Clinical trial NCT03559192
Conditions: Depressive Disorder, Major
Sponsor: Janssen Research & Development, LLC
Start date: 2018-07-16; Completion date: 2020-05-06
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of JNJ-67953964 compared to placebo when administered as adjunctive treatment in participants with Major Depressive Disorder (MDD) partially responsive to selective serotonin reuptake inhibitor/ serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) treatment in terms of reduction of symptoms of depression, as assessed by the change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) in non-responders during the placebo lead-in period.

Detailed description:

Arms: arm 1: Participants will receive matching placebo for the entire duration of the lead-in period. arm 2: Participants who respond or do not respond (based on reduction from lead-in baseline in MADRS) in the placebo lead-in period will receive either matching placebo or 10 (2\*5) milligram (mg) JNJ-67953964 capsules in a 1:1 ratio for 6 weeks. arm 3: Participants who complete the double-blind treatment period prior to the end of Week 11 will receive matching placebo for the remaining time of the treatment phase of the study.
Interventions: intervention 1: JNJ-67953964 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-67953964 10 mg will be administered as two 5-mg capsules orally once daily. intervention 2: Matching placebo will be administered as 2 capsules orally once daily.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 28 August 2019
Janssen Research & Development *
Clinical Protocol
A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center 
Study Investigating the Efficacy, Safety, Tolerability and Pharmacokinetics of JNJ-
67953964 in Subjects with Major Depressive Disorder.
Short Title:
A study to explore the efficacy JNJ-67953964
in the treatment of depression.
Protocol 67953964MDD2001, Amendment INT-3; Phase 2a
JNJ-67953964
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. 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 Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; 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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312)
EudraCT NUMBER: 2019-000695-41.
Status:
Approved
Date:
28 August 2019
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-ERI-158697750, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03559192


JNJ-67953964
Clinical Protocol 67953964MDD2001, Amendment INT-3
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Approved, Date: 28 August 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 5
1.
PROTOCOL SUMMARY ................................................................................................................... 14
1.1.
Synopsis......................................................................................................................................... 14
1.2.
Time and Events Schedule (TES).................................................................................................. 25
2.
INTRODUCTION................................................................................................................................ 27
2.1.
Study Rationale.............................................................................................................................. 27
2.2.
Background .................................................................................................................................... 28
2.2.1.
Nonclinical Studies ..................................................................................................................... 28
2.2.2.
Clinical Studies ........................................................................................................................... 29
2.3.
Benefit/Risk Assessment ............................................................................................................... 32
3.
OBJECTIVES .................................................................................................................................... 33
4.
STUDY DESIGN ................................................................................................................................ 34
4.1.
Overall Design................................................................................................................................ 34
4.2.
Scientific Rationale for Study Design............................................................................................. 36
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 41
4.3.
Justification for Dose...................................................................................................................... 42
4.4.
End of Study Definition................................................................................................................... 42
5.
STUDY POPULATION ...................................................................................................................... 43
5.1.
General Considerations ................................................................................................................. 43
5.2.
Inclusion Criteria ............................................................................................................................ 43
5.3.
Exclusion Criteria ........................................................................................................................... 46
5.4.
Lifestyle Considerations................................................................................................................. 50
5.5.
Screen Failures .............................................................................................................................. 51
6.
STUDY TREATMENTS ..................................................................................................................... 51
6.1.
Study Treatments Administered..................................................................................................... 51
6.2.
Preparation, Handling, and Storage............................................................................................... 52
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 53
6.4.
Study Medication Compliance ....................................................................................................... 54
6.5.
Concomitant Therapy..................................................................................................................... 54
6.6.
Intervention After the End of the Study.......................................................................................... 56
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 56
7.1.
Unblinded Data Review.................................................................................................................. 56
7.2.
Completion ..................................................................................................................................... 56
7.3.
Participant Discontinuation/Withdrawal from the Study................................................................. 57
7.4.
Protocol Stopping Criteria .............................................................................................................. 58
7.5.
Withdrawal from the Use of Research Samples ............................................................................ 58
7.6.
Lost to Follow-up............................................................................................................................ 58
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 58
8.1.
Overview ........................................................................................................................................ 58
8.2.
Study procedures........................................................................................................................... 60
8.2.1.
Screening.................................................................................................................................... 60
8.2.2.
Baseline Visit (Visit 2)................................................................................................................. 61
8.2.3.
Double-blind Treatment Period................................................................................................... 61


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8.2.4.
Early Withdrawal Visit................................................................................................................. 62
8.3.
Efficacy Assessments .................................................................................................................... 62
8.3.1.
Rater Qualification ...................................................................................................................... 62
8.3.2.
Primary........................................................................................................................................ 62
8.3.3.
Secondary................................................................................................................................... 63
8.3.4.
Exploratory.................................................................................................................................. 65
8.4.
Safety Assessments....................................................................................................................... 65
8.4.1.
Physical and Neurological Examination ..................................................................................... 65
8.4.2.
Vital Signs................................................................................................................................... 65
8.4.3.
Electrocardiogram (ECG) ........................................................................................................... 66
8.4.4.
Clinical Safety Laboratory Assessments .................................................................................... 66
8.4.5.
Suicidal Risk Monitoring ............................................................................................................. 66
8.4.6.
Other Safety Evaluations............................................................................................................ 66
8.5.
Adverse Events and Serious Adverse Events ............................................................................... 67
8.5.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 68
8.5.2.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 68
8.5.3.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 68
8.5.4.
Pregnancy................................................................................................................................... 68
8.6.
Treatment of Overdose .................................................................................................................. 69
8.7.
Pharmacokinetics........................................................................................................................... 69
8.8.
Genetics ......................................................................................................................................... 70
8.9.
Biomarkers ..................................................................................................................................... 70
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 71
9.1.
Sample Size Determination ........................................................................................................... 71
9.2.
Efficacy Analyses ........................................................................................................................... 71
9.2.1.
Primary........................................................................................................................................ 71
9.2.2.
Secondary................................................................................................................................... 72
9.2.3.
Exploratory.................................................................................................................................. 73
9.3.
Biomarker Analyses ....................................................................................................................... 73
9.4.
PK analysis .................................................................................................................................... 73
9.5.
Safety Analyses ............................................................................................................................. 74
9.6.
Interim Analysis.............................................................................................................................. 75
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 76
10.1.
Appendix 1: Abbreviations ............................................................................................................. 76
10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 80
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 82
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 93
10.5.
Appendix 5: Drugs to be avoided................................................................................................... 98
10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information........................... 99
10.7.
Appendix 7: Liver Safety: Suggested Actions and Follow-up Assessments................................ 100
10.8.
Appendix 8: The SHAPS.............................................................................................................. 103
10.9.
Appendix 9: Self-Assessment of Treatment Experience ............................................................. 106
10.10.
Appendix 10: Cognitive and Physical Functioning Questionnaire (CPFQ).................................. 107
10.11.
Appendix 11: Columbia Suicide Severity Rating Scale. .............................................................. 108
10.12.
Appendix 12: Arizona sexual experiences scale (ASEX)©.......................................................... 112
10.13.
Appendix 13: The Karolinska Sleepiness Scale. ......................................................................... 114
10.14.
Appendix 14: Protocol Amendment History ................................................................................. 115
11.
REFERENCES................................................................................................................................. 116
INVESTIGATOR AGREEMENT ............................................................................................................... 118


JNJ-67953964
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LIST OF IN-TEXT FIGURES
Figure 1:
Flow diagram of the study......................................................................................................... 16
Figure 2:
Flow diagram of the study......................................................................................................... 35


JNJ-67953964
Clinical Protocol 67953964MDD2001, Amendment INT-3
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment INT-3
28 August 2019
Amendment INT2, GER-1
04 July 2019
Amendment INT2, GBR-1
21 May 2019
Amendment INT-2
26 February 2019
Amendment INT-1
18-June-2018
Original Protocol
14-March-2018
Amendment INT-3 (28-August-2019)
Overall Rationale for the Amendment: To harmonize aspects of local amendments (GBR-1 and 
GER-1) into one common protocol; to include corrections already documented in note-to-files and to 
include some administrative corrections.
Section number
and Name
Description of Change
Brief Rationale
Section 4.4, End of Study 
Definition
Following text was added:
End of Study Definition
The end of study is considered as the last 
visit for the last participant in the study.
A header Study Completion Definition was added
Based on Amendment 
GER-1: An end of study 
definition was missing in 
the protocol
Section 5.2, Inclusion 
Criteria, Inclusion 
criterion 5.
Original text:

Men who are sexually active with a woman 
of childbearing potential and have not had a 
vasectomy must agree to use a barrier 
method of birth control e.g., either condom 
or partner with occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository 
for 
the 
duration of the study plus 3 months after 
receiving the last dose of study drug, and all 
men must not donate sperm during the study 
and for 3 months after receiving the last dose 
of study drug. In addition, their female 
partners should also use an additional 
method of birth control (which may include 
a hormonal method, an intrauterine device 
[IUD] or an intrauterine system [IUS]) for at 
least the same duration.
Changed into:

Men who are sexually active with a woman 
of childbearing potential and have not had a 
vasectomy must agree to use a barrier 
method of birth control i.e., a condom with 
spermicidal foam/gel/film/cream/suppository 
for the duration of the study plus 3 months 
after receiving the last dose of study drug, 
and all men must not donate sperm during 
the study and for 3 months after receiving 
Based on Amendment 
GER-1: Men with WOCBP 
partners should use a 
barrier method of birth 
control (condom) in every 
case.


JNJ-67953964
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Section number
and Name
Description of Change
Brief Rationale
the last dose of study drug. In addition, their 
female partners should also use an additional 
method of birth control (which may include 
a hormonal method, an intrauterine device 
[IUD] or an intrauterine system [IUS]) for at 
least the same duration.
Section 5.2, Inclusion 
Criteria, inclusion criterion 
6.1.
Original text:
Not of childbearing potential: postmenopausal (>45 
years of age with amenorrhea for at least 12 months, 
or any age with amenorrhea for at least 6 months and 
a serum follicle stimulating hormone (FSH) level at 
screening >40 IU/L without hormonal replacement 
therapy); permanently sterilized (e.g., tubal occlusion 
[tubal cauterization and other comparable methods], 
hysterectomy, bilateral salpingectomy); or otherwise 
be incapable of pregnancy.
Changed into:
Not of childbearing potential defined as: 
Postmenopausal (amenorrhea for at least 12 months 
without an alternative medical cause. A serum 
follicle stimulating hormone (FSH) level at 
screening >40 IU/L in women not using hormonal 
contraception or hormonal replacement therapy may 
be used for confirmation, however in the absence of 
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement is insufficient) or 
Permanently sterilized (including hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy) 
or
Otherwise be incapable of pregnancy.
Based on Amendment 
GBR-1.
Section 5.3, Exclusion 
Criteria, Exclusion criterion 
13.
Original text:
Subject has a history of hepatitis B surface antigen 
(HBsAg) or hepatitis C antibody (anti-HCV) positive, 
or other clinically active liver disease, or tests positive 
for HBsAg or anti-HCV at Screening. If subjects have 
been successfully treated for HCV and are RNA 
negative, they will be allowed in the study.
Changed into:
Subject has a history of hepatitis B surface antigen 
(HBsAg) or hepatitis C antibody (anti-HCV) positive, 
or other clinically active liver disease, or tests positive 
for HBsAg or anti-HCV at Screening. If subjects have 
been successfully treated for or have been 
spontaneously recovered from HCV and are RNA 
negative, they will be allowed in the study.
Some subjects recover 
spontaneously from HCV 
without any treatment. 
These subjects have a 
positive antibody test but a 
negative RNA-test.
Section 5.3, Exclusion 
Criteria, Exclusion 
criterion 16.
Original text:
Subject has positive test result(s) for alcohol or drugs 
of abuse (including barbiturates, methadone, opiates, 
cocaine, cannabinoids, 
As benzodiazepines may 
be allowed under certain 
conditions, a positive urine 
drug screen on 


JNJ-67953964
Clinical Protocol 67953964MDD2001, Amendment INT-3
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Approved, Date: 28 August 2019
Section number
and Name
Description of Change
Brief Rationale
amphetamine/methamphetamine, benzodiazepines 
and ecstasy) at Screening or at baseline (Visit 2).
Subjects with a positive alcohol or drug screen may 
have the test repeated once, based on the 
investigator's discretion. This determination, and the 
reason for permitting a repeat test, must be recorded 
in the subject's source documents and initialed by the 
investigator. A positive, repeat alcohol or drug screen 
is exclusionary.
Changed into:
Subject has positive test result(s) for alcohol or drugs 
of abuse (including barbiturates, methadone, opiates, 
cocaine, cannabinoids, 
amphetamine/methamphetamine, and ecstasy) at 
Screening or at baseline (Visit 2).
A positive test result for benzodiazepines is not 
exclusionary if the subject is taking such drugs per 
protocol.
Subjects with a positive alcohol or drug screen may 
have the test repeated once, based on the 
investigator's discretion. This determination, and the 
reason for permitting a repeat test, must be recorded 
in the subject's source documents and initialed by the 
investigator. A positive, repeat alcohol or drug screen 
is exclusionary.
benzodiazepines is not 
always exclusionary. 
Section 5.3, Exclusion 
Criteria, Exclusion 
criterion 25.
Original text:

Has known allergies, hypersensitivity, or 
intolerance or any contraindication to 
JNJ-67953964 
(refer 
to 
IB 
for 
JNJ-
67953964).
Changed into:

Has known allergies, hypersensitivity, or 
intolerance or any contraindication to any of 
the excipients of JNJ-67953964 or placebo 
(refer to IB for JNJ-67953964).
Based on Amendment 
GER-1: To exclude 
subjects with an allergy, 
hypersensitivity, 
intolerance or any 
contraindication to the use 
of placebo
Section 7.3, Participant 
Discontinuation/Withdrawal 
from the Study
Original text:

Subjects who drop out will be replaced if the 
number of subjects completing the study will 
be below 96. Replacement subjects will 
receive a new subject ID-number and will be 
assigned to a new randomization code in the 
IWRS.
Changed into:

Subjects who drop out, other than for safety 
reasons related to the study drug or study 
procedures, will be replaced if the number of 
subjects completing the study will be below 
96. A maximum of 32 subjects (1/3 of 
targeted subjects) will be allowed to be 
Based on Amendment 
GER-1: To define a 
maximum number of 
replacement subjects. In 
addition, only those 
subjects will be replaced 
which have not withdrawn 
due to adverse drug 
reactions or adverse events 
based on study procedures.


