congenital abnormalities resulting in sterility.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who
is not heterosexually active becomes active), a female participant must begin a highly effective
method of contraception, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by male participants or female participants must be consistent
with local regulations regarding the acceptable methods of contraception for those participating in
clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED FOR MALE OR FEMALE
PARTICIPANTS DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the female of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception must be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulation
oral
injectable
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective –failure rate of 1% per year)
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
Male or female condom with or without spermicideb
Cap, diaphragm, or sponge with spermicide
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)b
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus-interruptus)
Spermicides alone
Lactational amenorrhea method (LAM)
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a) Typical use failure rates may differ from those when used consistently and correctly. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Male condom and female condom must not be used together (due to risk of failure with friction).
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history of alcohol use, other meds including acetaminophen, NSAID, over-the-counter (OTC)
herbal supplements, vitamins, nutritional supplements, traditional medicines, and street drugs;
and document whether or not there has been any recent change in any other prescription drugs
and start-stop dates.
2. Obtain travel history to endemic areas for hepatitis A, hepatitis E. Ask for history of any prior
blood transfusions and when they were performed. Perform physical examination, obtain vital
signs and BMI, and document presence or absence of scleral icterus, palpable liver including
size, degree of firmness or tenderness, palpable spleen including size, ascites, and stigmata of
chronic liver disease (spider angiomata, gynecomastia, palmar erythema, testicular atrophy).
Allow free text in eCRF for other relevant history and physical information.
Mandatory liver ultrasound with consideration of further imaging (eg, computerized tomography
[CT], magnetic resonance imaging [MRI], magnetic resonance cholangiopancreatography
(MRCP), endoscopic retrograde cholangiopancreatography [ERCP], Doppler studies of hepatic
vessels, etc, if indicated based on ultrasound findings or clinical situation). If total bilirubin (Tbili)
is >2 x ULN, request fractionation to document the fraction that is direct bilirubin and to rule out
indirect hyperbilirubinemia indicative of Gilbert’s syndrome, hemolysis or other causes of indirect
hyperbilirubinemia. Complete blood count (CBC) with WBC and eosinophil count platelet count,
international normalized ratio (INR), and total protein and albumin (compute globulin fraction)
should also be documented. If INR is abnormal, prothrombin time (PT), partial thromboplastin
time (PTT) should be obtained and these values should be followed until normal, along with
documentation of whether parenteral vitamin K was given along with the effect of such treatment
on INR. If initial liver function tests (LFTs) and ultrasound do not suggest Gilbert’s syndrome,
biliary tract disease or obstruction, viral hepatitis serology should be obtained including anti-
hepatitis A virus immunoglobin M (anti-HAV IgM), anti-HAV total, HbsAg, anti-HBs, anti-HB
core total, anti-HB core IgM, anti-HCV, anti-hepatitis E virus IgM (anti-HEV IgM) (even if has
not traveled to an endemic area for hepatitis E), Epstein-Barr virus (EBV) and Cytomegalovirus
(CMV) screen.
If participant is immunosuppressed, test for HCV RNA and HEV RNA.
If HbsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to detect
active HepB, especially in participants who are immunosuppressed.
If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive test,
HBV DNA should be obtained to detect reactivation of hepatitis B.
Assuming that the history, physical, and initial imaging and laboratory has not revealed a cause of
elevated LTs, screen for other causes of liver disease including: Total protein and albumin
(estimate globulin fraction and obtain quantitative immunoglobulins if elevated), antinuclear
antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), anti-liver-kidney
microsomal antibodies (anti-LKM antibodies), anti-smooth  muscle antibodies (ASMA),
erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). If the pattern of laboratory
abnormalities is not hepatocellular, but cholestatic or a mixed pattern (see definitions in table
above), then GGT, anti-mitochondrial antibody (AMA) and anti-neutrophil cytoplasmic antibody
(pANCA) should also be tested. If there is an indication by history or elevated baseline LTs that
there may be an underlying chronic liver disease possibly exacerbated by exposure to the study
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intervention in the clinical trial or making the participant more susceptible to DILI, test iron/Total
iron binding capacity (TIBC) and ferritin (hemochromatosis), and alpha-1-antitrypsin level. If
participant is sick enough to be hospitalized and is under 50 years of age, a slit lamp examination
to detect Kayser-Fleischer rings and a 24-hour urine collection for copper should be measured.
Consider serum ethanol and/or acetaminophen level and urine drug tests as clinically appropriate.
A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology and if
immunosuppressive therapy is contemplated.
A liver biopsy may be considered:
if there is unrelenting rise in liver biochemistries or signs of worsening liver function despite
stopping the suspected offending agent.
if peak ALT level has not fallen by >50% at 30-60 days after onset in cases of hepatocellular
DILI, or if peak AP has not fallen by >50% at 180 days in cases of cholestatic DILI despite
stopping the suspected offending agent.
in cases of DILI where continued use or re-exposure to the implicated agent is expected.
if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence of
chronic liver diseases and chronic DILI.
If pertinent, copies of hospital discharge summary, radiology, pathology and autopsy reports
should be obtained.
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10.6.2. 
Follow-up Assessments
10.6.2.1. 
Phase 3-4 Liver Chemistry Increased Monitoring Criteria with
Continued Study Intervention
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study
Intervention
Criteria 
Actions
ALT or AST- 5 x ULN and 
<8 x ULN and total bilirubin 
<2 x ULN or INR<1.5 without 
symptoms believed to be related to 
liver injury or hypersensitivity, and  
who can be monitored weekly for 
2 weeks
OR
ALT or AST- 3x ULN and
<5 x ULN and total bilirubin
<2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks 
Notify the sponsor within 24 hours of learning of
the abnormality to discuss participant safety
Participant must return weekly for repeat liver
chemistry tests (ALT, AST, alkaline phosphatase,
total bilirubin) until the abnormalities resolve,
stabilize, or return to baseline
If at any time, the participant meets liver
chemistry stopping criteria, proceed as described
in Section 10.6.1
If ALT or AST- decreases from ALT or AST-
5 x ULN and <8 x ULN to ≥3 x ULN but
<5 x ULN, continue to monitor liver chemistries
weekly
If, after 4 weeks of monitoring, ALT or AST-
<3 x ULN and total bilirubin <2 x ULN, monitor
participants twice monthly until liver chemistry
tests resolve, stabilize, or return to baseline
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10.7. Appendix 7: Prohibited Concomitant Therapies
This list of medications is not all-inclusive; if necessary, please contact the sponsor’s medical
monitor for any questions regarding a medication(s).
Please refer to the local prescribing information of the participant’s non-study medications for
information regarding prohibited concomitant medications. Except where specifically noted, the
prohibited medications listed in the following table are prohibited from 1 week (or 5 half-lives,
whichever is longer) prior to the first dose of study intervention until after the last dose of study
intervention.
Of note, for any concomitant medication that is not listed below but has the potential to be a strong
CYP
 inhibitor or inducer or dual moderate CYP
 inhibitor/inducer or coadministration
of moderate CYP
 inhibitor and moderate CYP
 inhibitor, please check with the sponsor’s
medical monitor.
Drug Class 
Episodic
Use
(PRN)
Continuous
Use
Comments 
Reason for Prohibition
Attention-deficit 
hyperactivity disorder 
(ADHD) medications 
(eg, atomoxetine,
guanfacine)
N 
N 
See also 
“Psychostimulants”
row.
Potential PD interaction
Agomelatine 
N 
N 
Potential PD interaction
Amantadine 
N 
N 
Potential PD interaction
Amitifadine 
N 
N 
Potential PD interaction
 