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Clinical Protocol 67953964MDD2001, Amendment INT-3
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Approved, Date: 28 August 2019
Section number
and Name
Description of Change
Brief Rationale
replaced. Replacement subjects will receive 
a new subject ID-number and will be 
assigned to a new randomization code in the 
IWRS.
Section 7.3, Participant 
Discontinuation/Withdrawal 
from the Study
The text in section 7.3 will be changed from:
A subject will be discontinued from the study if the 
QTcF interval is higher than 500 msec or is prolonged 
>60 msec from the baseline value. Similarly, subjects 
presenting with a first-degree bundle branch block 
(BBB; PR > 200 msec) will be discontinued. QTc 
interval prolongation and BBB should be confirmed 
by collecting 2 additional ECGs as soon as possible 
after the initial ECG. The average value of the QTcF 
interval of the three ECG’s will be used to determine 
whether a subject should be discontinued. If the QTcF 
is not readily available, the QTcB may be used 
instead. The subject will continue to be monitored 
(maximum 12 hours) by repeated 12 lead ECGs (at 
least every 60 minutes) until the ECG normalizes.
To
A subject will be discontinued from the study if the 
QTcF interval is higher than 500 msec or is prolonged 
>60 msec from the baseline value. QTc interval 
prolongation should be confirmed by collecting 
2 additional ECGs as soon as possible after the initial 
ECG. The average value of the QTcF interval of the 
three ECG’s will be used to determine whether a 
subject should be discontinued. If the QTcF is not 
readily available, the QTcB may be used instead. The 
subject will continue to be monitored (maximum 12 
hours) by repeated 12 lead ECGs (at least every 60 
minutes) until the ECG normalizes.
A withdrawal criterion for 
the PR-interval (> 200 
msec) has been included 
which is conflicting with 
inclusion criterion 3 
(subject with PR-interval 
>220 are excluded). 
This withdrawal criterion 
on the PR-interval will be 
removed from Section 7.3. 
The rationale for this 
removal is
•
Subjects with a PR-
interval ≥220 msec are 
already excluded from the 
study per inclusion 
criterion 3.
•
The PR-interval does 
not increase under the 
influence of any medicinal 
product.
Section 8.5.1, Time Period 
and Frequency for 
Collecting Adverse Event 
and Serious Adverse Event 
Information
Original Text:

All SAEs occurring during the study must be 
reported to the appropriate sponsor contact 
person by study-site within 24 hours after 
their knowledge of the event.
Changed into:

All SAEs occurring during the study must be 
reported to the appropriate sponsor contact 
person by study-site personnel immediately, 
without undue delay, under no circumstances 
later than 24 hours after their knowledge of 
the event.
Based on Amendment 
GER-1: To adjust the 
wording of the timeframe 
for reporting SAEs in line 
with the German law 
(Section 12 para 4 GCP 
ordinance) and European 
rules (2011/C 172/01/EC, 
„CT-3", 4.3.1, 29.).
Section 10.11, Appendix 11
Added: Past x years = Past 1 year
Correction of omission
Protocol amendments
Correct date of Amendment INT-2 to 26 February 
2019
This 
date 
was 
not 
consistent in Amendment 
INT-2.


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Approved, Date: 28 August 2019
Amendment INT-2 (26-February-2019)
Overall Rationale for the Amendment: Administrative change to add the EudraCT number because of 
additional trial execution in the EU, changes of inclusion criterion on female sterilization, exclusion
criteria on concomitant medication due to reconsideration of current clinical practices and some changes 
on request of clinical sites.
Section number
and Name
Description of Change
Brief Rationale
Section 5.3, 
Exclusion Criteria, 
exclusion criterion
5.
Has failed (no more than 25% response on ATRQ) 
three or more antidepressant treatments including 
the current SSRI/SNRI and including the current 
and all previous depressive episodes despite an 
adequate dose (per ATRQ) and duration (at least 6 
weeks).
Changes into: 
Has failed (no more than 25% response on ATRQ) 
three or more antidepressant treatments including 
the current SSRI/SNRI during the current
depressive episode despite an adequate dose (per 
ATRQ) and duration (at least 6 weeks).
To align better to the current clinical 
practice. Obtaining data from 
previous episodes is complex in 
clinical practice.
Section 5.3, 
Exclusion Criteria, 
exclusion 
criterion 17.
Original text:

Antipsychotic 
drugs 
(D2-antagonists) 
within 2 weeks before screening.
Changed into:

Antipsychotic 
drugs 
(D2-antagonists) 
within 
2 
weeks 
before 
screening. 
However, Seroquel (quetiapine) in a dose 
≤100 mg is allowed when used in a stable 
dose for at least 8 weeks prior to 
screening. Quetiapine treatment should be 
continued unchanged during the study.
Low dose quetiapine and trazodone 
are used a sedative drug during 
treatment of depression. The effect on 
depression itself when used in a 
stable low dose is limited
Section 5.3, 
exclusion criterion 
18.
Original text:

benzodiazepines.
Changed into:

Benzodiazepines when used only as needed
(PRN) is not allowed. A subject may continue 
to take a benzodiazepine treatment only if:
• The subject has been taking a stable daily 
dose for at least 6 weeks prior to screening
• The dose does not exceed an equivalent of 
2 mg of lorazepam per day.
• Allowed 
benzodiazepines 
are 
lorazepam 
(≤2 mg/day), clonazepam (≤0.5 mg/day) and 
alprazolam (≤1 mg/day) being taken daily. 
Other benzodiazepines should be discussed 
before subject enrollment with the study 
responsible physician.
• Treatment will be continued unchanged 
during the study.
Benzodiazepines in stable use have 
limited effects on current depression 
and anxiety severity levels.


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Section number
and Name
Description of Change
Brief Rationale
Section 6.5
Concomitant 
medication
Original text:

benzodiazepines.
Changed into:

Benzodiazepines when used only as needed
(PRN) is not allowed. A subject may continue 
to take a benzodiazepine treatment only if:
• The subject has been taking a stable daily 
dose for at least 6 weeks prior to screening
• The dose does not exceed an equivalent of 
2 mg of lorazepam per day.
• Allowed 
benzodiazepines 
are 
lorazepam 
(≤2 mg/day), clonazepam (≤0.5 mg/day) and 
alprazolam 
(≤1 
mg/day). 
Other 
benzodiazepines should be discussed before 
subject enrollment with the study responsible 
physician.
• Treatment will be continued unchanged 
during the study.
Benzodiazepines in stable use have 
limited effects on current depression 
and anxiety severity levels.
Section 6.5
Concomitant 
medication
Original text:

Antipsychotic drug (D2-antagonists), lithium 
and other mood stabilizers from 2 weeks before 
screening. 
Changed into:

Antipsychotic drugs (D2-antagonists) within 2 
weeks before screening. However, Seroquel 
(quetiapine) in a dose ≤100 mg is allowed when 
used in a stable dose for at least 8 weeks prior 
to screening. Quetiapine treatment should be 
continued unchanged during the study.

Trazodone for treatment of insomnia in a dose 
≤100 mg when used for at least 8 weeks at a 
stable dose will be allowed.
Low dose quetiapine and trazodone 
are used a sedative drug during 
treatment of depression. The effect on 
depression itself when used in a 
stable low dose is limited
Section 2.3 and 
references.
Update: Investigator brochure is now edition 3, 
January 2019
Section 4.1 Overall 
design
Added “audio” to recording
specification
Section 5.2
Inclusion criteria, 
inclusion criterion 6 
first bullet point
Added: tubal cauterization and other surgical 
interruption of the fallopian tubes as an allowed
means for female sterilization.
Update on current medical practice.
Section 5.4
Lifestyle 
considerations. 
No 3.
Added units of alcohol (UK standards)
On request of UK-based sites
Section 8.2.3
Double-blind 
treatment period
Added: At their last study visit, each study 
participant will be invited to complete an IEC/IRB 
approved Experience Survey, to share to his/her 
experience as a volunteer in this study. The 
responses will be collected by an external party and 
anonymously provided to the sponsor.
Was missing in previous version.


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Section number
and Name
Description of Change
Brief Rationale
Section 8.3.1, Rater 
Qualification
This section about the rater qualification and 
training process has been added.
Policy to optimize rater training.
Section 10.2

Follicle stimulating hormone (FSH)
Changed into

For postmenopausal women only: Follicle 
stimulating hormone (FSH)
To limit unnecessary testing
Section 1.2 Time 
and Events 
schedule
Added: meals during study visits.
Download and install Q.16 app
Changed into
Download and install app(s) at screening and
baseline.
Missing elements in previous version 
of protocol.
Amendment INT-1 (18-June-2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment: To harmonize with procedures of some vendors, to update dosing 
instructions and to correct some typo’s.
Section number
and Name
Description of Change
Brief Rationale
Section 5.3, 
Exclusion Criteria, 
exclusion 
criterion 5.
Original text:
5.
Has failed (no more than 20% response) three or more 
antidepressant 
treatments 
with 
a 
different 
pharmacological mode of action including the current 
SSRI/SNRI despite an adequate dose (per ATRQ) and 
duration (at least 6 weeks) during a previous or the 
current depressive episode.
Changed into:
1.
Has failed (no more than 25% response on ATRQ) three 
or more antidepressant treatments including the current 
SSRI/SNRI and including the current and all previous 
depressive episodes despite an adequate dose (per 
ATRQ) and duration (at least 6 weeks).
The ATRQ form uses ≤25% 
as the lowest response 
criterion. The exclusion 
criterion is now harmonized 
with the ATRQ.
To harmonize the study 
procedures with those of the 
independent reviewers and to 
prevent that too many 
‘unrecognized therapy 
resistant subjects’ will be 
randomized in the study, the 
wording “with a different 
pharmacological mode of 
action” has been removed.
Section 5.3, 
exclusion criterion 
17.
Original text:

Proton pump inhibitors within 2 weeks before 
screening.
Changed into:

Proton pump inhibitors within 4
weeks before 
screening.
Typo, was inconsistent with 
exclusion criterion 3.
Time and Events 
Schedule (TES); 
PROTOCOL 
SUMMARY, 
Sections 4.1, 6.1
Remove “morning” from several sections.
Time and Events schedule, footnote “d”: 
Original text: At home: In the morning in fasting condition.
At clinic visit days: In fasting condition after completion of 
Study medication should be 
taken after 4-hours fasting. 
This is preferably done in the 
morning. However, 
medication may also be 
taken before lunch and 


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Section number
and Name
Description of Change
Brief Rationale
and 8.2.2.
predose assessments.
Changed into: At home: In fasting condition. At clinic visit 
days: Use blisters dispensed at the previous visit. In fasting 
condition after completion of predose assessments.
Section 4.1 and summary:
Original text: 
The first dose will be taken at home next morning on Day 2.
Changed into: 
The first dose will be taken at home on Day 2.
Section 6.1 and summary:
Original text:
All subjects will take 2 capsules QD. The capsules will be 
taken daily from Day 2 to Day 78 every morning (at home 
and when being in the clinic) in fasting condition with some 
water (fasting for at least 4 hours before dosing; water 
intake is permitted during that period).
The subjects will take the study medication with them at 
each study visit and will take study medication at the site in 
fasting condition after completion of predose study 
assessments and blood collections. Dosing will be witnessed 
by the study staff.
Changed into:
All subjects will take 2 capsules QD. The capsules will be 
taken daily from Day 2 to Day 78 (at home and when being 
in the clinic) in fasting condition with some water (fasting 
for at least 4 hours before dosing; water intake is permitted 
during that period Study medication will be taken before 
breakfast. If the subject has forgotten to take the study 
medication before breakfast, this should be done before the 
next following meal, at the latest at dinner of the same day. 
If the subject remembers later than dinner, the dose of that 
day should be omitted, and the subject should take his dose 
before breakfast on the next day.
The subjects will take the study medication with them at 
each study visit and will take study medication - from the 
blisters dispensed at the previous study visit - at the site in 
fasting condition after completion of predose study 
assessments and blood collections. Dosing will be witnessed 
by the study staff.
before dinner. Because of the 
long t½ of the study drug, 
drug intake may be up to 12 
hours after the planned 
dosing time.
Additionally, during a study 
visit, study drug from the 
blisters dispensed at the 
previous visit should be 
dosed.
Section 6.4
Original text: 
Dosing will be documented by an app using the subjects’ 
smartphone.
To add specific information 
about the AiCure-app to 
record compliance of drug 
intake.


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Section number
and Name
Description of Change
Brief Rationale
Changed into:
Dosing will be documented by app’s using the subjects’ 
smartphone, or on a smartphone provided to the subject if 
they are unable to use their own. The Q1.6-app will present 
an electronic diary asking subjects to confirm dosing of 
study medication. When available, also a medication 
adherence monitoring platform (AiCure®-app) will be used. 
The Platform uses artificial intelligence on smartphones to 
visually confirm proper medication administration and 
ingestion of the study drug in real time without human 
intervention.  Video recordings of the drug intake are also 
recorded and stored to AiCure’s secure server for further 
analysis to reconfirm proper medication administration, to 
identify any usability issues or intentional non-adherence, 
and to check for duplicate enrollment. In addition, built-in 
reminders and a communication system allow real-time 
intervention by study personnel in case of improper drug 
administration or interruptions by the subject.
Section 8.1
Added:
• Manuals for investigator and subject for the AiCure-app to 
assess treatment compliance by video recording the drug 
intake. The AiCure-app will be downloaded on the subjects’ 
own smartphone, or a smartphone with the app included will 
be provided to the subject.
To inform about additional 
materials supplied for 
AiCure-app
Section 8.2.1
Original text:
As duplicate enrollment and protocol violations are risk 
factors for poor quality data and safety concerns, each 
subject in this study must have their current study status 
checked by a clinical trials verification system. This is a 
mandatory process.
Changed into:
As duplicate enrollment and protocol violations are risk 
factors for poor quality data and safety concerns, each 
subject in this study will have their current study status 
checked by a clinical trials verification system when 
available.
The verification system may 
not be available for this 
study due to new privacy 
regulations in the EU. As a 
global company, Janssen has 
determined that the 
requirements of the EU 
privacy regulations will be 
followed for all studies even 
in cases where no study sites 
are located in the EU.


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1.
PROTOCOL SUMMARY
1.1.
Synopsisa
A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center 
Study Investigating the Efficacy, Safety, Tolerability and Pharmacokinetics of 
JNJ-67953964 in Subjects with Major Depressive Disorder.
JNJ-67953964, previously known as Cerecor (CERC)-501 and LY2456302, is a small molecule, 
high-affinity, selective kappa opioid receptor (KOR) antagonist. JNJ-67953964 is orally 
bioavailable and suitable for once-daily (QD) administration. 
KORs and their native ligand dynorphin are localized in areas of the brain that effect reward and 
stress and may play a key role in mood, stress, and addictive disorders. Chronic stress, substance 
abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and 
subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing 
to negative affective states. The behavioral pharmacology of KOR antagonism has been tested in 
animal models of anhedonia, depression, and anxiety and found to have meaningful effects that 
may translate to therapeutic benefit in humans. KOR antagonists may be effective for the 
treatment of patients with mood disorders, perhaps by modulating the negative affective state 
associated with stress response.
Only about 50% of patients with major depressive disorder (MDD) show a meaningful response 
(>50% improvement to a first line antidepressant treatment), leaving many patients with 
substantial persistent impairment. Therapeutic strategies such as switching antidepressants and 
using adjuvant drug treatments can improve response, however almost 40% of patients remain 
symptomatic and fail to achieve full remission. Recently, Alkermes (ALKS) 5461, a combination 
of buprenorphine, which is a partial -opioid receptor agonist and KOR antagonist, and 
samidorphan, a potent -opioid receptor antagonist, has been tested in Phase 2 trials in subjects 
with MDD who have had only a partial response to treatment with a selective serotonin reuptake 
inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Adjunctive treatment 
with ALKS 5461 was associated with greater symptom reduction compared to placebo, 
suggesting that a KOR antagonist could provide a meaningful clinical benefit for patients being 
treated for MDD. 
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate the efficacy of JNJ-67953964 compared to 
placebo when administered as adjunctive treatment in subjects with MDD partially responsive to 
SSRI/SNRI treatment in terms of reduction of symptoms of depression, as assessed by the 
change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) in non-
responders during the placebo lead-in period.
                                                
a This section has been amended by amendment INT-1


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Secondary Objectives
The secondary objectives of this study are:

To evaluate the efficacy of JNJ-67953964 compared to placebo when administered as 
adjunctive treatment in subjects with MDD partially responsive to SSRI/SNRI treatment in 
terms of reduction of symptoms of depression, as assessed by the change from baseline on 
the Montgomery Asberg Depression Rating Scale (MADRS) in both responders and non-
responders during the placebo lead-in period.

To investigate the overall safety and tolerability of treatment with adjunctive JNJ-67953964
in subjects with MDD when used in combination with a SSRI or SNRI.

To investigate the effect of JNJ-67953964 versus placebo on depression related anhedonia 
as assessed by the Snaith-Hamilton Pleasure Scale (SHAPS).

To investigate the effect of JNJ-67953964 on symptoms of depression using the Clinical 
Global Impression-Severity (CGI-S), the patient reported Symptoms of Major Depressive 
Disorder Scale (SMDDS) and the self-assessment of treatment experience (SATE). 

To investigate the effect of JNJ-67953964 on symptoms of anxiety using the Hamilton 
Anxiety Scale (HAM-A) and on core symptoms of anxiety using the HAM-A6 subscale.

To assess the plasma pharmacokinetics (PK) of JNJ-67953964 in subjects with MDD and 
explore its relationship with efficacy and safety parameters.
Exploratory objectives:

To explore the effect of JNJ-67953964 on aspects of cognitive and executive function using 
the Cognitive and Physical Functioning Questionnaire (CPFQ).

To explore mood-related biomarkers (including but not limited to growth factors, 
hypothalamic–pituitary–adrenal [HPA] axis markers, immune system activation, metabolic 
markers) and genetic/epigenetic variation that may be related to clinical response, 
nonresponse, or safety and tolerability parameters of JNJ-67953964.
Hypothesis
The primary hypothesis is that 6-weeks of adjunctive treatment with JNJ-67953964 is superior to 
placebo in improving symptoms of depression, as measured by the change from baseline in the 
MADRS, in subjects with MDD who are partially responsive to SSRI/SNRI treatment.
OVERVIEW OF STUDY DESIGN
This will be a multi-center, placebo-controlled, randomized, double-blind study in subjects with 
MDD who have had inadequate response to SSRI/SNRI treatment. Approximately 142 subjects 
will be included in the study.
For each subject, the study will consist of two phases: a screening phase of up to 5 weeks and a 
double-blind treatment phase lasting 11 weeks.
Subjects with MDD who have had treatment initiated with an SSRI/SNRI allowed by the 
protocol and have had an inadequate or only partial response to this treatment will be screened at 


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the investigational site. Assessments by qualified site personnel including the MINI, 
Antidepressant Treatment History Questionnaire (ATRQ, Chandler 2010), and MADRS will be 
audio recorded at screening for review of eligibility of the subject for enrollment into the study 
by an independent central reviewer contracted by the sponsor. The following key inclusion 
criteria/assessments will be reviewed by a central independent reviewer: the clinical history of 
MDD, SSRI/SNRI treatment of adequate dose and duration for the current episode of depression, 
and current symptom severity on the MADRS. In case of discrepancy of central reviewer and 
local rater, the central reviewer will discuss the discrepancy with the local rater. If the 
discrepancy persists, the local rater will overrule central review.
If 2 weeks or more elapse between the MADRS rating at screening and Visit 2, the local rater 
will complete the MADRS again by a telephone interview up to 4 days before Visit 2 to 
determine whether the subject still meets the thresholds for inclusion. 
Subjects who meet the inclusion and exclusion criteria and are enrolled will be maintained on the 
SSRI/SNRI without change throughout the study to determine whether adjunctive treatment with 
JNJ-67953964 can reduce symptoms of MDD.
The treatment phase of the trial will consist of 3 periods. A placebo lead-in period of concealed 
duration, after which subjects will enter the double-blind treatment period when they will be 
randomly assigned to 10 mg JNJ-67953964 or continue placebo for 6 weeks. Subjects who 
complete the treatment period, will then enter the withdrawal period and be treated with placebo 
for the remaining time of the treatment phase of the study. The total study duration for each 
subject will be approximately 16 weeks. There will be 11 scheduled visits to the clinical research 
center including screening during the study. An overall flow diagram of the study is shown in 
Figure 1.
Figure 1:
Flow diagram of the study 


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Eligibility Screening Examination
After giving written informed consent, subjects will be screened within 35 to 2 days prior to 
Day 1 to ascertain their eligibility for the study per the inclusion and exclusion criteria. Upon 
completion of all informed consent form (ICF) procedures, recording of adverse events (AEs) 
and concomitant medication will start. Each subject in this study must have their current study 
participation status checked by a clinical trials verification system when such a system is 
available for this study.
The symptoms of depression will be assessed using the (structured interview guide for the) 
MADRS.
Double-blind Treatment Phase
The duration of the double-blind treatment phase will be 11 weeks divided into 3 periods.
Subjects will visit the study center for baseline visits on Day 1. The subject will receive study 
medication after completion of the visit on Day 1. The first dose will be taken at home on Day 2.
Medication will be dispensed at each study visit during this double-blind period. All study 
medication will be taken in fasting condition. 
During the double-blind study phase, the subjects will visit the study center for out-patient visits 
every 1 to 2 weeks as indicated in the Time and Events Schedule (TES).
Lead-in period
Subjects who successfully complete the baseline examination visit at the clinical site/unit, will be 
treated with placebo for the entire duration of the lead-in period. Investigators and subjects will 
be blinded to the exact duration of lead-in period for each subject in the study.
Treatment period
At the end of the lead-in period both placebo lead-in responders and placebo lead-in 
non-responders will be randomized to receive either placebo or 10 mg JNJ-67953964 in a 1:1 
ratio for 6 weeks. Investigators and subjects will remain blinded to exact timing of the 
randomization, response criterion and study drug treatment assignment for each subject.
Withdrawal period
Subjects who complete the double-blind treatment period prior to the end of Week 11 will enter 
the withdrawal period where they will be treated with placebo for the remaining time of the 
treatment phase of the study. Investigators and subjects will be blinded to the exact duration of 
withdrawal period for each subject in the study.


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Early withdrawal visit
Subject who prematurely withdraw from the study are encouraged to complete Visit 11. The 
procedures to be completed during this visit are listed in the TES.
SUBJECT POPULATION
Approximately 142 subjects with MDD who have inadequately responded to a SSRI/SNRI will 
be enrolled in this study.
Subjects will be enrolled after reading the subject information sheet and signing the ICF 
indicating that they understand the purpose of and procedures required for the study and are 
willing to participate in the study and comply with the study procedures.
DOSAGE AND ADMINISTRATION
JNJ-67953964 will be supplied for this study as 5-mg capsules. Placebo will be supplied as 
matching capsules.
All subjects will take 2 capsules QD. The capsules will be taken daily from Day 2 to Day 78 (at 
home and when being in the clinic) in fasting condition with some water (fasting for at least 
4 hours before dosing; water intake is permitted during that period). Study medication will be 
taken before breakfast. If the subject has forgotten to take the study medication before breakfast, 
this should be done before the next following meal, at the latest at dinner of the same day. If the 
subject remembers later than dinner, the dose of that day should be omitted, and the subject 
should take his dose before breakfast on the next day.
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed. After 
having taken the study medication, subjects should try not to eat or drink for at least 30 minutes. 
This period should be controlled when the subject is in the clinic. When outside the clinic, 
violation of this effort (including drug intake in fasting condition) will not be considered a 
protocol violation.
The first dose will be taken in fasting condition on Day 2 of the double-blind phase when the 
subject is at home. 
The subjects will take the study medication with them at each study visit and will take study 
medication - from the blisters dispensed at the previous study visit - at the site in fasting 
condition after completion of predose study assessments and blood collections. Dosing will be 
witnessed by the study staff.
The dose of the study medication is:

10 mg JNJ-67953964: 2 capsules of 5 mg JNJ-67953964 

Placebo: 2 placebo capsules.


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Study medication dose may be adjusted to 5 mg QD based on the results of a blinded review of 
the safety data by the study responsible physician (SRP) or by an unblinded review by the Data 
Review Committee (DRC) or a physician who is not a member of the study team (See 
Section 7.1). When a dose reduction has been decided on, this will only apply to new subjects in 
study and the dose of study medication will be:

5 mg JNJ-67953964: 1 capsule of 5 mg JNJ-67953964 

Placebo: 1 placebo capsule.
EVALUATIONS OF EFFICACY
Clinician rated measures for depression

Montgomery–Åsberg Depression Rating Scale (MADRS)

Clinical Global Impression scale - Severity of Illness (CGI-S)
Patient rated measures for depression

Symptoms of Major Depressive Disorder Scale (SMDDS)

The Self-Assessment of Treatment Experience (SATE) 
Patient rated measure for anhedonia
Snaith–Hamilton Pleasure Scale (SHAPS)
Clinician rated measures for anxiety

Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A)

HAM-A6. The HAM-A6 is a 6-item subscale derived from the original HAM-A.
Patient rated measure for cognition
Cognitive and Physical Functioning Questionnaire (CPFQ).
PHARMACOKINETIC EVALUATIONS
Venous blood samples of 6 mL will be collected for determination of JNJ-67953964 plasma 
concentrations and metabolites when required specified in the TES. In addition, some samples 
may be used to measure plasma concentrations of the SSRI/SNRI used by the subject.
A PK blood sample will be collected at the same time as the blood samples for biomarkers when 
indicated in the TES. 
BIOMARKER EVALUATIONS 
During the study, blood and saliva will be collected for the assessment of biomarkers at the time 
points indicated in the TES.


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In blood and/or saliva, biomarkers related to the HPA axis activation including but not limited to
adrenocorticotropic hormone (ACTH) and cortisol, neurotropic factors, inflammation and 
metabolic factors may be investigated.
Biomarker essays may be added or deleted based on scientific information or technical 
innovations under the condition that the total volume of blood collected will not be increased. 
The biomarker evaluations will include blood collection for genetic/pharmacogenomic and 
epigenetic testing to characterize gene expression in relation MDD symptoms and biomarker 
results. Participation in the genetic/pharmacogenomic part of this study is mandatory.
SAFETY EVALUATIONS
The collection of AEs and concomitant medications will start after the ICF has been signed and 
will continue until the final visit. AEs of special interest include pruritus and gastrointestinal (GI)
complaints such as dyspepsia, abdominal pain, constipation, or diarrhea. If these are of moderate 
or severe intensity (sufficient discomfort to cause interference with normal activity and/or 
warrant treatment), investigators should provide a narrative to describe the event. 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. 
Apart from this, the following safety assessments will be done: physical examination, 
neurological examination, body weight, vital signs (including temperature), 12-lead 
electrocardiogram (ECG), urine drug testing, pregnancy testing (female subjects only), clinical 
labs (hematology, chemistry panel, gastric mucosa integrity panel) and urinalysis. At screening 
only: serology, thyroid function, and HbA1c (diabetic subjects only).
Additional blood and urine samples may be taken or vital signs and ECGs recorded at the 
discretion of the investigators.   
Additionally, emergence of suicidal ideation will be assessed using the Colombia suicide 
severity rating scale (C-SSRS) at screening, and during each study visit. Arizona Sexual 
Experiences (ASEX) will be used to document sexual dysfunction and the Karolinska Sleepiness 
Scale (KSS) will be used to document sleepiness/sedation.
STATISTICAL METHODS
Sample size determination
The sample size for the study is determined based on the assumption of a treatment effect size of 
0.45 in the mean change from baseline (Visit 2) in MADRS total score between JNJ-67953964
treatment group and placebo. The assumed effect size is based on review of the literature looking 
at the adjunctive treatment with ALKS 5461, a combination of buprenorphine (partial -opioid 
receptor agonist and KOR antagonist) and samidorphan (a potent -opioid receptor antagonist)
in MDD patients with an inadequate response to one or two courses of an antidepressant (Fava 
2016 and Enrich 2015).


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Using the data from the same studies, an estimate of 11 for standard deviation in the change in 
MADRS total score from baseline was made. Detection of 0.45 effect size with a power of 90% 
at an overall 1-sided significance level of 0.20, requires 45 subjects in each treatment group 
(90 subjects in total).
When adjusted for a drop-out rate of approximately 5% of subjects during the treatment period, 
the required number of subjects to be randomized is 96. To achieve this, the estimated number of 
subjects to enter the lead in period is 142, after adjusting for an estimated placebo response rate 
of 25% and drop-out rate of 10% during the lead-in period. 
A blinded sample size re-estimation is anticipated with 180 as the maximal number of subjects to 
be enrolled in the trial.
Efficacy analysis
Primary
Primary efficacy analyses will be based on the intention-to-treat analysis set from enriched
population (eITT) which consists of randomized lead-in placebo non-responders receiving at
least one dose of study medication and having at least one post-treatment baseline efficacy 
measurement.
The JNJ-67953964 treatment group will be compared with placebo using the primary efficacy
endpoint: change from treatment baseline in MADRS score during the treatment period. The 
comparison will be performed by means of a mixed-effects model for repeated measures 
(MMRM), with time, treatment (placebo, JNJ-67953964) and time-by-treatment interaction as 
factors and baseline total MADRS score as a continuous covariate. Other covariates of interest 
may be included in the MMRM model. The treatment-placebo differences will be obtained using 
the appropriate contrast in the MMRM models at the 6-week endpoint.
Descriptive statistics for actual values and changes from baseline for MADRS Score at each time 
point of the double-blind treatment phase will be provided by treatment group using both: eITT 
and fITT analysis sets. Mean differences between the treatments with corresponding confidence 
intervals (CIs) will be reported.
Frequency tables for response and remission of depressive symptoms (derived from the 
MADRS) will be provided by treatment group at each time point of the double-blind treatment 
phase using both: eITT and fITT analysis sets. Chi square test to test the overall differences 
between the treatment groups will be performed.
Secondary
Evaluation of Anhedonia
Change from treatment baseline in SHAPS score during the treatment period will be analyzed 
with the same MMRM model as primary efficacy variable (MADRS) using both: eITT and fITT 
analysis sets. The JNJ-67953964 treatment group will be compared with placebo using the 
appropriate contrast in the MMRM model at the 6-week endpoint.


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The effect of JNJ-67953964 on depression symptoms across different baseline levels of 
anhedonia will be explored. Descriptive statistics for actual values and changes from baseline in 
MADRS Score within different anhedonia levels (no anhedonia, low level of anhedonia and high 
level of anhedonia; cutoff values will be provided in Statistical Analysis Plan) will be presented 
by treatment group using both: eITT and fITT analysis set.
Evaluation of Depression
Descriptive statistics for actual values and changes from baseline for CGI-S and SMDDS (total) 
scores at each time point of the double-blind treatment phase will be provided by treatment 
group using both: eITT and fITT analysis sets. In addition, for CGI, frequency tables will be 
provided by treatment and time-point.
Evaluation of Anxiety
Descriptive statistics for actual values and changes from baseline for SIGH-A total score as well 
as HAM-A6 score at each time point of the double-blind treatment phase will be provided by 
treatment group using both: eITT and fITT analysis sets. Mean differences between the 
treatments with corresponding confidence intervals (CIs) will be reported.
Exploratory
Cognitive Functioning Analysis
The actual values of CPFQ and changes from baseline will be summarized at each scheduled 
time point by treatment. These analyses will be performed on both: eITT and fITT analysis sets.
Biomarker Analyses
Biomarker levels will be tabulated for each time point and summary statistics will be calculated. 
Posttreatment changes in biomarker levels will be assessed by treatment group. Analysis of 
variance (ANOVA) and t-test will be used to assess differences across groups and time points. 
Correlations between biomarker levels and clinical endpoints will be evaluated.
All biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity, phenotypes, and biomarkers.
Pharmacokinetic Analyses
Plasma concentrations for JNJ-67953964 will be analyzed. Based on the individual plasma 
concentration-time data from all subjects, exposure parameters of JNJ-67953964 will be derived 
using population PK (popPK) modeling. Potential baseline covariates (eg, demographics such as 
age, sex and race, body weight, laboratory variables such as creatinine clearance, etc.) may be 
included in the models, if relevant. The following exposure parameters will be derived using 
Bayesian feedback analysis: AUC24h and C0h. Results will be tabulated and summary statistics 
will be generated. Individual plasma concentrations per study visit will be listed. 
Pharmacokinetic and pharmacodynamic relationship will be explored, if feasible. Details of 
population PK analysis and PK/PD analysis will be given in an analysis plan and the results will 
be presented in a separate report.