N 
N 
 
N 
N 
 
N 
N 
Anorexiants (eg, 
phentermine,
phendimetrazine)
N 
N 
Potential PD interaction
Anticholinesterase 
Inhibitors 
N 
N 
Participant population is
excluded
Anticonvulsants 
N 
Y 
- Participants with  
uncontrolled (current or 
past 6 months)seizures
are excluded.
-
- Use as adjunctive
treatment for major
Potential PD interaction
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Drug Class 
Episodic
Use 
(PRN)
Continuous
Use
Comments 
Reason for Prohibition
depressive disorder
(MDD) is prohibited.
Antidepressants and 
medications used for 
treatment of depression 
(other than the specific 
antidepressant 
monotherapies listed in 
inclusion criteria of the 
protocol) 
N 
N 
- Only one of the oral 
antidepressant treatment
options listed in Section
Inclusion Criteria is
permitted.
- If a participant is
taking a monoamine
oxidase inhibitor
(MAOI) during the
Screening Phase, there
must be a minimum
washout interval of 2
weeks prior to the first
dose of study
intervention.
- Even if used for other
indications (eg,
trazodone for sleep), the
use of any medication
(except the SSRI/SNRI
options listed in
protocol) is not
permitted during the
treatment phase.
Potential PD interaction
 
N 
N 
 
) are allowed
on a case-by-case
assessment in
consultation with
sponsor’s medical
monitor.
Antipsychotics 
N 
N 
Potential PD interaction
 
N 
N 
 
N 
N 
Appetite Suppressants 
Y 
N 
Potential PD interaction
 
N 
N 
 
N 
N 
Barbiturates 
N 
N 
Potential PD interaction,
Benzodiazepines (at 
dosages equal to or less 
than the equivalent of 
4 mg/day lorazepam) 
and non-benzodiazepine
Y 
Y 
Prohibited within 12 
hours prior to cognition
testing or RLT
completion.
Potential PD interaction
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Drug Class 
Episodic
Use 
(PRN)
Continuous
Use
Comments 
Reason for Prohibition
sleeping medication
(including zolpidem,
zaleplon, eszopiclone,
and ramelteon)
Benztropine 
Y 
N 
Potential PD interaction
 
N 
N 
Buspirone 
N 
N 
Potential PD interaction
Chloral hydrate, 
melatonin, valerian
N 
N 
Potential PD interaction
Clonidine 
N 
Y 
Continuous use for 
blood pressure control
is allowed.
Potential PD interaction
 
N 
N 
 
Y 
N 
 
 are
permitted (chronic use
prohibited). Episodic or
continuous oral use can
be discussed on a case-
by-case basis with
sponsor’s medical
monitor.
 
N 
N 
Dopamine Receptor 
Agonists (not listed
elsewhere)
N 
N 
Potential PD interaction
Dextromethorphan  
N 
N 
Episodic use can be 
discussed on a case-by-
case basis with
sponsor’s medical
monitor.
Potential PD interaction
Glutamatergic Agents 
(ketamine, esketamine) 
N 
N 
Episodic use (eg, 
anesthesia) can be
discussed on a case-by-
case basis with
sponsor’s medical
monitor.
Potential PD interaction
 
N 
N 
Methyldopa 
N 
N 
PD interaction
Metyrosine 
N 
N 
Potential PD Interaction
Memantine 
N 
N 
Potential PD interaction
Monoamino-oxydase 
inhibitors (MAOIs)
N 
N 
Potential PD interaction
Mood Stabilizing 
Agents (eg, lithium)
N 
N 
Potential PD interaction
Norepinephrine and 
dopamine reuptake
inhibitors (eg,
bupropion)
N 
N 
Potential PD interaction
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Drug Class 
Episodic
Use 
(PRN)
Continuous
Use
Comments 
Reason for Prohibition
Opioids 
N 
N 
With sponsor approval, 
brief treatment with
opiates may be allowed
for treatment of acute
injuries, etc.
Potential PD interaction
Opioid Receptor 
Agonists or Antagonists
N 
N 
Potential PD interaction
Psychostimulants 
(eg, amphetamines, 
methylphenidate,
modafinil, armodafinil)
N 
N 
Potential PD interaction
Psychedelics 
N 
N 
Potential PD interaction
Reserpine 
N 
N 
Potential PD interaction
Scopolamine 
N 
N 
Potential PD interaction
 