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Safety analyses
Statistical analysis of the safety data will be done by the sponsor or under the authority of the 
sponsor. Specific details will be provided in the Statistical Analysis Plan.
All subjects receiving at least one dose of study drug will be included in the safety analysis. 
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities 
(MedDRA). All reported AEs with onset during the double-blind treatment phase (i.e., treatment-
emergent adverse events [TEAEs], and AEs that have worsened since baseline) will be included 
in the analysis. Serious adverse events (SAEs) will be summarized separately.
Laboratory data will be summarized by type of laboratory test and treatment. Descriptive 
statistics will be calculated for each laboratory analyte at baseline and at each scheduled time 
point, and for changes from baseline.
The percentage of subjects with values out of normal
limits will be summarized. Data listings of subjects with at least one abnormal value will be 
provided.
Descriptive statistics of pulse, supine blood pressure (systolic and diastolic), temperature and 
body weight values and changes from baseline will be summarized at each scheduled time point 
by treatment. The percentage of subjects with values beyond clinically important limits will be 
summarized. Data listings of subjects with at least one abnormal value will be provided.
Heart rate and ECG intervals (RR, PR, QRS and QT), corrected QT intervals according to 
Bazett’s formula (QTcB) and Fridericia’s formula (QTcF) and changes from baseline will be 
summarized at each scheduled time point using descriptive statistics. The number and percentage 
of subjects with at least one occurrence of a treatment-emergent potentially clinically important 
QTc measurement (QTc value >450, >480, or >500 msec) or with a change from baseline in 
QTc>30 msec or 60 msec, will be summarized by treatment group. Data listings of subjects with 
any potentially clinically important values or with a change from baseline in QTc will be 
provided.
Subjects with abnormal physical and neurological examination findings will be presented in a 
data listing.
The suicidal ideation and behavior data collected from the C-SSRS will be summarized 
descriptively at each scheduled timepoint by treatment group. Data from the subjects with 
suicidal ideation and behavior will be presented in data listing. ASEX and KSS data collected 
will be summarized descriptively at each scheduled timepoint by treatment group. All the data 
will be listed.
Interim Analysis 
An interim analysis may be executed. The procedures for the interim analysis will be described 
in a separate charter.


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A blinded data review for purpose of sample size re-estimation may be performed during the 
study after minimally 50% of the subjects are randomized and have completed Week 6 of the 
double-blind treatment period. Sample size may be re-adjusted if the observed SD substantially
deviates from the hypothesized SD or if the lead-in response and dropout rate substantially 
deviate from the assumed values. The maximal number of subjects to be enrolled in the trial will 
not surpass 180.


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1.2.
Time and Events Schedule (TES)a
                                                
a This section has been amended by amendment INT-1 and INT-2
P ha s e
S c re e ning
Visit number
1
2
3
4
5
6
7
8
9
10
11 o r EWb
Week (end of)
-5  to  0
0
1
2
3
4
6
7
8
9
11
Study Day
-3 5  to  -2
1
8
15
2 2
2 9
4 3
5 0
5 7
6 4
7 8
Screening
Informed consent
X
Medical History and study participation status
X
Demographic information
X
Prestudy therapy by ATRQ
X
Serology, thyroid function, HbA1c (only in 
diabetic subjects)
X
MINI 7.0 interview
X
Download and install app(s) at screening and 
baselinem
X
X
Inclusion/exclusion criteria
X
X
Safety assessments
Physical and neurological examination
X
X
X
X
Height
X
Weight
X
X
X
Urine drug and alcohol breath test
X
X
Pregnancy test
c
X
X
X
X
12-Lead ECG
X
X
X 
X 
X 
X 
X
Vital signs (supine BP, pulse)
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X
Tympanic or oral temperature
X
X
X
X 
X
X 
X
ASEX
X
X
X 
X
X
X
KSS
X
X
X 
X
X
X
Suicidality by C-SSRS
X
X
X 
X
X
X
X
X
X
X
X
Dosing
Randomization
X
X
X
X
Supply new study medication
X
X
X
X
X
X
X
X
X
Oral dose study medication
d
Meal after dosing
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Xl
Blood and urine collection
Clinical laboratory Tests: hematology, serum 
chemistry, and urinalysis
Xf
Xf
Xg
Xg
Xg
Gastric mucosa panel
Xf
Xg
Xg
Supply subject with tubes for saliva collection
X
X
X
Saliva collection for cortisol
X
h
X
h
X
h
Blood sample for pharmacokinetics
X
X
i
X
i
X
i
X
i
Blood sample for biomarkers and (epi)genetics
X
f
X
g
X
g
Clinical Assessments
Structured Interview Guide MADRS
X
j
X
X
X
X
X
X
X
X
X
X
Structured Interview Guide SIGH-A
X
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
X
X
SMDDS
X
X
X
X
X
CPFQ
X
X
X
X
X
SHAPS
X
X
X
X
X
X
X
X
X
X
X
SATE
k
Ongoing subject review
Assessment of subject study engagementk
X
Adverse events
Concomitant medication
D o uble -blind tre a tm e nt phas e a
Day 2 until and including Day 78
e
once weekly while at home
up to 3 occasion when at home
continuous
continuous


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EW= early withdrawal
(a) Visits should be conducted ± 3 days of the scheduled day (based on Visit 2, not based on previous visit).
(b) If a subject discontinues treatment before the end of the double-blind treatment phase, early withdrawal (EW) 
visit should be completed. 
(c) WOCBP only, serum pregnancy test at screening; urine pregnancy test at the other visits.  
(d) At home: In fasting condition. At clinic visit days: Use blisters dispensed at the previous visit. In fasting 
condition after completion of predose assessments.
(e) When Visit 11 is planned up to 3 days later, continue medication until study visit. 
(f) Collected in fasted condition when possible.
(g) In fasted condition, before dosing in the clinic.
(h) At home: Between 7:00 and 10:00 pm in the evening before the study visit and immediately after awakening on 
the day of the study visit. 
(i) Before and 2 hours after dosing in the clinic.
(j) During the first screening visit and by telephone up to 4 days before Visit 2, if 2 weeks or more elapse between 
the MADRS rating at screening and Visit 2. 
(k) Using Q1.6-app on subjects' smartphone. 
(l) Breakfast, lunch or dinner after drug intake at site.
(m) Download and install Q.16 app and Aicure at screening. At screening check for Aicure if the phone is 
compatible. If the subject has an older phone, reinstall on provided phone at Visit 2.


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2.
INTRODUCTION
JNJ-67953964, previously known as Cerecor (CERC)-501 and LY2456302, is a small molecule, 
high-affinity, selective kappa opioid receptor (KOR) antagonist. JNJ-67953964 is orally bioavailable 
and suitable for once-daily (QD) administration. 
KORs and their native ligand dynorphin are localized in areas of the brain that effect reward and 
stress and may play a key role in mood, stress, and addictive disorders. Chronic stress, substance 
abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and 
subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to 
negative affective states. The behavioral pharmacology of KOR antagonism has been tested in animal 
models of anhedonia, depression, and anxiety and found to have meaningful effects that may 
translate to therapeutic benefit in humans. KOR antagonists may be effective for the treatment of 
patients with mood disorders, perhaps by modulating the negative affective state associated with 
stress response.
Only about 50% of patients with major depressive disorder (MDD) show a meaningful response 
(>50% improvement to a first line antidepressant treatment), leaving many patients with 
substantial persistent impairment. Therapeutic strategies such as switching antidepressants and 
using adjuvant drug treatments can improve response, however almost 40% of patients remain 
symptomatic and fail to achieve full remission. Recently, Alkermes (ALKS) 5461, a combination 
of buprenorphine, which is a partial -opioid receptor agonist and KOR antagonist, and 
samidorphan, a potent -opioid receptor antagonist, has been tested in Phase 2 trials in subjects 
with MDD who have had only a partial response to treatment with a selective serotonin reuptake 
inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Adjunctive treatment 
with ALKS 5461 was associated with greater symptom reduction compared to placebo, 
suggesting that a KOR antagonist could provide a meaningful clinical benefit for patients being 
treated for MDD. 
For the most comprehensive nonclinical and clinical information regarding JNJ-67953964, refer 
to the latest version of the Investigator's Brochure (IB) for JNJ-67953964 (Janssen R&D 2018).
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
Based on nonclinical data, the compound is expected to show stress-reduction activity and 
reduction in anhedonia and, therefore, may also be expected to be potentially effective in the 
treatment of MDD. The current study will be conducted to assess the efficacy, safety, 
tolerability, pharmacokinetics
(PK), and pharmacodynamics
(PD)
of treatment with 
JNJ-67953964 adjunctive treatment in subjects with MDD who have an inadequate response to 
an SSRI or SNRI.


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2.2.
Background
2.2.1.
Nonclinical Studies
In nonclinical safety pharmacology studies with JNJ-67953964, there were no effects on the 
central or peripheral nervous systems or respiratory function in rats given doses up to 800 mg/kg.
In dog, cardiovascular safety study of single doses up to 1,000 mg/kg, there were no statistically 
significant changes in blood pressure, heart rate, or QT and corrected QT (QTc) by Fridericia’s
method (QTcF) intervals. However, there was an apparent trend for increased QT and QTc 
intervals following 1,000 mg/kg compared to vehicle, which was not statistically significant.
Toxicology
The toxicity profile of JNJ-67953964 has been characterized in rat, mouse, dog, rabbit, and 
monkey through a package of in vitro, safety pharmacology, repeat-dose toxicity (up to 2 weeks 
in mice, 6 months in rats and dogs, and 1 week in monkeys), reproductive toxicity, genotoxicity, 
and other toxicity studies. No adverse effects were observed in dogs at a high dose of 
2,000 mg/kg/day.
In the 6-month repeated dose toxicity study in rats, doses were given at 30, 150 and 500 mg/kg. 
Gastric lesions (non-inflammatory gastropathy that is mainly characterized by apoptosis of the 
parietal cells [acid producing cells]) were mainly present from 150 mg/kg onwards. Since 1 male 
in the low dose also showed gastric lesions, a NOAEL dose could not be established in this 
6-month repeated dose study. These lesions are regarded as compound related and were also 
present in mice. The effects are reversible. Mechanistic studies are initiated to find the 
mechanism behind these lesions and to look for the relevance to men. In addition, a GLP 
3-month repeated dose toxicity study in rats is planned with lower doses in order to set a 
NOAEL.
Dose levels of 2,000 mg/kg/day in mice, ≥800 mg/kg/day in rats, or ≥200 mg/kg/day in rabbits 
exceeded the maximum tolerated dose (MTD) resulting in adverse clinical signs, decreased food 
consumption and body weight, and mortality/euthanasia. Convulsions were also noted after 1 or 
2 doses of JNJ-67953964 at 2,000 mg/kg (mice), 1,500 mg/kg (rats), or 1,000 mg/kg (rabbits). 
JNJ-67953964 was not genotoxic in a standard battery of genotoxicity tests.
In the 6-month studies, the dose level of 30 mg/kg/day in rats and 2,000 mg/kg/day in dogs, 
corresponded to animal-to-human exposure multiples (AUC24h basis) of 4-fold and 10-fold in 
male and female rats, respectively, and >800-fold in dogs, based on a 10-mg clinical dose.
These nonclinical toxicology results demonstrate an acceptable safety profile for the proposed 
clinical study of JNJ-67953964.
Pharmacokinetics and Metabolism in Animals
Single-dose PK of JNJ-67953964 was determined in rats and dogs. Intravenous clearance and 
oral bioavailability were 89.3 mL/min/kg and 25%, respectively, in rats, and 20.3 mL/min/kg and 
88%, respectively, in dogs.


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Rats were given daily oral doses of 30, 150, or 500 mg/kg of JNJ-67953964 for 6 months. In rats, 
AUC0-24hr increased with dose and trended higher (up to approximately 3-fold at 30 and 
150 mg/kg) in females than in males. Exposure (AUC from 0 to time t [AUC0-t]) in rabbits was 
greater than proportional to dose and increased approximately 2-fold at the mid- and high-dose 
levels following multiple dosing compared with a single dose. In dogs, AUC0-24hr was less than 
proportional to dose and increased approximately 3-fold after multiple dosing for 3 months (no 
further increase was noted from 3 to 6 months of dosing). In monkeys, the mean AUC0-24hr
increased with dose from 100 to 600 mg/kg following a single dose and 300 to 1,000 mg/kg 
following 5 doses.
Metabolites were characterized in rat, guinea pig, dog, and monkey hepatocytes in addition to 
human. The major metabolites of JNJ-67953964 in hepatocytes were carboxamide hydrolysis, 
sequential N-deamination and oxidation to LSN2559342, and sequential oxidations of the 
parent. These major metabolites were also observed as circulating metabolites in rat and dog 
from toxicokinetic studies and in monkey from high dose exposure studies.
2.2.2.
Clinical Studies
Three phase-1 clinical pharmacology studies, I2Z-MC-LAFA (referred as “LAFA”), I2Z-MC-
LAFB (referred as “LAFB”), and I2Z-MC-LAFC (referred as “LAFC”), have been completed. 
Four studies to investigate the efficacy of JNJ-67953964 have been executed or are in progress:

In a recent completed clinical study (Referred as Study D), 70 subjects (40 healthy 
volunteers, 23 subjects diagnosed with cocaine dependence in early abstinence and 7 drug-
free former cocaine-dependent subjects) have been dosed for 4 days with 10 mg 
JNJ-67953964 (Reed 2018).  

A study in subjects who were cigarette smokers not seeking treatment for tobacco use 
disorder (study C501-201, referred as Study E) in 71 subjects has been completed. Subjects 
received 15 mg JNJ-67953964 and placebo over 7 days each in a cross-over design. 

A study on Smoking Cessation (C501-202, referred as Study F) has been stopped for 
business reasons. This is a double-blind, placebo-controlled, two-period, crossover design 
study examining 10 mg/day JNJ-67953964 compared to placebo in subjects who are cigarette 
smokers currently not seeking treatment for tobacco use disorder and who currently smoke at 
least 10 cigarettes per day. Subjects received 10 mg JNJ 67953964 and placebo over 7 days 
each in a cross-over design. 13 subjects completed the study. Data are pending.

A phase 2a study in 88 subjects with mood and anxiety disorders and anhedonia who are 
treated with 10 mg JNJ-67953964 or placebo over 8 weeks has been recently completed
(Referred as Study G). Data analysis is in progress. However, safety listings have been made 
available.


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Pharmacokinetics, Product Metabolism, and Pharmacodynamics
After single-dose administration of JNJ-67953964 in Study LAFA, PK analysis revealed rapid 
absorption with peak plasma concentrations typically occurring at 1.5 to 2 hours postdose, 
followed by a bi-exponential disposition. Overall, dose-proportional increases in exposure were 
observed with increasing dose.
After multiple-dose administration of JNJ-67953964 in Study LAFB, exposure of JNJ-67953964 
increased with increasing multiple doses of JNJ-67953964 and reached steady-state within 7 to 
8 days of once-daily (QD) dosing.
The accumulation ratios for Cmax and AUC were around 1.5 and 2, respectively, indicating that 
some moderate accumulation would be expected on multiple dosing. The mean Cmax (and 
coefficient of variation percentage [CV%] after 10 mg QD (the maximum dose assessed in this 
LAFB-study) was 34.4 ng/mL (37%). This is well below the maximum desired mean exposure 
(MDE) of 180 ng/mL, which is 30-fold below the NOAEL for convulsive or potentially 
pre-convulsive activity from the rabbit pilot embryo/fetal (EF) development study.
No appreciable interactions between steady state JNJ-67953964 plasma levels and single dose 
ethanol were detected.
Using the KOR tracer [11C]-JNJ-67953964 and positron emission tomography (PET), data from 
Study LAFC showed that single oral doses of 0.5 mg up to 25 mg JNJ-67953964 penetrated the 
blood-brain barrier, led to specific target engagement, and blocked, significantly and in a dose-
related manner, KORs in the brain.
Approximately 2.5 hours postdose (“peak scan”), brain KORs were almost saturated at a single 
dose of 10 mg or more. Sustained and substantial target engagement was observed for at least 
22.5 hours.
Safety and Tolerability
JNJ-67953964 was well tolerated after single-dose administration up to 60 mg in Study LAFA, 
multiple-dose administration up to 35 mg in Study LAFB, and single-dose administration up to 
25 mg in Study LAFC. There were no deaths or serious adverse events (SAEs) reported in any 
study. One subject in Study LAFA was discontinued due to a mild treatment-related adverse 
event (AE) of 5-beat ventricular tachycardia; no subjects were discontinued due to AEs in Study 
LAFB and Study LAFC.
In Study LAFA, 126 AEs were reported by 20 of 32 subjects; 18 AEs were considered by the 
investigator to be related to JNJ-67953964, with the most common (occurring >1 incidence) in 
JNJ-67953964-treated subjects being headache (5 events), diarrhea (3 events), nausea (2 events), 
and anxiety (2 events). 
In Study LAFB, 52 AEs were reported by 19 of 37 subjects; 22 AEs were considered by the 
investigator to be related to JNJ-67953964, with the most common (occurring >1 incidence) in 


JNJ-67953964
Clinical Protocol 67953964MDD2001, Amendment INT-3
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Approved, Date: 28 August 2019
JNJ-67953964-treated subjects being dyspepsia (5 events), pruritus generalized (3 events), 
headache (2 events), diarrhea (2 events), and abdominal pain (2 events).
In Study LAFC, 21 AEs were reported by 11 of 13 subjects; none of the AEs was considered by 
the investigator to be related to JNJ-67953964. Most AEs in these 3 Phase 1 studies were of mild 
to moderate severity.
In the 3 Phase 1 studies, there were no overall trends in mean clinical laboratory data. Six
subjects experienced transient increases in liver function enzymes: 

Study LAFA: 1 subject experienced ALT and AST >2 X ULN after a single dose of 4 mg, 
not considered to be related to study drug. Both AST and ALT returned to normal values 
within 4 days.

Study LAFB: 5 subjects experienced increases in AST and/or ALT: 2 on placebo and 3 on 
10 mg JNJ-67953964. All subjects had normal values at the end of the 14-day treatment 
period with study drug, which had been administered in combination with alcohol. All
elevations were reported 2 weeks after the last dose of study drug and returned to normal 
within up to 17 days. Most of the elevations of AST and/or ALT remained below 2 x ULN. 
Only one subject treated with JNJ-67953964 experienced ALT 6.8 x ULN and one subject 
treated with placebo experienced AST 3.2 x ULN.
No clinically significant changes were observed in, prolactin, and luteinizing hormone. There 
were no clinically significant changes in vital signs and electrocardiograms (ECGs), including no 
evidence of QTc prolongation. In Study LAFB, cortisol ratios (concentrations normalized to 
predose) declined less on Day 1 in subjects who received 10 mg or 35 mg doses, 2 to 8 hours 
after dose compared to placebo controls (n=2 for 10 mg, n=6 for 35 mg).  This was not seen on 
Day 14.  There was no effect on adrenocorticotropic hormone (ACTH). 
In Study D, the compound was well tolerated. The most common AEs were transient mild 
pruritus, ‘modestly positive’ mood changes, somnolence and abdominal discomfort. 
A total of 71 subjects were randomized in study E, of which 62 (87%) received at least one dose 
of 15 mg JNJ-67953964 and 67 (94%) received at least one dose of placebo. JNJ-67953964 was 
generally well tolerated with AEs that were mostly considered mild in severity. There were no 
discontinuations due to AEs, and there were no SAEs. Fifteen (21%) subjects discontinued the 
study, 13 subjects (18%) discontinued in Period 1 and 2 subjects (3%) discontinued in Period 2 
of the study. Two subjects on placebo discontinued due to AE.
In study G, the AE’s that showed an incidence greater than 5% and were at least double that 
observed in the placebo group were pruritus, anxiety, rash, constipation, tinnitus, blurred vision, 
abnormal coordination, disturbance in attention, postural dizziness, non-cardiac chest pain and 
dysuria.
No SAEs have been reported from any of the clinical studies.


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Clinical Protocol 67953964MDD2001, Amendment INT-3
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Based on safety data from the 3 Phase 1 clinical studies and the studies D to G, no potential risks 
related to JNJ-67953964 administration have been identified. Only a limited number of AEs 
observed in the single-dose and multi-dose PK studies, Study LAFA and Study LAFB, were 
considered by the investigator to be related to JNJ-67953964. Additionally, there were no 
clinically significant changes in vital signs or ECGs in the studies.
An update of safety data from ongoing studies will be presented in the IB or addenda to the IB.
2.3.
Benefit/Risk Assessmenta
To date, 3 Phase 1 clinical studies have been completed and 4 efficacy studies have been 
completed or are ongoing (See Section 2.2.2).
In total, 73 healthy subjects have been exposed to single or multiple doses of JNJ-67953964 in 
the 3 completed (LAFA, LAFB, and LAFC) clinical pharmacology studies. No significant safety 
concerns were encountered in Study LAFA after single-dose administration of JNJ-67953964 up 
to 60 mg, in Study LAFB after multiple-dose administration of JNJ-67953964 up to 35 mg, and 
in Study LAFC after single-dose administration of JNJ-67953964 up to 25 mg.
In Study G, recruitment of study subjects has been completed. In total 45 subjects have been 
dosed with 10 mg JNJ-67953964 over 8 weeks. No SAEs have been reported in this study up to 
now.
The primary objective of this study is to investigate the efficacy of JNJ-67953964 as an 
adjunctive therapy in subjects with MDD. Subjects will receive double-blind treatment for a 
period of 11 weeks during which active study medication (JNJ-67953964) or placebo will be 
administered for 6 weeks. During the other days during the double-blind treatment period, 
subject will receive placebo. Subjects may not benefit from the study in terms of long term 
improvement of their symptoms. However, subjects with poor response to their current treatment
may benefit from the extensive medical review and disease follow-up during the study. 
Additionally, the safety and tolerability data so far accumulated for JNJ-67953964 in both 
healthy subjects and subjects with MDD were generally acceptable based on a thorough review 
of the safety information from completed and ongoing clinical studies. No death or SAEs have 
been reported after subjects received JNJ-67953964. The most commonly reported treatment-
emergent adverse events (TEAEs) in JNJ-67953964-treated subjects were dyspepsia, pruritus 
generalized, headache, diarrhea, and abdominal pain. 
The antidepressant effect of JNJ-67953964 has not been established yet, however in a proof-of-
mechanism study, ALKS 5461, a combination of buprenorphine, which is a partial -opioid 
receptor agonist and KOR antagonist, and samidorphan, a potent -opioid receptor antagonist, 
showed a signal of efficacy in MDD subject when given as adjunctive therapy.
                                                
a This section has been amended by amendment INT-2.


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To ensure safe use of the study drug, besides routine safety monitoring and subject management,
this protocol also includes specific risk mitigation strategies such as paying special attention to 
clinically significant AEs that are known to have been reported in this drug (e.g., assessment of
the status of stomach mucosa); and reducing suicidality risk inherent in the underlying 
depression by excluding high risk subjects (Section 5.3, Exclusion Criteria) and performing the 
Colombia suicide severity rating scale (C-SSRS) at every site visit (Section 8.4.5, Safety 
Evaluations/C-SSRS).
The risk/benefit of JNJ-67953964 is positive and the currently available safety and efficacy data 
support the proposed clinical trial 67953964MDD2001 to investigate efficacy of JNJ-67953964
after 42 days of QD dosing in subjects suffering from MDD.
More detailed information about the known and expected benefits and risks of JNJ-67953964
may be found in the IB for JNJ-67953964 (Janssen R&D 2019).
3.
OBJECTIVES 
OBJECTIVES
Primary Objective
The primary objective of this study is to evaluate the efficacy of JNJ-67953964 compared to 
placebo when administered as adjunctive treatment in subjects with MDD partially responsive to 
SSRI/SNRI treatment in terms of reduction of symptoms of depression, as assessed by the 
change from baseline on the Montgomery Asberg Depression Rating Scale (MADRS) in non-
responders during the placebo lead-in period.
Secondary Objectives
The secondary objectives of this study are:

To evaluate the efficacy of JNJ-67953964 compared to placebo when administered as 
adjunctive treatment in subjects with MDD partially responsive to SSRI/SNRI treatment in 
terms of reduction of symptoms of depression, as assessed by the change from baseline on 
the Montgomery Asberg Depression Rating Scale (MADRS) in both responders and non-
responders during the placebo lead-in period.

To investigate the overall safety and tolerability of treatment with adjunctive JNJ-67953964
in subjects with MDD when used in combination with a SSRI or SNRI.

To investigate the effect of JNJ-67953964 versus placebo on depression related anhedonia 
as assessed by the Snaith-Hamilton Pleasure Scale (SHAPS).

To investigate the effect of JNJ-67953964 on symptoms of depression using the Clinical 
Global Impression-Severity (CGI-S), the patient reported Symptoms of Major Depressive 
Disorder Scale (SMDDS) and the self-assessment of treatment experience (SATE). 

To investigate the effect of JNJ-67953964 on symptoms of anxiety using the Hamilton 
Anxiety Scale (HAM-A) and on core symptoms of anxiety using the HAM-A6 subscale.


JNJ-67953964
Clinical Protocol 67953964MDD2001, Amendment INT-3
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
To assess the plasma PK of JNJ-67953964 in subjects with MDD and explore its 
relationship with efficacy and safety parameters.
Exploratory Objectives

To explore the effect of JNJ-67953964 on aspects of cognitive and executive function using 
the Cognitive and Physical Functioning Questionnaire (CPFQ).

To explore mood-related biomarkers (including but not limited to growth factors, 
hypothalamic–pituitary–adrenal [HPA] axis markers, immune system activation, metabolic 
markers) and genetic/epigenetic variation that may be related to clinical response, 
nonresponse, or safety and tolerability parameters of JNJ-67953964.
Hypothesis
The primary hypothesis is that 6-weeks of adjunctive treatment with JNJ-67953964 is superior to 
placebo in improving symptoms of depression, as measured by the change from baseline in the 
MADRS, in subjects with MDD.
4.
STUDY DESIGN
4.1.
Overall Designa
This will be a multi-center, placebo-controlled, randomized, double-blind study in subjects with 
MDD who have had inadequate response to SSRI/SNRI treatment. Approximately 142 subjects 
will be included in the study.
For each subject, the study will consist of two phases: a screening phase of up to 5 weeks and a 
double-blind treatment phase lasting 11 weeks.
Subjects with MDD who have had treatment initiated with an SSRI/SNRI allowed by the 
protocol and have had an inadequate or only partial response to this treatment will be screened at 
the investigational site. Assessments by qualified site personnel including the Mini International 
Neuropsychiatric Interview (MINI), Antidepressant Treatment History Questionnaire (ATRQ), 
and MADRS will be audio recorded at screening for review of eligibility of the subject for 
enrollment into the study by an independent central reviewer contracted by the sponsor. The 
following key inclusion criteria/assessments will be reviewed by a central independent reviewer: 
the clinical history of MDD, SSRI/SNRI treatment of adequate dose and duration for the current 
episode of depression, and current symptom severity on the MADRS. In case of discrepancy of 
central reviewer and local rater, the central reviewer will discuss the discrepancy with the local 
rater. If the discrepancy persists, the local rater will overrule central review.
If 2 weeks or more elapse between the MADRS rating at screening and Visit 2, the local rater 
will complete the MADRS again by a telephone interview up to 4 days before Visit 2 to 
determine whether the subject still meets the thresholds for inclusion. 
                                                
a This section has been amended by amendment INT-1 and INT-2


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Subjects who meet the inclusion and exclusion criteria and are enrolled will be maintained on the 
SSRI/SNRI without change throughout the study to determine whether adjunctive treatment with 
JNJ-67953964 can reduce symptoms of MDD.
The treatment phase of the trial will consist of 3 periods. A placebo lead-in period of concealed 
duration, after which subjects will enter the double-blind treatment period when they will be 
randomly assigned to 10 mg JNJ-67953964 or continue placebo for 6 weeks. Subjects who 
complete the treatment period, will then enter the withdrawal period and be treated with placebo 
for the remaining time of the treatment phase of the study. The total study duration for each 
subject will be approximately 16 weeks. There will be 11 scheduled visits to the clinical research 
center including screening during the study. An overall flow diagram of the study is shown in 
Figure 2:
Figure 2:
Flow diagram of the study
Eligibility Screening Examination
After giving written informed consent, subjects will be screened within 35 to 2 days prior to 
Day 1 to ascertain their eligibility for the study per the inclusion and exclusion criteria. Upon 
completion of all informed consent form (ICF) procedures, recording of AEs and concomitant 
medication will start.
The symptoms of depression will be assessed using the (structured interview guide for the) 
MADRS.
Double-blind Treatment Phase
The duration of the double-blind treatment phase will be 11 weeks divided into 3 periods.
Subjects will visit the study center for baseline visits on Day 1. The subject will receive study 
medication after completion of the visit on Day 1. The first dose will be taken at home on Day 2.


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Medication will be dispensed at each study visit during this double-blind period. All study 
medication will be taken in fasting condition. 
During the double-blind study phase, the subjects will visit the study center for out-patient visits 
every 1-2 weeks as indicated in the TES.
Lead-in period
Subjects who successfully complete the baseline examination visit at the clinical site/unit, will be 
treated with placebo for the entire duration of the lead-in period. Investigators and subjects will 
be blinded to the exact duration of lead-in period for each subject in the study.
Treatment period
At the end of the lead-in period both placebo lead-in responders and placebo lead-in 
non-responders will be randomized to receive either placebo or 10 mg JNJ-67953964 in a 1:1 
ratio for 6 weeks. Investigators and subjects will remain blinded to exact timing of the 
randomization, response criterion and study drug treatment assignment for each subject.
Withdrawal period
Subjects who complete the double-blind treatment period prior to the end of Week 11 will enter 
the withdrawal period where they will be treated with placebo for the remaining time of the 
treatment phase of the study. Investigators and subjects will be blinded to the exact duration of 
withdrawal period for each subject in the study.
Early withdrawal visit
Subject who prematurely withdraw from the study are encouraged to complete Visit 11. The 
procedures to be completed during this visit are listed in the TES.
4.2.
Scientific Rationale for Study Design
Design aspects, blinding and control
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. 
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints, both efficacy and AEs, that may occur in the absence of active treatment. A placebo 
lead-in period will be used to enrich the population in the treatment phase and minimize the
impact of the expectation bias on the part of subjects and investigators on treatment effect. For 
the same reason, the investigators and subjects will be blinded for the definition of 
responder/non-responder during the lead-in period. 


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The primary analysis includes only those subjects who do not have a significant decline during 
the placebo run-in period (‘non-responders to placebo treatment’) to increase the sensitivity to a 
signal of efficacy of JNJ-67953964.
Placebo lead-in responders will also be randomized to active or placebo during the treatment 
period to expose more subjects to JNJ-67953964 and to obtain the estimate of its effect and 
safety in a more general population.
Withdrawal placebo period will be used to aid the blinding of the lead-in period duration and 
exact beginning and ending of the treatment period and will allow exploration of duration of 
effect and for indication of symptoms of withdrawal from treatment with JNJ-67953964 
including re-emergence of symptoms.
Blinding of the lead-in and withdrawal period duration, exact point of randomization and 
treatment assignment will be used to reduce potential expectation bias from subjects and 
investigators during evaluation of clinical endpoints as well as AEs.
The double-blind treatment duration is 6 weeks. This is considered an acceptable duration of 
treatment in a study with antidepressant medication and is supported by available preclinical data 
(US FDA 1977).
As there will be a placebo withdrawal period after the active treatment period, there will be no 
separate follow-up period in this study.
Study population
The target population for this study is male or female subjects with MDD who are at least 
18 years old but less than 65 years old and have an inadequate response to SSRI/SNRI treatment.
As ascertainment of the degree of symptom improvement will rely on clinical history, failure to 
show an adequate response will be defined as subjects with MDD who have been treated for a 
current episode with an adequate dose of SSRI/SNRI treatment for at least 6 weeks and manifest 
depressive symptom severity as measured by the total score MADRS ≥25. Both men and women 
will be recruited to participate in the study. Inclusion of women of childbearing potential 
(WOCBP) is enabled by the Segment II reproductive toxicology studies. WOCBP will use a 
highly effective birth control method as outlined in the in/exclusion criteria below. 
Placebo as the control
All subjects will receive placebo in the lead-in period and withdrawal period in addition to 
ongoing treatment with an SSRI/SNRI. Subjects will be randomly assigned to receive placebo or 
JNJ-67953964 for 6 consecutive weeks during the double-blind treatment phase. Subjects 
randomized to receive placebo will receive no other active medication for 11 weeks during the 
study apart from the ongoing SSRI/SNRI. The placebo group controls for any further 
improvement on the existing SSRI/SNRI.
In this study, subjects with at least moderate depression (MADRS total score ≥25) will be 
included. Depression is a serious mental condition with significant morbidity and mortality. 