N 
N 
Potential PD interaction
Thyroxine/ 
triiodothyronine (T3),
thyroid hormone
prescribed for
depression
N 
N 
Potential PD interaction
Thyroid hormone 
supplement for 
treatment of thyroid 
condition only (not for 
depression) 
N 
Y 
Participants needing 
supplements must be on
a stable thyroid
supplement dose for at
least 3 months prior to
start of the treatment
phase.
Potential PD interaction
Trazodone 
N 
N 
Not allowed even if 
used for other
indications (eg, for
sleep).
Potential PD interaction
Abbreviations: ADHD: attention-deficit hyperactivity disorder; IM: intramuscular; IV: intravenous; MAOI:
monoamine oxidase inhibitor; N: Prohibited; NNRTI: non-nucleoside reverse transcriptase inhibitor; PD:
pharmacodynamics; PK: pharmacokinetics; PO: oral; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI:
selective serotonin reuptake inhibitor; T3: triiodothyronine; Y: Permitted, with restrictions (please refer to the
column labeled “Comments” for additional guidance or contact medical monitor).
Note: Herbal agents or supplements used for the treatment of depression should be discontinued as well unless
agreed for continuation by sponsor’s medical monitor.
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Status: Approved,  Date: 26 January 2024
10.8. Appendix 8: Administration of a Patient-Reported Outcome (PRO) at
Scheduled Visits
The following guidance will be followed to administer a PRO:
Provide a quiet, semi-private location for the participant to complete the PROs.
Ensure participants have access to study staff for questions.
Instruct participants to complete paper PRO assessments using a blue or black ballpoint pen.
Explain that all of the information on the PRO assessment(s) is confidential, and that someone
from the study staff will only check for completeness and not share the results with other
clinical staff.
Explain to participants the reasons why they are being asked to complete the PRO
assessment(s), ie, they are part of the overall medical assessment and are designed to find out
more information about how having their disease has affected their life.
Allow as much time as the participant needs to orient themselves and complete all PRO
assessments.
Instruct the participants to:
Read the instructions for each questionnaire carefully.
Note the recall period for each questionnaire.
Complete all PROs.
Instruct the participant not to skip any questions/or questionnaires.
Participants must interpret questions and complete the PRO assessment(s) without help from
anyone. If asked for help interpreting or completing the PRO assessment by the participant,
please simply reply that there are no right or wrong answers and he/she should use his/her best
judgment to complete each question (based on what the participant thinks the question is
asking).
Do not attempt to interpret or explain the instructions, questions, or response options.
If the participant has difficulty choosing between 2 response options, simply state “choose the
answer that most closely matches your experience.”
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Status: Approved,  Date: 26 January 2024
10.9. Appendix 9: Study Conduct During a Natural Disaster/Major Disruption/
Pandemic
10.9.1. 
Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgment of the
investigator to protect the health and well-being of participants and site staff. If, at any time, a
participant’s safety is considered to be at risk, study intervention will be discontinued, and study
follow-up will be conducted.
Re-consenting of participants will be performed (including remote consenting by phone or video
consultation) as applicable for the measures taken and according to local guidance for informed
consent applicable during the COVID-19 pandemic.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, and the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the CRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID 19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
Clinical Study Report.
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10.9.2. 
Guidance Specific to this Protocol
These provisions are meant to minimize the risk of exposure to COVID-19 and to safely maintain
participants on study intervention while site capabilities are compromised by COVID-19-related
restrictions. As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves,
sites should revert to original protocol conduct as soon as feasible.
At each contact, participants will be interviewed to collect safety data. Participants will also be
questioned regarding general health status to fulfill any physical examination requirement.
Evaluate the participant’s situation on a case-by-case basis and contact the study responsible
physician for discussion and decision if necessary. Certain measures, such as those listed below, may
be necessary and should be instituted in accordance with applicable (including local) laws, regulations,
guidelines, and procedures.
The safety of study participants is priority; investigators may make the decision to provide
other available therapy to participants in the study. Please discuss any decision to provide
other therapy outside of the protocol with the study responsible physician and ensure that this
is recorded in the source document and the CRF along with the reason for administration.
Reminder: If a scheduled dose is missed, participants are advised not to administer 2 doses at a
time the next day. Dosing should resume the next day. Information about the missing dose should
be recorded in participant diaries and in the eCRF study intervention log.
Discontinuations of study intervention and withdrawal from the study due to COVID-19
AEs/SAEs should be documented as discontinuation due to AE. If a participant dies due to
COVID-19, “death” should be selected as the reason for treatment discontinuation.
Discontinuations for other COVID-19 reasons should be documented with the prefix “COVID-19-
related” in the CRF.
Screening Phase
The following recommendations apply to those sites within countries/territories where there is a
high localized rate of COVID-19 infection:
Screening of new participants should be postponed until the rate of COVID-19 infection is reduced
and under control.
Due to uncertainty around the ability to conduct on-site clinical visits, participants that are
currently in screening should be screen failed and clinical standard-of-care for the treatment of
depression should be arranged by the study investigator and/or the participant's treating physician.
The decision to continue with the participant's current oral antidepressant treatment regimen
should be at the discretion of the investigator.
The sponsor will evaluate and approve/reject requests to rescreen an individual participant on a
case-by-case basis after the COVID-19 infection is under control.
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Study Intervention
In the event that it is not feasible for the participant to be assessed and receive study intervention
at the study site (eg, due to temporary site closure), study intervention may be delivered to the
participant's home. If this is not feasible the participant may discontinue after consultation with
the sponsor's medical monitor.
Study-related Procedures
Rating scales/ safety assessments can continue to be administered via video teleconferencing
(MADRS) or phone (other assessments). Every effort should be made to complete the
MADRS assessment via video teleconferencing and within the scheduled timeframe; if this
cannot occur, the sponsor medical monitor or delegate should be contacted for direction.
Missed/ out of window visits or individual assessments should be documented with
“COVID-19-related” in the comment section of the CRF.
It is recommended that close contact be maintained with study participants and remote contact
arranged consistent with the participant’s regularly scheduled visit interval.
In the event that participants who show worsening, the investigator should contact the Sponsor's
medical monitor to discuss the best course of action.
Laboratory Assessments
If laboratory samples cannot be collected by Covance/central laboratory, sample collection and
analysis can be performed using the site’s local laboratory at the discretion of the investigator.
Local laboratory results will not be collected in the electronic data capture (eDC). Only abnormal
laboratory values should be reported as (S)AEs.
If the investigator does not feel laboratory assessments are required at this time, and
participant(s) want to avoid any risk to COVID-19 exposure, this rationale should be
documented in the source documents.
Exposure to COVID-19
If a participant develops COVID-19 infection (or suspected) during the screening, DB
Treatment Phase or Follow-up Phase, the investigator should contact the sponsor’s medical
monitor to discuss the best course of action based on individual symptoms/ patient setting and
risk-benefit relationship.
If a participant develops COVID-19 infection (or suspected) during the follow-up period, the
investigator should contact the sponsor’s medical monitor and assessments should be
completed remotely.
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Data Collection
For clinician-completed (MADRS, C-SSRS, CGI-S)a scale assessments conducted by a
telephone or video contact, the data should be entered directly onto the paper assessment.
Ensure that the correct date is present on the assessment form in the eCRF.
For patient-completed assessments, the DARS, PGI-S anhedonia, PHQ-9, and PGI-S
depression should be prioritized and collected via the eCOA device.
Missed doses should be documented in the CRF in accordance with the CRF completion
guidelines.
For missed doses, enter a logline with 0 as number of taken tablets to document the missed
dose and a “COVID-19 related” comment entered on the Comments form.
All COVID-19-related deviations from the main study protocol will be documented according
to the CRF completion guidelines.
A mitigation plan has been created to address the impact of the COVID-19 global pandemic
on the completion of in-person COA assessments.
Statistical Analysis
The sponsor will evaluate the totality of the impact of COVID-19 on collection of key study data,
and additional data analyses will be outlined in the Statistical Analysis Plan.
a 
C-SSRS=Columbia Suicide Severity Rating Scale; CGI-S=Clinical Global Impression - Severity; DARS  =Dimensional
Anhedonia Rating Scale; MADRS=Montgomery-Åsberg Depression Rating Scale; PGI-S=  Patient Global Impression of
Severity; PHQ-9=Patient Health Questionnaire, 9-Item.
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10.10. Appendix 10: Study Design
Completer continuing in 67953964MDD3003
Completer not continuing in 67953964MDD3003
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Status: Approved,  Date: 26 January 2024
Premature discontinuation
Abbreviations: EOS=End of Study, EOT=End ofTreatment, EW=Early Withdrawal, SCR=Screening,
SNRI=serotonin-norepinephrine reuptake inhibitor, SSRI=selective serotonin reuptake inhibitor
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Status: Approved,  Date: 26 January 2024
10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Amendment 2 (22-Feb-2023)
Overall Rationale for the Amendment:  Updates are made based on feedback received from interactions
with health authorities, to ensure alignment across the program and to improve participant selection. Minor
changes are made throughout the protocol for clarification and to correct errors.
The changes made to the clinical protocol 67953964MDD3001 as part of Protocol Amendment 2 are listed
below, including the rationale of each change and a list of all applicable sections. Changes made in previous
protocol amendments are listed in Section 10.11. Appendix 11: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
1. Synopsis, Overall
Design;
4.1.2 Screening Phase;
5.1 Inclusion Criteria
Revised Inclusion Criterion 5:
Have had an inadequate response to at least 1
but no more than 3 antidepressants oral
antidepressant treatment (see the inclusion
criterion below), administered at an adequate
dose (at or above the minimum therapeutic
dose per MGH ATRQ) and duration (at least
6 weeks) in the current episode of depression.
An inadequate response is defined as <50%
reduction in depressive symptom severity
but with some improvement (> 0%) during
the current antidepressant trial (ie, there may
be minimal some minor to moderate
symptomatic improvement since the initiation
of treatment, but some of the initial symptoms
are still present, troubling to the participant
and affecting behavior and function) as
assessed by the MGH ATRQ. An adequate
duration is defined as an antidepressant
treatment for at least 6 weeks on a stable dose
at or above the minimum therapeutic dose
specified in the MGH ATRQ. This must also
apply 
to 
the 
participant's 
current
antidepressant treatment.
Definition for inadequate
response to the current
antidepressant (SSRI/SNRI) is
updated based on major Health
Authority feedback to include
MDD participants with >0% to
<50% improvement to the current
antidepressant based on the MGH
ATRQ criteria for amount (%) of
improvement. The updates allow
inclusion of a broader MDD
population for whom an add-on
strategy is considered a viable
treatment option following
inadequate response to a standard
of care antidepressant.
Additionally, the upper limit of up
to 3 inadequate antidepressants is
removed to allow enrolment and
evaluation of adjunctive
aticaprant in participants with
MDD with inadequate response to
later lines of antidepressants.
1.1. Synopsis, Objectives
and Endpoints;
3. Objectives and Endpoints
Revised definition of remission of depressive
symptoms to a MADRS total score of ≤10.
Update is made to align with the
more commonly used cut-off for
defining remission using MADRS
total score.
2.2. Background 
Additional information added to Human
Pharmacokinetics.
To add new information from
completed clinical pharmacology
studies.
3. Objectives and 
Endpoints; 
9.4.5.3 Biomarker Analyses
Added clarifying text to exploratory digital
biomarkers and related statistical analyses.
Clarification of analyses.
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Section Number 
and Name
Description of Change 
Brief Rationale
5.1. Inclusion Criteria 
Revised Inclusion Criterion 6: 
Is currently receiving and tolerating well any 
one of the following SSRI or SNRI for 
depressive symptoms at screening, in any 
approved formulation and available in the 
participating country/territory: citalopram, 
duloxetine, escitalopram, fluvoxamine, 
fluoxetine, milnacipran, levomilnacipran,
paroxetine, sertraline, venlafaxine,
desvenlafaxine at a stable dose (at or above
the minimum a therapeutic dose per MGH
ATRQ) for at least 6 weeks. and with some
minor to moderate symptomatic
improvement (>25%). The current
antidepressant cannot be the first
antidepressant treatment for the first lifetime
episode of depression.
Clarification made to improve
understanding of the definition of
“stable dose” for the current
SSRI/SNRI antidepressant.
Some text is removed as the
information is captured in
Inclusion Criterion 5.
5.2. Exclusion Criteria 
Revised Exclusion Criterion 1 to exclude 
participants who have had no 
response/treatment failure to 5 or more 
antidepressant treatments (including the 
current SSRI/SNRI). 
Criterion is updated following
feedback from a major Health
Authority to broaden the study
population and ensure exclusion
of participants with a level of
treatment resistance that are
unlikely to benefit from an
adjunctive treatment strategy.
5.2. Exclusion Criteria 
Revised Exclusion Criterion 5 to exclude 
participants with an inadequate response to 
adequate course of treatment with 
intravenous or intranasal ketamine or 
esketamine; electroconvulsive therapy (ie, at 
least 7 treatments), vagal nerve stimulation, 
or deep brain stimulation device during the 
current episode.
Criterion is updated to better align
with the study population and
ensure exclusion of participants
with non-response to treatment
strategies in the ongoing episode
who are unlikely to benefit from
an adjunctive treatment strategy.
5.2. Exclusion Criteria 
Added clarifying text to Exclusion 
Criterion 12 to specify on-site drug testing 
and clarify retesting is only permitted for
stated reasons.
Added text to clarify that a positive test for
both cannabis and/or alcohol can lead to
participant exclusion for the study.
To improve understanding of this
criterion.
1.1. Synopsis, Objectives 
and Endpoints; 
3. Objectives and Endpoints 
Revised safety endpoint for ASEX to 
proportion of participants with clinically 
relevant sexual dysfunction. 
To align the endpoint with the
approach that the instrument
developer recommends for
analysis of the ASEX and to
provide better analysis for
assessment of presence or absence
of sexual dysfunction.
1.1. Synopsis, Statistical 
Methods, Efficacy 
Analysis;
9.4.1. General
Considerations
Aligned definition of the full analysis set 
(FAS_ANH+) with text in Section 9.3.
Consistency with Section 9.3.
1.1. Synopsis, Statistical 
Methods 
Added text describing the interim analysis. 
For completeness and consistency
with Section 9.5.
NCT05455684

JNJ-67953964 Aticaprant
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
141
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis, Number of 
Participants; 
1.1. Synopsis, Statistical 
Methods, Sample Size
Calculation;
1.2. Schema;
4.1. Overall Design;
9.2. Sample Size
Calculation
Removed reference to China and Japan. 
Information is not applicable as
these countries are not
participating in this study.
1.3. Schedule of Activities 
Removed row in Screening/Administrative 
section for diary for current antidepressant 
compliance. 
Removal of duplicate entry;
schedule for diary completion is
listed under Ongoing Review.
1.3. Schedule of Activities 
Removed Pharmacogenomic and Epigenetic 
(DNA, RNA) Assessments at Visit 2.3 
(Day 15) and Visit 2.5 (Day 29)
Removal of assessments added in
error in Amendment 1.
1.3 Schedule of Activities 
Added text to Note to clarify that at Visit 2.1 
(Day 1), PROs, MADRS, CGI-S, and C- 
SSRS must be completed prior to dosing. 
To provide clarification for
assessments to be completed prior
to dosing.
1.3. Schedule of Activities 
Added assessment at Visit 2.7 (EOT/EW) 
under evaluation current antidepressant
compliance.
To add a missing assessment.
1.3. Schedule of Activities 
SHAPS assessments were added at Visits 2.3 
(Day 15), 2.5 (Day 29), and 3.1 (Follow-Up).
To match with the DARS.
1.3. Schedule of Activities, 
footnote “y” 
Added footnote “y” to specific study 
procedures and assessments at Visit 2.1 
(Baseline). 
To clarify that these study
procedures and assessments must
be performed before
randomization.
1.3. Schedule of Activities, 
Footnote “p”; 
5.1. Inclusion Criteria, 
Criteria 5 and 6; 
6.8.1. Current (SSRI/SNRI) 
Antidepressant Therapy  
Added instructional text to clarify methods to 
confirm compliance to current antidepressant 
treatment during screening and the DB 
Treatment Phase. 
To provide further clarity to the
sites about acceptable means of
evaluating during study
compliance to the current
antidepressant treatment (SSRI or
SNRI).
1.3 Schedule of Activities; 
3. Objectives and
Endpoints;
8.1.2. Efficacy Assessments
Added “anhedonia” to PGI-C. 
Alignment edit.
1.3 Schedule of Activities 
Replaced “video” teleconferencing with 
“audio” teleconferencing for HDRS-17.
To correct an error.
2.1. Study Rationale; 
4.2.1. Study Population  
Removed “core” from text describing 
symptoms persisting in patients treated with
current antidepressants.
To align text with DSM-5 criteria.
3.0. Objectives and 
Endpoints 
Revised exploratory endpoint for GAD-7 
from change from baseline over time to 
change from baseline to Day 43.
The GAD-7 is only collected at
baseline and at Day 43.
4.1.3. Double-blind 
Treatment Phase; 
4.1.5. Open-label 
Long-term Safety Study; 
6.4. Study Intervention 
Compliance 
Clarifications were made regarding missed 
doses and non-compliance with study 
intervention. 
Missed doses due to temporary
interruption for clinically relevant
reasons (eg, adverse event, etc)
are not considered
non-compliance with the study
intervention.
4.2.3. Study-Specific 
Ethical Design 
Considerations;
Updated blood volume to be collected from 
each participant. 
Blood volume collected in study
updated to include samples for
NCT05455684