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Therefore, withholding other adjunctive active treatment than the study medication could result 
in increased symptoms of depression with the subject. 
For this reason, stopping criteria have been established in this study (see Section 7.3) which will 
ensure subjects who experience any harmful worsening of their symptoms are withdrawn from
the study to permit transfer onto alternative active adjunctive treatment and referral to a 
psychiatrist when required (see Section 6.6). Subjects will be seen weekly or every 2 weeks so 
any deterioration will be detected quickly. The weekly self-assessment of treatment experience 
questions will be linked to an alert system in case of deterioration of the depressive symptoms.
Biomarkers of depression
As part of a more extensive investigational project to identify MDD related biomarkers, different 
biomarkers in blood will be measured in this study to explore a relation to the seriousness of 
depressive symptoms or exposure to JNJ-67953964. 
Clinical depression has long been associated with abnormalities of the HPA axis and increased 
ACTH and cortisol levels. In Study LAFB, cortisol ratios (concentrations normalized to predose) 
declined less on Day 1 in subjects who received 10 mg or 35 mg doses, 2 to 8 hours after dose 
compared to placebo controls (n=2 for 10 mg, n=6 for 35 mg).  This was not seen on Day 14, and 
no increase in ACTH was observed on either day.  In a 4-day open-label study with 
JNJ-67953964 in cocaine users, (Reed 2018), modest increases in plasma ACTH and serum 
cortisol levels have been noticed. The effect on ACTH and cortisol after 6-week treatment with 
JNJ-67953964 will be investigated in this study.
Negative emotions and stress stimulate the release of interleukin (IL)-6, mainly in the morning 
hours. At the same time, IL-6 has significant neuroendocrine effects including being a strong 
activator of the HPA axis (Alesci 2005). Alesci noticed that that the increased morning IL-6 may 
be a more consistent marker of chronic stress than cortisol. For this reason, both morning IL-6 
and cortisol levels will be measured in this study. 
Disruption of the kynurenine pathway also is linked to major depression (DeWitt 2018, Umehara 
2017, Sorgdrager 2017) and this pathway is triggered by the presence of inflammatory cytokines. 
Cytokines stimulate tryptophan to enter the kynurenine pathway (thus depleting levels of 
monoamines) where kynurenic acid and quinolinic acid are synthesized in astrocytes and 
microglia respectively, leading to the disruption of glutamatergic function. Understanding the 
role of kynurenine pathway dysregulation by monitoring concentrations of pathway metabolites 
may provide additional information related to stress and MDD.
Clinical assessments
Depression
Montgomery–Åsberg Depression Rating Scale (MADRS)
The 10-item clinician-administered MADRS was designed to be used in subjects with MDD
to measure the overall severity of depressive symptoms (Montgomery 1979). The MADRS
scale has been selected as the primary efficacy measure for this study because it is validated,


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reliable, and acceptable to regulatory health authorities as a primary scale to determine efficacy
in major depression. The MADRS be administered using the Structured Interview Guide for the 
MADRS (SIGMA).
The primary efficacy endpoint is the change in the MADRS total score from baseline
(Day 1) to the end of the 6-week double-blind treatment phase.
Clinical Global Impression – Severity (CGI-S)
The CGI-S is included to rate the severity of the subject’s illness at the time of assessment,
relative to the clinician’s past experience with subjects who have the same diagnosis and
improvement with treatment (Guy 1976).
Symptoms of Major Depressive Disorder Scale (SMDDS) 
Apart from assessment of the severity of depression by the investigator, also the subjective rating 
of the patient self could contribute to the correct interpretation of the clinical efficacy of 
JNJ-67953964. The SMDDS (McCarrier 2016) is a 16-item patient reported outcome (PRO)
measure intended for use as an endpoint in MDD clinical trials to support medical product 
labeling. The SMDDS uses a 7-day recall period and verbal rating scales.
Self-assessment of treatment experience (SATE)
A one or two-question SATE will be administered weekly when the subject is at home to follow-
up on improvement or deterioration of depressive symptoms of the subjects over a short period 
of time.
Anhedonia
Snaith-Hamilton Pleasure Scale (SHAPS) 
Anhedonia is one of the core symptoms of depression. At least mild symptoms of anhedonia are 
present in about 90% of patients suffering from MDD (Snaith 1995). Kappa receptor agonists 
produce dysphoria and anhedonia (see Knoll 2010 for overview). Therefore, it may be expected 
that a kappa antagonist may have a positive effect on these key characteristics of depression. To 
assess a potential effect on anhedonia, the SHAPS (Snaith 1995) will be completed by the 
subject at the timepoints specified in the TES. The SHAPS is a validated scale for the 
measurement of anhedonia. The SHAPS is a subject completed scale in which subjects score 
whether or not they experience pleasure in performing a list of activities or experiences.
Anxiety
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A)
This original HAM-A scale assesses the severity of different anxiety-related symptoms 
(Hamilton 1959; Hamilton 1969) with a score range of 0 to 52. It is the most widely used 
symptom severity measure for anxiety. Each of the 14 items is rated by the clinician on a 5-point 
scale ranging from 0 (not present) to 4 (maximum degree). The HAM-A has an inter-rater 
reliability correlation of r = .74 (Maier 1988) and the internal consistency of the measure is 


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reported to be high with a coefficient alpha of .86 (Clark and Donovan, 1994). The symptoms 
can be grouped into two clusters: psychic anxiety and somatic anxiety.
As the original HAM-A lacks instructions for administration and clear anchor points for the 
assignment of severity ratings, the structured interview guide version will be used in the current 
study (Shear 2001).  The SIGH-A has been shown to have high inter-rater and test-retest 
reliability and produced similar but consistently higher (+ 4.2) scores compared to the original 
HAM-A. Correlation with a self-report measure of overall anxiety has also been shown to be 
high (Shear 2001). Subscales, such as the HAM-A6 which focuses on psychic anxiety and may 
be more sensitive to certain treatments, can be derived from the SIGH-A.
HAM-A6
The HAM-A6 is a 6-item subscale derived from the original (HAM-A scale) (Hamilton 1959; 
Hamilton 1969). Because the HAM-A, is a multi-dimensional scale, Bech derived a 6-item 
subscale, the HAM-A6, comprising five psychic anxiety symptoms: anxious mood, psychic 
tension, fears, intellectual disturbances, and anxious behavior observed at the interview, as well 
as one somatic item, muscular tension (Bech 2007), with a score range of 0 to 24. In an analysis 
of four pooled dose-response trials in generalized anxiety disorder (GAD), a Mokken analysis of 
the HAM-A6 yielded Loevinger coefficients above 0.40 individually and combined, indicating 
that unlike the full HAM-A, the HAM-A6 subscale is uni-dimensional. Given a fundamental 
requirement for a drug to be considered to have an anxiolytic effect is that it has shown efficacy 
in terms of symptom reduction in the core symptoms of anxiety, and as these symptoms are 
captured by HAM-A6 (which is more in accordance with the Diagnostic and Statistical Manual 
of Mental Disorders 4th edition (DSM-IV) criteria for GAD than the full HAM-A), the total 
HAM-A6 score is considered a sufficient statistic. 
Effects on Cognition
The Cognitive and Physical Functioning Questionnaire (CPFQ)
The CPFQ (Fava 2009) is a brief self-report scale that provides additional information regarding 
the impact of adjunctive treatment on aspects of cognitive and executive function including 
attention, memory and mental acuity. Subjects with MDD are often reported to have difficulties 
with functioning in this area.
DNA Collection
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in drug distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to a drug. The goal of the pharmacogenomic component is to collect deoxyribonucleic 
acid (DNA) to allow the identification of genetic and/or epigenetic factors that may influence 
PK, PD, safety and/or tolerability of JNJ-67953964, and to identify genetic and epigenetic 
factors associated with neuropsychiatric/neurodegenerative disorders. Genes and epigenetic 


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changes in genes known to be in pathways relevant to depression (HPA axis, inflammation, 
growth factors, monoamine transporters, ion channels, circadian rhythm) also will be evaluated.
DNA samples may be used to help address emerging issues and to enable the development of
safer, more effective and ultimately individualized therapies in the future. Pharmacogenomic
data obtained from this study may also be included in an ongoing cross-study analysis to
investigate the relationship between depression severity and phenotypes and biomarkers.
Safety assessments
Standard safety assessments including physical and neurological examination, vital signs, 
12-lead ECG, clinical chemistry, hematology, and urinalysis will be performed. Based on 
observations of gastrointestinal (GI) complaints in previous studies, a panel including
pepsinogen I (PGI), pepsinogen II (PGII), gastrin-17 (G17) and helicobacter IgG antibodies (Hp 
IgG) will be added to the clinical laboratory test panel to test for stomach mucosa status (Agréus 
2012, Syrjänen 2017).
Additionally, emergence of suicidal ideation will be assessed using the C-SSRS (Posner 2007). 
The C-SSRS has been used frequently in clinical studies and is a standard measure for suicidal 
ideation assessment according to FDA guidance (US FDA 2012).  
As JNJ-67953964 is a central acting compound, central sedating effects like sleepiness may be 
present. The Karolinska Sleepiness Scale (KSS, Akerstedt 1990) is a subject-reported assessment 
used to rate sleepiness on a scale of 1 to 9, ranging from ‘extremely alert’ (1) to ‘very sleepy, 
great effort to keep awake, fighting sleep’ (9).
Sexual dysfunction is one of the most common side effects during the treatment of MDD with 
SSRI’s/SNRI’s. To investigate whether JNJ-67953964 has a further positive or negative effect 
on sexual function, the Arizona Sexual experiences scale (ASEX, McGahuey 2000), will be used 
in this study.
4.2.1.
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.
Although some of the MDD subjects in this study may benefit from the 6-week treatment period, 
subjects will not be allowed to continue the treatment after completion of the study. This is 
explained by the limited experience with long term treatment with JNJ-67953964. So, no long-
term benefit is to be expected in this study. Subjects might benefit from the clinical evaluations 
and the information collected as part of this study. The results of the investigation of 
JNJ-67953964 may help future patients.


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The primary ethical concern is the use of placebo in addition to the ongoing treatment with an 
SSRI/SNRI over the complete double-blind treatment period of 11 weeks in some of the subjects
while symptoms of at least moderate depression are present at screening and baseline visit. The 
rationale for this placebo treatment and the impact on the study population has been described in 
Section 4.2, ‘Placebo as the control’. Although placebo treatment may not harm most of the 
subject, subjects who may deteriorate during the treatment period (See Section 7.3), will be 
withdrawn from the study and will be referred to treatment according to local standards. The 
status of the depression will be assessed and documented weekly or every 2 weeks. 
Moreover, the Q1.6-app will alert the investigator when a subject has indicated that the 
depression is ‘much worse’ or very much worse’ when answering the weekly SATE. The Q1.6-
app will be installed on the subjects’ smartphone. The Q-1.6 app will ask questions to the 
subjects as programmed for this study. The same Q1.6-app will ask the subjects for their 
engagement to the study at the start and end of the study and up to 3 times during the study. For 
the investigators and sponsor, this may help to gain insight into the relationship between patient 
engagement and patient retention in the study.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of a 
Red Cross blood donation.
4.3.
Justification for Dose
Single doses between 2 and 60 mg have been given to healthy subjects in a human single 
ascending dose study (LAFA-study). Multiple doses of 2 and 35 mg once daily over 14 days 
have been investigated in the LAFB-study. Single doses of 0.5 to 25 mg were given in the 
LAFC-PET study. About 44 subjects received 10 mg JNJ-67953964 over 8 weeks (ongoing 
study), 70 subjects received 10 mg JNJ-67953964 over 4 days (Reed 2018) and 62 subjects 
received 15 mg JNJ-67953964 over 7 days (Study C501-201). In all these studies JNJ-67953964 
was well tolerated.
In the LAFC study it was demonstrated that approximately 2.5 hours post-dose, brain KOR’s 
were almost saturated at doses of 10 mg or more. At 22.5 hours after dosing the mean receptor 
occupancy was still 72%. 
Based on the pupillometry data from the multiple-dose Study LAFB and RO data from Study 
LAFC, a 10-mg dose appears to provide KOR selectivity, while at the same time near maximal 
KOR occupancy. For this reason, 10 mg has been selected as a clinical dose in this POC study. 
4.4.
End of Study Definitiona
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the 
11-weeks double blind treatment and the assessments at Visit 11 of the study. 
                                                
a The Section has been amended by Amendment INT-3.


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Participants who prematurely discontinue study medication for any reason before completion of 
the double-blind phase will not be considered to have completed the study. Any subject who 
withdraws after receiving the study drug will have an early withdrawal evaluation as described in 
Section 8.2.4.
End of Study Definition
The end of study is considered as the last visit 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 visit at that study site, in the time frame specified in the Clinical Trial Agreement.
5.
STUDY POPULATION
5.1.
General Considerations 
Approximately 142 subjects with MDD currently being treated with one SSRI/SNRI will be 
enrolled in this study.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following sections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the study responsible physician before entering the subject into 
the study. Exceptional and limited retesting of abnormal screening values that would otherwise 
lead to exclusion may be allowed after discussion and approval by the sponsor during the 
screening phase (to reassess eligibility). This should only be considered if there is no anticipated 
impact on subject safety.
Subjects will be enrolled after reading the subject information sheet and signing the ICF
indicating that they understand the purpose of and procedures required for the study and are 
willing to participate in the study and comply with the study procedures.
5.2.
Inclusion Criteriaa
Each potential subject must satisfy all the following criteria to be enrolled in the study. 
1. Subjects must be men or women, 18 to 64 years of age, inclusive. 
Note: Subjects should be at least 18 years of age or older as per the legal age of consent in 
the jurisdiction in which the study is taking place.
2. Have a Body Mass Index (BMI) between 18 and 35 kg/m2 inclusive (BMI = weight/height2). 
3. Subjects must be medically stable based on clinical laboratory tests, medical history, 
vital 
signs, and 12-lead ECG performed at screening and baseline (Visit 2) For clinical laboratory 
tests only screening results will be considered. If the results of the serum chemistry panel, 
hematology, or urinalysis are outside the normal reference ranges, retesting of an abnormal 
lab value(s) that may lead to exclusion will be allowed once during the screening phase. In 
12-lead ECG, QTcF should be ≤ 450 msec for males or ≤470 
msec 
for 
females 
and 
                                                
a This section has been amended by amendment INT-2 and INT-3.


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PR-interval < 220 msec at screening. A retest of an abnormal ECG value will be allowed 
once in the screening phase. Blood pressure will be the average of 2 measurements.
The subject 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 subject's source 
documents and initialed by the investigator.
4. Criterion modified by Amendment INT-3.
4.1. Population specific:

Subjects must have a primary Diagnostic and Statistical Manual of Mental Disorders 
5th edition (DSM-5) diagnosis of MDD. Subjects with a diagnosis of comorbid 
Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), or Panic 
Disorder may be included, if the investigator considers MDD to be the primary 
diagnosis (confirmed by an independent central rater through review of the MINI 
interview obtained by the site at screening). The current episode should be less than 
18 months.

Subjects must be currently treated with an SSRI/SNRI antidepressant approved in this 
protocol (see Section 6.5) at an adequate dose, as defined by the ATRQ, and for at least 
6 continuous weeks but not more than 12 months.

Have a MADRS total score of ≥25 at screening.  If 2 weeks or more elapse between the 
MADRS rating at screening and Visit 2, the local rater will complete the MADRS again 
by a telephone interview up to 4 days before Visit 2. At this telephone interview, 
MADRS total score should again be ≥25 and should not demonstrate a clinically 
significant change (i.e., an improvement of >20%). 