JNJ-67953964 Aticaprant
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
142
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
8. Study Assessments and 
Procedures 
antidepressant compliance and
volume of tube for DNA sample.
6.2. Preparation/Storage 
/Handling/Accountability
Deleted duplicate template text. 
To remove duplication.
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
Modified the statement on the number of 
randomization lists that will be generated. 
Generalized the statement as the
number of lists may further be
refined to provide the opportunity
to analyze other definitions of
anhedonia.
6.8. Concomitant Therapy  
Revised text to clarify the 6 months prior to 
Screening applies to all of the listed 
medications. 
To clarify recording the
medications used in past 6
months.
7.1. Discontinuation of 
Study Intervention 
Removed 2 reasons for discontinuation of 
study intervention related to noncompliance 
with study intervention. 
Revised criteria for discontinuation of study 
intervention to align Phase 3 studies. 
These 2 reasons are removed as
reasons for discontinuation
because study participants will
not be automatically withdrawn if
they discontinue study
intervention before the end of the
DB Treatment Phase.
To provide consistency across the
Phase 3 studies.
8. Study Assessments and 
Procedures 
Added clarifying text for order of completion 
for PRO assessments. 
Added for consistency across
Phase 3 studies.
8. Study Assessments and 
Procedures 
Added additional 12-lead ECG at Visit 2.7 
(EOT/EW). 
To align with assessments shown
in the SoA.
8. Study Assessments and 
Procedures
Removed duplicate text. 
To remove duplication.
8.1.2.4. Clinical Global 
Impression-Severity 
(CGI-S) 
Added a statement describing rater 
separation. 
To clarify that efficacy raters who
perform the CGI-S will not be
involved in assessing AEs.
1.3. Schedule of Activities, 
Footnote “n”; 
8.2.3 Electrocardiograms 
Added text to clarify that triplicate ECGs are 
only required during screening or at Visit 2.1 
if the QTcF is prolonged on the initial ECG
or during DB Treatment Phase in case of
abnormality.
To clarify when triplicate ECGs
are required.
8.2.6. Columbia Suicidality 
Severity Rating Scale 
(C-SSRS) 
Corrected time to be recorded in the eCRF 
for suicidal ideation and/or suicidal behavior 
at screening. 
Suicidal ideation in the past 3
months and/or suicidal behavior
in the past 6 months are being
collected in the eCRF.
8.2.6. Columbia Suicidality 
Severity Rating Scale;
11. References
Added reference for the C-SSRS. 
To add missing reference.
8.2.7. Arizona Sexual 
Experiences Scale (ASEX) 
Revised description of the ASEX to align 
with the revised safety endpoint.
Alignment edits.
8.3.6. Adverse Events of 
Special Interest 
Deleted text related to moderate/severe AESI 
in the reporting instructions. 
To clarify that all AESI are to be
reported and additional
information to be collected on all
cases.
8.4.1. Speech/Facial Digital 
Biomarker Analysis 
Added facial digital biomarker analysis. 
To include facial digital
biomarker analysis.
8.4.3. Reward Learning 
Task (RLT) 
Added learning rate and reward sensitivity to 
list of measures of the RLT.
To add missing measures.
9.3. Participant Analysis 
Sets 
Revised “Enrolled” to “All Participants” in 
the table describing analysis sets. 
To clarify that the term ‘All
Participants’ pertains to all
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
143
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
screened participants, while
‘Enrolled’ pertains to randomized
participants.
9.4.5.3. Biomarker 
Analyses 
Revised description of digital biomarker 
analyses. 
To clarify digital biomarker
analyses.
10.2. Appendix 2: Clinical 
Laboratory Tests 
Revised bullet 3 under Other Tests (at 
Screening, Baseline, or During Treatment) to 
clarify that in some countries a urine or blood
sample may be collected to assess
compliance with current antidepressant
medications.
To clarify that this sample is not
required.
10.3.5. Long-term 
Retention of Samples for 
Additional Future Research
Added a sentence to define the start of the 
retention period. 
To clarify when the long-term
retention period begins.
10.4.3.1. Guidance for 
Assessing Severity of 
Adverse Events of Special 
Interest
Added a new appendix to provide guidance 
to investigators for assessing the severity of 
AESI. 
To provide recommendations to
consider when assessing the
severity of
 and 
10.5. Appendix 5: 
Contraceptive and Barrier 
Guidance 
Removed footnote “b” from “implantable 
progestogen-only hormone contraception 
associated with inhibition of ovulation” and
“combined (estrogen- and progestogen-
containing) hormonal contraception
associated with inhibition of ovulation.”
Footnote b is not relevant to these
examples.
10.7. Appendix 7: 
Prohibited Concomitant 
Therapies 
Added barbiturates to list of prohibited 
therapies and removed anxiolytics except 
buspirone. 
To clarify that barbiturates are not
permitted.
To clarify that some anxiolytics
are permitted, but buspirone
remains a prohibited medication.
10.9.2. Guidance Specific to 
this Protocol, Data 
Collection  
Revised bullet for missed doses to remove 
reference to removal of dosing form. 
To correct the procedure for
recording missed doses due to
COVID-19.
1.1. Synopsis, Overall 
Design; 
1.1. Synopsis, Benefit-Risk
Assessment;
1.1. Synopsis, Statistical
Methods;
1.3. Schedule of Activities;
2.3.2. Benefit-Risk
Assessment for Study
Participation;
3. Objectives and
Endpoints;
4.1. Overall Design;
4.1.3. Double-blind
Treatment Phase;
4.1.5. Open-label Long-
term Safety Study;
4.2.1. Study Population;
4.2.3. Study-Specific
Ethical Design
Considerations;
4.2.4. Biomarker Sample
Collection;
Minor text edits and clarifications were made 
for alignment. 
To provide consistency within the
document.
NCT05455684
CCI
CCI

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 January 2024
4.3 Justification of Dose;
4.4. End of Study
Definition;
6.1. Study Intervention(s)
Administered;
6.3. Measures to Minimize
Bias: Randomization and
Blinding;
7.2. Participant
Discontinuation/Withdrawal
from the Study;
8.8. Pharmacogenomic and
Epigenetic (DNA, RNA)
Assessments;
8.9. Participant Medical
Information Prior to, During
and After the Study
(Optional Real-world Data
Collection);
9.4.5.3. Biomarker
Analyses;
9.4.5.7. Pharmacogenomic
Analyses;
10.7. Appendix 7:
Prohibited Concomitant
Therapies
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.
NCT05455684

JNJ-67953964 Aticaprant
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 January 2024
Amendment 1 (9 August 2022)
Overall Rationale for the Amendment:
Updates are made based on feedback received from interactions with health authorities, key opinion leaders in the
MDD field and potential investigational sites involved in the study feasibility, to ensure alignment across the program
and to improve patient selection. Minor changes are made throughout the protocol for compliance with updated
protocol template text, for clarification, and to correct errors.
The changes made to the Clinical Protocol 67953964MDD3001 as part of Protocol Amendment 1 are listed below,
including the rationale of each change and a list of all applicable sections.
Section Number 
and Name
Description of Change 
Brief Rationale
Synopsis Overall Design, 
1.3. Schedule of Activities 
footnote c, 4.1. Overall 
Design, 6.6. Continued 
Access to Study Intervention 
After the End of the Study, 
7. Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal,
7.2. Participant
Discontinuation/Withdrawal
from the Study
Removed Post Treatment Observation 
Phase. 
In order to implement treatment
policy under Estimand 2, data
after the participant discontinued
study intervention were to be
collected in the PTOP. As
Estimand 2 has been removed
from the protocol, PTOP is no
longer required.
Synopsis Overall Design, 
Synopsis Statistical 
Methods, 1.2. Schema, 
4.1. Overall Design, 
9.2. Sample Size 
Determination, 
9.4.1. General 
Considerations,
9.4.2. Efficacy Analysis,
9.5. Interim Analysis
Modified statement regarding enrollment of 
participants in China and Japan. 
Language pertaining to interim lock of the 
database once the rest of world population 
completes study participation has been 
removed. 
In the event that China and/or
Japan participate in the study to
support local registration, details
about their participation will be
described in their respective
country/territory-specific
amendment.
Synopsis Statistical 
Methods, 9.4. Statistical 
Analyses 
Removed Estimand 2. 
To gain alignment across
submissions to different health
authorities.
Synopsis Statistical 
Methods, 9.4. Statistical 
Analyses 
Removed Estimand 3. 
In the event that China and/or
Japan will participate in the study,
Estimand 3 will be described in a
country/territory-specific
amendment.
Synopsis Benefit-Risk 
Assessment 
Added Benefit-Risk Assessment section to 
Synopsis. 
To align with most current
protocol template.
1.3. Schedule of Activities 
(SoA), 4.1.4. Follow-up 
Phase 
Indicated that the Follow-Up visit (ie, 
Visit 3.1) must indicate 7-14 days after Visit 
2.7 (EOT/EW), instead of 7-14 days after 
last dose of study intervention. 
Editorial change to align the SoA
with the protocol’s instructions
that follow-up visit is to occur
7-14 days after end-of-
treatment/early withdrawal visit.
1.3. Schedule of Activities 
(SoA) 
Moved the post-dose PK timepoint from 
Visit 2.3 (Day 15) to Visit 2.5 (Day 29). 
To reduce burden on participant
by aligning the frequency of post-
dose ECG and PK assessments,
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
146
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
thus reducing the number of visits
with post-dose assessments.
1.3. Schedule of Activities 
(SoA) 
Added footnote “m”: “For participants that 
require translation of the PROMIS-APS 8a 
into their local language, the collection of 
the PROMIS-APS 8a is optional until the 
final, approved translation is available.” 
To include a footnote allowing
flexibility for participant
enrollment to begin in regions
where translations are not yet
available.
1.3. Schedule of Activities 
(SoA) 
Updated footnote “o”: “The cognitive battery 
tests will only be performed in English-
speaking countries/territories a subset of
participants.”
Alignment edit.
1.3. Schedule of Activities 
(SoA) 
Updated footnote “p”: “A urine and/or blood 
sample will be collected and sent to the 
central laboratory to assess compliance with 
current antidepressant medications. If urine 
and/or blood test is negative, one retest may 
be performed at the discretion of the
investigator. With a negative test,
Additionally, other means of assessing
adherence, including confirming prescription
records and performing pill counts and prior
good compliance with antidepressant
medication may be sufficient to demonstrate
compliance per investigator’s judgment.”
To clarify the acceptable methods
of assessing participants
adherence/compliance to their
current antidepressant
medication.
Synopsis Objectives and 
Endpoints, 3. Objectives and 
Endpoints 
Removed “dose or” from Clinical 
Pharmacology Assessments, as there is only 
one dose level.
Alignment edit as no dose-
response analysis planned.
Synopsis Overall Design, 
4.1.2. Screening Phase, 
5.1. Inclusion Criteria 
Updated Inclusion Criterion 5 on number of 
inadequate treatments: 
“Have had an inadequate response to at least 
1 but no more than 2 3 antidepressants (see 
in the inclusion criterion below), 
administered at an adequate dose 
(therapeutic dose per MGH ATRQ) and 
duration (at least 6 weeks) in the current 
episode of depression. The current 
antidepressant cannot be the first 
antidepressant treatment for the first lifetime 
episode of depression.” 
Updated definition of inadequate response to 
current antidepressant: “An inadequate 
response is defined as <50% reduction but 
with some improvement during the current 
antidepressant trial (ie, there may be 
some minor to moderate symptomatic 
improvement >0% since the initiation of the 
antidepressant treatment, but some of the 
initial symptoms are still present, 
troubling to the participant and overall
good tolerability affecting behavior and
function) as assessed by the MGH ATRQ.
Note: Medical/pharmacy/prescription
records or records of conversation with
the treating physician, or other equivalent
Based on feedback received from
clinicians-opinion leaders and
practicing psychiatrists the
maximum number of historical
inadequate responses to current
antidepressant treatment is
updated to reflect clinical reality
and improve patient selection.
The change further aligns with
respective criteria for the
population enrolled in prior
programs of already approved
adjunctive agents.
Updates are made in the wording
of the criteria and information on
the clinical context to the
definition of “inadequate
response” is added to provide
clarity to the sites; ensure
alignment in assessing this
criterion and improve participant
selection.
NCT05455684