In a common population of subject suffering from MDD, about 90% have a SHAPS total 
score >20. The SHAPS total score will initially not be an inclusion criterion. However, 
after 50 subjects have been randomized, the subjects’ properties will be reviewed. If less 
than 50% of non-responding subjects have a SHAPS total score >20, then for the 
remaining subjects the following inclusion criterion will be added:

Have a SHAPS total score >20 at screening and baseline (Visit 2) 
5. Criterion modified by Amendment INT-3. 
5.1. Men who are sexually active with a woman of childbearing potential and have not had a
vasectomy must agree to use a barrier method of birth control i.e., a condom with 
spermicidal foam/gel/film/cream/suppository for the duration of the study plus 3 months 
after receiving the last dose of study drug, and all men must not donate sperm during the 
study and for 3 months after receiving the last dose of study drug. In addition, their 
female partners should also use an additional method of birth control (which may 
include a hormonal method, an intrauterine device [IUD] or an intrauterine system 
[IUS]) for at least the same duration.


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6. Criterion modified by Amendment INT-2
6.1. Criterion modified by Amendment INT-3
6.2 Before randomization, a woman must be either:

Not of childbearing potential defined as: 
o
Postmenopausal (amenorrhea for at least 12 months without an alternative medical 
cause. A serum follicle stimulating hormone (FSH) level at screening >40 IU/L in 
women not using hormonal contraception or hormonal replacement therapy may be 
used for confirmation, however in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient) or 
o
Permanently sterilized (including hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy) or
o
Otherwise be incapable of pregnancy.

Of childbearing potential and practicing a highly effective method of birth control consistent 
with local regulations regarding the use of birth control methods for subjects participating in 
clinical studies (i.e. one that results in a less than 1% per year failure rate when used 
consistently and correctly). This may include:
o
Established and ongoing use of oral hormonal methods of contraception in 
combination with barrier methods.
o
Established and ongoing use of patch, injected or implanted hormonal methods of 
contraception.
o
Placement of an IUD or IUS. 
Accepted barrier methods as indicated above include:
condom with spermicidal foam/gel/film/cream/suppository
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository.
Note that a barrier method on its own is not sufficient.
o
Male partner sterilization (the vasectomized partner should be the sole partner for that 
subject). 
o
True abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). 
Women must agree to continue using these methods of contraception throughout the 
study and for at least 3 months after receiving the last dose of study medication.
Note: If a woman of childbearing potential who is not heterosexually active becomes 
active after the start of the study, she must begin a highly effective method of birth 
control, as described above.  
7. A woman of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test before the first dose. 
8. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for at least 3 months after receiving the last dose of study 
drug.


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9. Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol.
10. Sign an ICF indicating that they understand the purpose of and procedures required for the 
study including peripheral biomarkers research (ie, blood) and are willing to participate in the 
study.
5.3.
Exclusion Criteriaa
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. The subject will be excluded if he or she:
1. Has current signs/symptoms of, liver or renal insufficiency, hypothyroidism or 
hyperthyroidism (a normal thyroid-stimulating function is required at screening; subjects 
who are on stable treatment with thyroid supplementation with normal thyroid-stimulating 
hormone [TSH] may participate but subjects with thyroid supplementation for antidepressant 
purposes are not allowed in the study*), significant cardiac disease (including current or past 
history of atrial fibrillation/flutter), vascular, pulmonary, endocrine, neurologic (including 
epilepsy), hematologic, inflammatory (e.g., rheumatoid arthritis, inflammatory bowel 
disease, Crohn’s disease) or metabolic disturbances. Diabetes mellitus (DM) may be allowed 
when the subject is stable (HbA1c less than 7.5% or 58 mmol/mol).
*Subjects with known hypothyroidism who have been on stable treatment for at least
3 months prior to screening are required to have TSH and free thyroxine (FT4) obtained. Any 
subject with an elevated TSH should also have FT4 measured. In any case where the TSH 
value is out of range, but FT4 is normal, the findings should be discussed directly with the 
medical monitor before the subject is enrolled. If the FT4 value is out of range, the subject is 
not eligible.
2. History of documented gastric disease (including documented peptic ulcer disease, gastritis, 
upper GI bleeding, esophagitis, or any GI precancerous condition), current clinically evident 
GI complaints. 
3. Chronic use of a proton pump inhibitors (PPIs). History of incidental use of PPIs is allowed 
but should have been stopped at least 4 weeks before screening. A history of chronic 
nonsteroidal anti-inflammatory drug (NSAID) or aspirin use. (Low dose aspirin e.g. in 
cardiovascular disease prevention is allowed).
4. Has a history of alcohol use disorder within the past year. 
5. Criterion modified by Amendment INT-1 
5.1.
Criterion modified by Amendment INT-2.
5.2.
Has failed (no more than 25% response on ATRQ) three or more antidepressant 
treatments including the current SSRI/SNRI during the current depressive episode 
despite an adequate dose (per ATRQ) and duration (at least 6 weeks).
6. Subject has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 3 months before the planned first dose of 
                                                
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study drug, or has participated in any interventional clinical studies on MDD in the previous 
1 year, or is currently enrolled in an interventional study.
7. Has signs or symptoms of Cushing’s Disease, Addison’s Disease, primary amenorrhea, or 
other evidence of significant medical disorders of the HPA axis.
8. Is breast feeding.
9. Subject has a history of malignancy within 5 years before screening (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 study 
responsible physician, is considered cured with minimal risk of recurrence).
10. Has one or more of the following diagnoses:

A primary DSM (5th edition) diagnosis of:
-
GAD
-
panic disorder
-
obsessive compulsive disorder (OCD)
-
posttraumatic stress disorder (PTSD)
Subjects with comorbid GAD, SAD, or panic disorder for whom MDD is considered the 
primary diagnosis are not excluded.

A current diagnosis or diagnosis in the past 1 year of:
-
psychotic disorder
-
MDD with psychosis
-
anorexia nervosa or bulimia nervosa. 
-
chronic fatigue syndrome
-
bipolar disorder (BD)
-
mental retardation
-
antisocial or borderline personality disorder
-
autism spectrum disorder.
11. Has a current or recent history of clinically significant suicidal ideation within the past 
6 months, corresponding to a score of 4 (active suicidal ideation with some intent to act, 
without specific plan) or 5 (active suicidal ideation with specific plan and intent) for ideation 
on the C-SSRS, or a history of suicidal behavior within the past 1 year, as validated by the 
C-SSRS at screening or Visit 2. Subjects with a prior suicide attempt of any sort, or prior 
serious suicidal ideation/plan > 6 months ago, should be carefully screened for current 
suicidal ideation and only included at the discretion of the investigator.
12. Ongoing psychological treatments (eg, Cognitive Behavior Therapy, Interpersonal 
Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 1 month prior to the 
screening phase. A subject who has been receiving ongoing psychological treatment for a 
period of greater than 1 month from the screening visit is eligible, if the investigator deems 
the psychological treatment to be of stable duration and frequency.
13. Criterion modified by Amendment INT-3
13.1.
Subject has a history of hepatitis B surface antigen (HBsAg) or hepatitis C 
antibody (anti-HCV) positive, or other clinically active liver disease, or tests 
positive for HBsAg or anti-HCV at Screening. If subjects have been successfully 


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treated for or have been spontaneously recovered from HCV and are RNA 
negative, they will be allowed in the study.
14. Subject has a history of human immunodeficiency virus (HIV) antibody positive, or tests 
positive for HIV at Screening. If subjects have been successfully treated for HIV and are 
ribonucleic acid (RNA) negative, they will be allowed in the study.
15. Subject has a history of substance use disorder according to DSM-5 criteria, except nicotine 
or caffeine, within 6 months before screening. Mild cases can be reviewed by investigator 
and study responsible physician on a case by case basis. Subjects who have completed a 
treatment for (alcohol) addiction more than 1 year prior to first dose administration, may be 
included if the risk of relapse is considered minimal, total duration of alcohol use disorder 
was less than a year, and no significant abnormalities are shown in clinical laboratory or 
other predose safety assessments.
16. Criterion modified by Amendment INT-3.
16.1.
Subject has positive test result(s) for alcohol or drugs of abuse (including 
barbiturates, 
methadone, 
opiates, 
cocaine, 
cannabinoids, 
amphetamine/methamphetamine, and ecstasy) at Screening or at baseline (Visit 
2).
A positive test result for benzodiazepines is not exclusionary if the subject is 
taking such drugs per protocol.
Subjects with a positive alcohol or drug screen may have the test repeated once, 
based on the investigator's discretion. This determination, and the reason for 
permitting a repeat test, must be recorded in the subject's source documents and 
initialed by the investigator. A positive, repeat alcohol or drug screen is 
exclusionary.
17. Criterion modified by Amendment INT-1
17.1.
Criterion modified by Amendment INT-2
17.2.
Subject has used:

Monoamine oxidase inhibitors (MAOIs) within 12 weeks before screening

A known inhibitor or inducer of cytochrome P450 (CYP)3A4 activity (e.g., systemic 
administration of erythromycin, clarithromycin, ketoconazole, itraconazole, rifampicin) 
within 14 days or a period less than 5-times the drug’s half-life, whichever is longer, 
before the first study drug administration on Day 1. Use of moderate and strong inhibitors 
and inducers of CYP3A4 are prohibited during the study (See Appendix 5).

St. John’s wort, ephedra, ginkgo, ginseng, or kava within 2 weeks before screening. 

Antipsychotic drugs (D2-antagonists) within 2 weeks before screening. However,
Seroquel (quetiapine) in a dose ≤100 mg is allowed when used in a stable dose for at least 
8 weeks prior to screening. Quetiapine treatment should be continued unchanged during 
the study.

Lithium or other mood stabilizers within 2 weeks before screening.

Opioids within 2 weeks before screening.

Psychostimulants such as methylphenidate or dextroamphetamine within 2 weeks before 
screening.


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
Psychotropics 
with 
antidepressant 
effects 
such 
as 
atomoxetine 
or 
thyroid 
supplementation, in addition to their SSRI or SNRI treatment within 2 weeks before 
screening.

Proton pump inhibitors within 4 weeks before screening.
18. Criterion modified by Amendment INT-2
18.1.
Subject is unable to stop the following medication from the baseline visit (Visit 2) 
and throughout the study (tapering during screening period allowed): 

Any hypnotics including but not limited to:
•
Benzodiazepines when used only as needed (PRN) are not allowed. A subject 
may continue to take a benzodiazepine treatment only if:

The subject has been taking a stable daily dose for at least 6 weeks prior to 
screening.

The dose does not exceed an equivalent of 2 mg of lorazepam per day.

Allowed benzodiazepines are lorazepam (≤2 mg/day), clonazepam 
(≤0.5 mg/day) and alprazolam (≤1 mg/day) being taken daily. Other 
benzodiazepines should be discussed before subject enrollment with the 
study responsible physician.

Treatment will be continued unchanged during the study.
•
Sedating antihistamines, including chronic use of diphenhydramine. 
•
Continuous use of zolpidem, zoplicon, eszopiclone and ramelteon. Note: 
Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon, and
eszopliclone) are allowed on an as needed (PRN) basis during the study but 
NOT within 24 hours before being in the clinic and not more than 2 nights in a 
row. 
•
S-adenosyl methionine (SAMe) 
•
Melatonin, agomelatine

NSAIDs and aspirin.
19. Is unwilling or unable to undergo multiple venipunctures because of poor tolerability or lack 
of easy access.
20. Is unable to read and understand the ICF and PRO, complete study-related procedures, and/or 
communicate with the study staff.
21. Subject has any condition for which, in the opinion of the investigator, participation would 
not be in the best interest of the subject (e.g., compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
22. Subject has had major surgery, (e.g., requiring local or general anesthesia) within 12 weeks 
before screening, or will not have fully recovered from surgery, or has surgery planned 
during the time the subject is expected to participate in the study.
23. Is a vulnerable subject (e.g., a person kept in detention).
24. Has received any prior treatment with electroconvulsive therapy, vagal nerve stimulation, or 
a deep brain stimulation device or treatment with ketamine or esketamine for MDD.


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25. Criterion modified by Amendment INT-3. 
25.1.
Has known allergies, hypersensitivity, or intolerance or any contraindication to 
any of the excipients of JNJ-67953964 or placebo (refer to IB for JNJ-67953964).
26. Has either donated 1 or more units (approximately 450 mL) of blood or acutely lost an 
equivalent amount of blood within 60 days before the first dose of study drug. 
27. Has cognitive impairment that would render the informed consent invalid or limit the ability 
of the subject to comply with the study requirements. 
28. Subject is an 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. 
If a subject's status changes (including laboratory results) after screening but before first dose of 
study drug is given such that they now meet an exclusion criterion, they should be excluded from 
participation in the study.
5.4.
Lifestyle Considerationsa
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation. 
1.
May not consume food or beverages containing, grapefruit juice, Seville oranges (including 
any orange marmalade), or quinine (e.g., tonic water) from 24 hours (72 hours in the case of 
grapefruit juice and Seville oranges) before the first dose of study medication and 
throughout the duration of the study until the final study visit. 
2.
Should not take any prohibited medication or food supplements as indicated in the section 
‘concomitant therapy’. For a list of prohibited medications, please see Section 6.5
(Concomitant Therapy).
3.
The use of limited amounts of alcohol (up to 2 standard drinks 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).
4.
Sleepiness and sedation may be induced by any central action compound. If these adverse 
effects are noticed by the subject, he/she should not drive a car or operate a machine.
5.
Strenuous exercise may affect study specified assessments and laboratory safety results; for 
this reason, strenuous exercise should be avoided within 24 hours before all planned study 
visits.
6.
May not consume food containing poppy seeds from 72 hours before the screening visit.
                                                
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5.5.
Screen Failures
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.
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 number and date of birth.
Rescreening will be permitted when the time between the first screening visit and the baseline 
visit exceeds 35 days. Individuals who do not meet the criteria for participation in this study 
(screen failure) may be rescreened once. Rescreened participants should be assigned a different
participant number as for the initial screening.
6.
STUDY TREATMENTS
6.1.
Study Treatments Administereda
JNJ-67953964 will be supplied for this study as 5-mg capsules. Placebo will be supplied as 
matching capsules. 
All subjects will take 2 capsules QD. The capsules will be taken daily from Day 2 to Day 78 (at 
home and when being in the clinic) in fasting condition with some water (fasting for at least 
4 hours before dosing; water intake is permitted during that period). Study medication will be 
taken before breakfast. If the subject has forgotten to take the study medication before breakfast, 
this should be done before the next following meal, at the latest at dinner of the same day. If the 
subject remembers later than dinner, the dose of that day should be omitted, and the subject 
should take his dose before breakfast on the next day.
When Visit 11 is planned up to 3 days later, continue medication until study Visit 11. Spare 
medication is available in each blister.
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed. After 
having taken the study medication, subjects should try not to eat or drink for at least 30 minutes. 
This period should be controlled when the subject is in the clinic. When outside the clinic, 
violation of this effort (including drug intake in fasting condition) will not be considered a 
protocol violation.
The first dose will be taken in fasting condition on Day 2 of the double-blind phase when the 
subject is at home. 
The subjects will take the study medication with them at each study visit and will take study 
medication - from the blisters dispensed at the previous study visit - at the site in fasting 
                                                
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condition after completion of predose study assessments and blood collections. Dosing will be 
witnessed by the study staff.
The dose of the study medication is:

10 mg JNJ-67953964: 2 capsules of 5 mg JNJ-67953964 

Placebo: 2 placebo capsules.
Study medication dose may be adjusted to 5 mg QD based on the results of a blinded review of 
the safety data by the study responsible physician (SRP) or by an unblinded review by the Data 
Review Committee (DRC) or a physician who is not a member of the study team (See 
Section 7.1). When a dose reduction has been decided on, this will only apply to new subjects in 
study and the dose of study medication will be:

5 mg JNJ-67953964: 1 capsule of 5 mg JNJ-67953964 

Placebo: 1 placebo capsule.
6.2.
Preparation, Handling, and Storage 
All study medication will be stored in a secure area with restricted access. Capsules must be 
stored at controlled room temperatures as indicated on the product specific labeling.
The investigator is responsible for ensuring that all study medication received at the site is 
inventoried and accounted for throughout the study. The dispensing of study medication to the 
participant, and the return of study medication from the participant, must be documented on the 
medication accountability form. Participants must be instructed to return all original blister 
strips, whether empty or containing study medication.
Study medication must be handled in strict accordance with the protocol and the blister label. 
Unused study medication, and study medication 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 medication, or used returned study medication for destruction, will be 
documented on the medication return form. When the study site is an authorized destruction unit 
and study medication supplies are destroyed on-site, this must also be documented on the 
medication return form.
Study medication should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Study medication will be 
supplied only to participants participating in the study. Returned study medication must not be 
dispensed again, even to the same participant. Study medication may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
medication from, nor store it at, any site other than the study sites agreed upon with the sponsor.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
Procedures for Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
one of two treatment groups based on the first of two computer-generated randomization 
schedules prepared before the study by, or under the supervision of the sponsor. 
The randomization will be balanced by using randomly permuted blocks stratified by lead-in 
response status and anhedonia (SHAPS total score <20 vs ≥20).
Exact timing of randomization for each subject will be blinded. The interactive web response 
system (IWRS) will assign a unique treatment code, which will dictate the treatment assignment 
and matching study drug kits for the subject. The requestor must use his or her own user 
identification and personal identification number each time when contacting the IWRS, and will 
then give the relevant subject details to uniquely identify the subject.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints.
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 subject.
Data that may potentially unblind the treatment assignment (e.g., study medication plasma 
concentrations, plasma biomarkers) 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. Also, the 
site staff should not discuss insights on unblinding of randomization with the subjects.
Under normal circumstances, the blind should not be broken until all subjects have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the treatment by contacting the IWRS. While the responsibility to break the treatment
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, time, and reason for the unblinding must be documented in the 
appropriate section of the electronic case report form (eCRF), and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner. Subjects who have had their treatment 
assignment unblinded should continue to return for required follow-up evaluations.