JNJ-67953964 Aticaprant
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
147
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
documents can be used to verify the
adequacy of the current antidepressant
trial.”
Removed note regarding participants with no
response/lack of clinically meaningful
improvement:
“Note: Participants with no improvement on
the current SSRI/SNRI should not be
enrolled in the study. If the participant has
received 2 SSRI/SNRI treatments of
sufficient dose and duration in the current
episode, and has shown ≤25% improvement
to both, then the participant would not
qualify based on exclusion criterion 1.”
4.1.2. Screening Phase 
Updated text on adequate trial definition: 
“An adequate trial is defined as an 
antidepressant treatment for at least 6 weeks
on a stable dose at or above the minimum
therapeutic dose specified in the MGH
ATRQ. This must also apply to the
participant’s current antidepressant
treatment. The inadequate response must
include the participant’s current SSRI/SNRI
treatment. Medical/pharmacy/prescription
records or records of conversation with the
treating physician, or other equivalent
documents can be used to verify the
adequacy of the current antidepressant
trial inadequate treatment status.”
To align with Inclusion
Criterion 5.
5.1. Inclusion Criteria 
Revised Criteria 11, 12, and 13 to specify 
participant’s characteristics by sex (not 
gender).
To align with health authority
guidance.
5.1. Inclusion Criteria 
Revised Criterion 6: 
“Is currently receiving and tolerating well 
any one of the following SSRI or SNRI for 
depressive symptoms at screening, in any 
formulation and available in the participating 
country/territory: citalopram, duloxetine, 
escitalopram, fluvoxamine, fluoxetine, 
milnacipran, levomilnacipran, paroxetine, 
sertraline, venlafaxine, desvenlafaxine at a 
stable dose (at a therapeutic dose level per
MGH ATRQ) for at least 6 weeks and with
some minor to moderate symptomatic
improvement (>25%). The current
antidepressant cannot be the first
antidepressant treatment for the first
lifetime episode of depression.”
Clarification made to improve
understanding regarding the
antidepressant (SSRI or SNRI)
the participant is currently taking
and will be continued in the
treatment phase. Last sentence is
moved from Inclusion Criterion 5
as the information pertains to the
current antidepressant.
5.2. Exclusion Criteria 
Updated Exclusion Criterion 1 on exclusion 
of participants with non-response to the 
current SSRI/SNRI: 
“Has a history of treatment resistant MDD, 
defined as Participant has a lack of 
response to 2 or more adequate
Update in wording is made in the
exclusion criterion to provide
further clarity to the definition of
non-response to the current
antidepressant treatment and
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
148
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
antidepressant treatments in the current 
episode, as indicated by no or minimal 
clinically meaningful improvement (≤25%
improvement) when treated with an
antidepressant of adequate dose (per MGH
ATRQ) and duration (at least 6 weeks). to
the current SSRI/SNRI (ie, the one
presumed to be continued in the
treatment phase) assessed using the MGH
ATRQ.”
which participants are not eligible
for the studies.
5.3.2. Activity  
Modified wording to indicate participants 
should (not must) “abstain from strenuous 
exercise…” and “be advised not to donate 
blood…” 
To reduce burden on participant
by making the lifestyle
considerations related to activities
only recommendations.
5.4. Screen Failures 
Added text: “When available, the 
investigator may generate screening and 
enrollment logs directly from IWRS.”
To align with most current
protocol template.
6.1. Study Intervention(s) 
Administered 
Added text: 
“Non-investigational Medicinal 
Product/Auxiliary Medicinal Product:
Current SSRI/SNRI antidepressant*
* Current antidepressant therapy must be
continued throughout the entire study, at the
same dose, every day without change, and at
approximately the same time of the day as
prior to entering the study. The following
antidepressants are permitted:
citalopram, duloxetine, escitalopram,
fluvoxamine, fluoxetine, milnacipran,
levomilnacipran, paroxetine, sertraline,
venlafaxine, and desvenlafaxine. For
further information regarding their use,
refer to the relevant local prescribing
information.”
To align with most current
protocol template.
6.4. Study Intervention 
Compliance 
Added text: “Missing study intervention 
doses due to protocol guidance will not be 
considered noncompliance.” 
To clarify that protocol-mandated
interruptions of study intervention
are not considered as
noncompliance.
6.8. Concomitant Therapy  
8.3.1. Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information  
Removed second occurrence of “All 
antidepressant treatment(s), taken during the 
current depressive episode…”
Removed second occurrence of “Information
regarding SAEs will be transmitted to the
sponsor using the Serious Adverse Event
Form, which must be completed and signed
by a physician from the study site and
transmitted to the sponsor within 24 hours.
The initial and follow-up reports of an SAE
should be transmitted electronically or by
facsimile (fax).”
Removed second occurrence of “If a
participant discontinues from the study in the
To remove a duplication of
information.
NCT05455684

JNJ-67953964 Aticaprant
Clinical Protocol 67953964MDD3001 VENTURA-1 Amendment 2/RS-1 Group 1 (Countries CZE, ESP, USA)
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
149
Status: Approved,  Date: 26 January 2024
Section Number 
and Name
Description of Change 
Brief Rationale
7.2. Participant 
Discontinuation/Withdrawal 
from the Study  
DB Treatment Phase (ie, prior to completion
of the Day 43 visit), an EOT/EW visit
(Visit 2.7) should be conducted preferably
the day after the last dose.”
7.1. Discontinuation of 
Study Intervention  
Updated discontinuation criterion: “AST 
and/or ALT exceeds or is equal to ≥3 x ULN 
and total bilirubin exceeds 1.5 ≥2 x ULN…”
To align with the liver chemistry
stopping criteria.
8. Study Assessments and 
Procedures 
Updated blood volume collections amounts. 
Blood volume collected in study
updated following removal of
sampling for hematology and
chemistry at Visit 3.1.
8.1. Assessments 
Modified text: It is recommended that the 
raters for the efficacy assessments not be 
involved in study intervention dosing, AE 
assessments, or other safety evaluations. To 
minimize the risk of unblinding the
treatment assignment, different site raters
will perform efficacy and safety
assessments; clinicians who perform the
MADRS assessments will not be involved
in assessing AEs.
To align with Section 8.1.2.1
(MADRS) and indicate that there
will be different raters for
efficacy and safety assessments.
8.1.1.1. 17-item Hamilton 
Depression Rating Scale 
(HDRS-17) 
Added Williams 1988 reference for SIGH-D  
and added text on audio recording: 
“HDRS-17 assessments will be administered 
by independent remote raters and will be 
audio recorded for the purpose of quality
monitoring.”
To provide a reference for
SIGH-D and clarify that
HDRS-17 assessments are
audio-recorded.
8.1.1.4. Site Independent 
Qualification Assessment 
(SIQA) 
Modified text: “Remote, iIndependent 
remote psychiatrists/psychologists will 
perform the qualification assessment for all
participants to confirm the validity of a
diagnosis of depression, the severity of the
depressive symptom and eligibility for the
study (Targum 2008). The interviewer will
review participant screening information and
conduct a live, remote interview with the
participant. This interview will include
conducting HDRS-17, to be performed by
the same rater, and will be video recorded
for the purpose of quality monitoring during
screening.”
HDRS-17 assessments are not
video-recorded.
8.1.2.1. 
Montgomery-Åsberg 
Depression Rating Scale 
(MADRS)
8.4.1. Speech Biomarker 
Analysis (Optional) 
Modified text: “All MADRS assessments 
will may be video-recorded for the purpose 
of quality monitoring.”
Modified text: “In this study, the MADRS
physician-patient interview will may be
recorded for data quality monitoring.”
Video-recording of MADRS
assessments is optional.
8.2.4. Clinical Safety 
Laboratory Assessments, 
10.2. Appendix 2: Clinical 
Laboratory Tests 
Revised text regarding FSH as follows: 
“follicle stimulating hormone (FSH) (female 
participants only, at screening only if
required for documentation that a female
participant is not of childbearing potential,
see Inclusion Criterion 12).”
Revised for consistency with text
in Section 8.2.4 and Section 10.2.
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Section Number 
and Name
Description of Change 
Brief Rationale
8.3.1. Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information, 
10.4. Appendix 4: Adverse 
Events, Serious Adverse 
Events, Product Quality 
Complaints, and Other 
Safety Reporting: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting 
In Section 8.3.1 the wording was updated to: 
“Information regarding SAEs will be
transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report
Form of the CRF, which must be completed
and reviewed signed by a physician from the
study site, and transmitted to the sponsor
immediately but no later than within 24
hours. The initial and follow-up reports of an
SAE should be transmitted electronically or
by facsimile (fax). Telephone reporting
should be the exception and the reporter
should be asked to complete the appropriate
form(s) first.”
The same wording added in Section 10.4.5.
To align with current template.
8.3.6. Adverse Events of 
Special Interest 
Added footnote ‘a’ regarding completion of 
Serious Adverse Event Form. 
To ensure PK sample is collected
around time of occurrence of
SAE.
8.4. Digital Biomarker 
Assessments 
Removed “(Optional)” from section title. 
One of the subtasks Reward
Learning Digital Biomarker
Assessments will not be optional
even though it will be
implemented in the English-
speaking countries/territories
only.
8.5.1. Evaluations 
Modified text regarding venous blood 
samples: “Venous blood samples will be 
collected, and each plasma sample will be 
divided into 2 aliquots (with 1 aliquot as a 
back up) for the analysis of aticaprant.”
To keep the text in the protocol
concise as other details on
aliquots can be included in
laboratory manual.
Synopsis Statistical 
Methods, 9.4. Statistical 
Analyses 
Listed discontinuation of both study 
intervention and current antidepressant 
therapy as an intercurrent event. 
In addition to the intercurrent
events in the original protocol,
discontinuation of both study
intervention and current
antidepressant therapy will also
affect interpretation of efficacy
data.
Synopsis Statistical 
Methods, 9.4.2.1. Primary 
Efficacy Endpoint(s) 
Participants who discontinue both treatment 
and AD will be considered as an intercurrent 
event. 
The language concerning
discontinuation of both study
intervention and current
antidepressant is clarified.
9.4.4. Safety Analyses 
Removed text regarding physical 
examinations. 
The results of the physical
examinations are not be entered
on the eCRF unless they are
clinically significant, in which
case an (S)AE is to be entered.
Updated to align with data
collection guidance.
9.4.5.3. Biomarkers 
Analyses 
Updated text on Digital Biomarker Analyses: 
“De-identified Speech/Video features 
during baseline patient interviews, and 
cognitive assessment data will may be
feature extracted.”
Adding “de-identified” to add
clarity on data handling and ease
privacy concerns.
10.2. Appendix 2: Clinical 
Laboratory Tests
Revised “women” to “female participants.” 
To align with current template.
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Section Number 
and Name
Description of Change 
Brief Rationale
Added statement regarding definition of
Hy’s law Case.
10.5. Appendix 5: 
Contraceptive and Barrier 
Guidance 
Removed footnote ‘b’ (“Hormonal 
contraception may be susceptible to 
interaction with the study intervention,
which may reduce the efficacy of the
contraceptive method. In addition, consider
if the hormonal contraception may interact
with the study intervention.”) from
Examples of Contraceptives table.
Template update in line with
comments from a HA.
10.7. Appendix 7: Prohibited 
Concomitant Therapies 
The prohibition of anticonvulsants was 
reconsidered based on the fact that only 
current or history of (6 months) seizures are 
exclusionary.
Use as adjunctive treatment for major
depressive disorder (MDD) is prohibited.
Added comment for trazodone: “Not allowed
even if used for other indications (eg, for
sleep).”
List of prohibited therapies
updated to align with exclusion of
seizures criterion.
10.10. Appendix 10: Study 
Design  
Updated figures based on changes in study
design.
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
 MD
Institution: 
Janssen Research & Development
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT05455684
PPD

Signature
User 
Date 
Reason
 
26-Jan-2024
16:47:44
(GMT)
Document Approval
NCT05455684
PPD