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In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim data review by an unblinded reviewer is 
specified (see Section 7.1), the randomization codes and, if required, the translation of
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim review.
6.4.
Study Medication Compliancea
Study medication will be taken at home by the subject. The first dose will be taken by the subject 
on Day 2 of the study at home.
Dosing will be documented by app’s using the subjects’ smartphone, or on a smartphone 
provided to the subject if they are unable to use their own. The Q1.6-app will present an 
electronic diary asking subjects to confirm dosing of study medication. When available, also a 
medication adherence monitoring platform (AiCure®-app) will be used. The Platform uses 
artificial intelligence on smartphones to visually confirm proper medication administration and 
ingestion of the study drug in real time without human intervention.  Video recordings of the 
drug intake are also recorded and stored to AiCure’s secure server for further analysis to 
reconfirm proper medication administration, to identify any usability issues or intentional non-
adherence, and to check for duplicate enrollment. In addition, built-in reminders and a 
communication system allow real-time intervention by study personnel in case of improper drug 
administration or interruptions by the subject.
When in the clinic, study medication will be self-administered on site as outlined in Section 6.1.
The administration of study medication will be witnessed by the investigator or a properly 
trained designee. The exact date and time of drug administration will be recorded in the eCRF.
The investigator or designated study personnel will maintain a log of all study drug dispensed 
and returned. Drug supplies will be inventoried and accounted for throughout the study. 
If appropriate, additional details may be provided in a pharmacy manual/study site 
investigational product manual that is provided separately and noted in Section 8.1, Study-
Specific Materials.
6.5.
Concomitant Therapyb
All prestudy therapies administered up to 30 days before screening must be recorded at screening
(and confirmed by treating physician). 
JNJ-67953964 is primarily metabolized by CYP3A. Subjects should not use medications that are 
moderate or strong CYP3A inhibitors or inducers from 14 days or at least 5-times the drug’s 
half-life (whichever is longer) prior to study drug administration until the last study visit. The 
prohibited medications include but are not limited to: CYP3A inhibitors such as systemically 
                                                
a This section has been amended by amendment INT-1
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administered erythromycin, clarithromycin, ketoconazole or itraconazole, and CYP3A inducers 
such as rifampin. Similarly, subjects should avoid consumption of grapefruit, grapefruit juice and 
Seville oranges (including orange marmalade) and herbal products containing St. John’s wort, 
ephedra, ginkgo, ginseng, or kava. Appendix 5 includes examples of concomitant drugs to be 
avoided (moderate or strong inhibitor/inducer of CYP3A4).
Subjects will be enrolled contingent on having initiated SSRI/SNRI antidepressant treatment for 
their current episode of MDD.  The following antidepressants are permitted: citalopram, 
escitalopram, sertraline, paroxetine, venlafaxine (XR), desvenlafaxine, fluoxetine, duloxetine, 
milnacipram, vilazodone, levomilnacipran and vortioxetine. Fluvoxamine is a CYP3A4 inhibitor 
and will not be allowed in this study. Subjects will only continue one of these allowed 
antidepressants at an adequate and tolerated dose (i.e. monotherapy) during the study. No 
changes in the antidepressant or dose are permitted from screening until the end of the study. 
For safety reasons, the use of hypnotic drugs or food supplements should be limited from the 
baseline visit (Visit 2) until the last study visit (may be tapered during screening period). 
However: Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon, and eszopliclone) are 
allowed on a PRN basis during the study but NOT within 24 hours before being in the clinic and
not more than 2 nights in a row.
Prohibited (from baseline and throughout the study) hypnotic drugs or food supplements include 
but are not limited to:

Benzodiazepines when used only as needed (PRN) are not allowed. A subject may 
continue to take a benzodiazepine treatment only if:
•
The subject has been taking a stable daily dose for at least 6 weeks prior to screening.
•
The dose does not exceed an equivalent of 2 mg of lorazepam per day.
•
Allowed benzodiazepines are lorazepam (≤2 mg/day), clonazepam (≤0.5 mg/day) 
and alprazolam (≤1 mg/day) being taken daily. Other benzodiazepines should be 
discussed before subject enrollment with the study responsible physician.
•
Treatment will be continued unchanged during the study.

Sedating antihistamines 

Continuous use of zolpidem, zopiclon, eszopiclone and ramelteon 

SAMe 

Melatonin, agomelatine.
Subject should also not use the following medication from screening and throughout the study:

MAOIs from 12 weeks before screening.

Opioids from 2 weeks before screening.

Psychostimulants such as methylphenidate or dextroamphetamine within 2 weeks 
before screening.


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
Psychotropics with antidepressant effects such as atomoxetine or thyroid 
supplementation, in addition to their SSRI or SNRI treatment within 2 weeks before 
screening.

Antipsychotic drugs (D2-antagonists), lithium and other mood stabilizers from 2 weeks 
before screening. However, Seroquel (quetiapine) in a dose ≤100 mg is allowed when 
used in a stable dose for at least 8 weeks prior to screening. Quetiapine treatment should
be continued unchanged during the study.

Trazodone for treatment of insomnia in a dose ≤100 mg when used for at least 8 weeks 
at a stable dose will be allowed.
If the administration of any concomitant therapy becomes necessary, it must be reported in the 
appropriate section of the CRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.6.
Intervention After the End of the Study
Investigators may re-contact the subject to obtain follow-up information regarding the subjects’
safety if there are any safety concerns at the last study visit visit.
Participants will be instructed that JNJ-67953964 will not be made available to them after they 
have completed/discontinued the study. Subjects should continue taking the SSRI/SNRI they 
were using during the study until such time as changes in their treatment are recommended by 
their treating physician. If the subject has persistent symptoms of depression at the completion of 
the study and has no access to a primary physician or psychiatrist, the investigator should ensure
appropriate medical care for the subject after completion of the study.
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study medication or withdraws from the study before the end of the
double-blind phase, the early withdrawal assessments should be obtained.
7.1.
Unblinded Data Review
Continuous or periodic blinded safety reviews will be done by the SRP. An unblinded review of 
the data will be conducted if there are safety concerns from this blinded review as a result of 
severe, serious or unexpected AEs that are at least possibly related to the study drug. This review 
will be done by a DRC. A DRC will consist of at least one medical expert in the relevant 
therapeutic area and at least one statistician; committee membership responsibilities, authorities, 
and procedures will be documented in its charter.
7.2.
Completion
A subject will be considered to have completed the study if he or she has completed the 
11-weeks of treatment and the assessments at Week 11 (Visit 11) of the study. Subjects who 


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prematurely discontinue study treatment for any reason before completion of the study will not 
be considered to have completed the study.
7.3.
Participant Discontinuation/Withdrawal from the Studya
A participant will be withdrawn from the study for any of the following reasons:

The investigator or sponsor believes (e.g. that for safety or tolerability reasons such as a 
SAE at least possibly related to the study drug) it is in the best interest of the subject to 
discontinue the study. 

Increased or intolerable symptoms of depression

At the discretion of the investigator after the subject reported a “much worse” or “very 
much worse” condition using the self-assessment of treatment experience or

≥30% increase of MADRS score (compared to Visit 2) during the double-blind 
treatment period.

The subject becomes pregnant.

A subject will be discontinued from the study if the QTcF interval is higher than 500 msec 
or is prolonged >60 msec from the baseline value. QTc interval prolongation should be 
confirmed by collecting 2 additional ECGs as soon as possible after the initial ECG. The 
average value of the QTcF interval of the three ECG’s will be used to determine whether a 
subject should be discontinued. If the QTcF is not readily available, the QTcB may be used 
instead. The subject will continue to be monitored (maximum 12 hours) by repeated 12 lead 
ECGs (at least every 60 minutes) until the ECG normalizes.

A subject who shows signals of clinically meaningful acute suicidal ideation at any time 
during the study should be withdrawn from the study and referred for appropriate 
medical/psychiatric care.

A subject will be discontinued from the study if the liver function tests exceed the values as 
presented in Section 10.7.
Also, a participant will be automatically withdrawn from the study for any of the following 
reasons:

Lost to follow-up

Withdrawal of consent. When a subject withdrawals consent, effort should be made to 
determine if the cause of withdrawal was due to tolerability or lack of efficacy.

Noncompliance to take the study medication. Noncompliance will be decided on a case-by-
case basis depending on the number of missed capsules and the interval between missed 
doses. 
Subjects who drop out, other than for safety reasons related to the study drug or study 
procedures, will be replaced if the number of subjects completing the study will be below 96. A 
maximum of 32 subjects (1/3 of targeted subjects) will be allowed to be replaced. Replacement 
                                                
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subjects will receive a new subject ID-number and will be assigned to a new randomization code 
in the IWRS.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject.
Any subject who withdraws after receiving the study drug will have an early withdrawal
evaluation as described in Section 8.2.4.
7.4.
Protocol Stopping Criteria
Blinded medical monitoring by the sponsor will occur on a continuous basis including laboratory 
and ECG data. When there is any concern about the safety of the participants as a result of severe 
or serious AEs that are at least possibly related to JNJ-67953964 or if the frequency of 
discontinuations due to TEAEs exceeds 10% of subjects, an unblinded review of the safety data 
will take place drug (see Section 7.1). The study will be stopped at any time if safety concerns 
are related to JNJ-67953964 as per the reviewers’ decision. The principal investigator may 
decide to stop study participation at any time when he/she estimates there is an acute risk for 
his/her subjects in study.
7.5.
Withdrawal from the Use of Research Samples
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Section 10.3). 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 ICF. 
7.6.
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented. Refer to Section 7.3, Participant 
Discontinuation/Withdrawal from the Study.
8.
STUDY ASSESSMENTS AND PROCEDURES
8.1.
Overviewa
The TES summarizes the frequency and timing of efficacy, PK, PD, biomarker, and safety
measurements applicable to this study.
When possible, all PRO assessments should be conducted/completed before any tests, 
procedures, or other consultations to prevent influencing participant perceptions.
                                                
a This section has been amended by amendment INT-1.


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However, during the site visits, it should be considered that the study medication has to be taken 
in fasted condition and it is preferred to have the PRO’s and other assessments done in fed 
condition. So, during the site visits 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 investigator (SIGMA, SIGH-A and C-SSRS), safety assessments. Blood 
collections for PK and PD assessments should be kept as close to the specified time as possible. 
When a subject is expected to be impacted by blood draw, the sequence may be: PRO, blood and 
urine collection (when in fasted condition), dosing, breakfast, interview with investigator 
(SIGMA, SIGH-A and C-SSRS), safety assessments.
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.
The total blood volume to be collected from each participant will be approximately 217 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
For each participant, the maximum amount of blood drawn from each participant in this study 
will not exceed 300 mL.
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-treatment assessments)
- Hematology
2
5
10
- Serum chemistry, HbA1c and gastric mucosa panel
6.5
5
32.5
Serology (HIV, hepatitis)
5
1
5
TSH/FT4
2.5
1
2.5
Serum -hCG pregnancy tests, FSH
5
1
5
Pharmacokinetic samples
6
9
54
Biomarkers serum[b]
20
3
60
Biomarker plasma
10
3
30
Genotyping/(epi)genetics
6
3
18
Approximate Total[c]
217
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Biomarker serum sample represents combined volume of more than one tube
c.   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 on the laboratory requisition 
form. If blood samples are collected via an indwelling cannula, an appropriate amount 
(depending of the length of the line during daytime or at night) of serosanguineous fluid slightly 
greater than the dead space volume of the lock will be removed from the cannula and discarded 
before each blood sample is taken. After blood sample collection, the cannula will be flushed and 


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charged with a volume equal to the dead space volume of the lock. If a mandarin (obturator) is 
used, blood loss due to discard is not expected.
Refer to the TES 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 JNJ-67953964

Pharmacy manual/study site investigational product manual or equivalent document e.g., 
Investigational Product Preparation Instructions

Laboratory manual, tubes and labels

Electronic systems or paper documents for the completion of C-SSRS, ASEX, KSS, 
SMDDS, CPFQ, SHAPS, CGI-S, SIGH-A and SIGMA.

Manuals for investigator and subject for the Q1.6-app to complete the follow-up on 
treatment compliance, saliva collection, follow-up on subject retention and self-assessment 
of treatment experience. The Q1.6-app will be downloaded on the subjects’ own 
smartphone. The Q1.6-app will ask the pre-programmed study related questions after 
opening/unlocking the smartphone by the subject. A privacy statement will be provided by 
the Q1.6 provider. The Q1.6-app will report non-compliance of the subject to the 
investigator.

Manuals for investigator and subject for the AiCure-app to assess treatment compliance by 
video recording the drug intake. The AiCure-app will be downloaded on the subjects’ own 
smartphone, or a smartphone with the app included will be provided to the subject.

Paper forms for MINI 7.0

Sample ICF

IWRS Manual

Electronic data capture (eDC) Manual.
8.2.
Study procedures
8.2.1.
Screening
Subjects will report to the clinical unit for the first eligibility screening assessment within 35 to 
2 days prior to Day 1. Before any study specific procedures are conducted and following an 
explanation of the purpose and risks of the study, subjects will sign an ICF. Recording of 
AEs/concomitant medication will start following consent and will continue until end of 
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As duplicate enrollment and protocol violations are risk factors for poor quality data and safety 
concerns, each subject in this study will have their current study status checked by a clinical 
trials verification system when available. After having the ICF signed, each subject will be 
checked in the vendors’ database. Partial identifiers will be utilized. This will include checking a 
valid form of picture ID such as a driver’s license, national ID card, passport, or government 
issued picture ID when possible. The first 3 initials of the first and last name will be entered 
along with the middle initial, date of birth, sex, and last 5 digits of that ID. If the research subject 
is a verification success they may proceed in the study. Verification failures will not be permitted 
to screen.
The Structured Interview for MADRS will be completed during the screening visit. If 2 weeks or 
more transpires between the MADRS rating at screening and Visit 2, the local rater will 
complete the MADRS by a telephone interview up to 4 days before Visit 2 to determine whether 
the subject still meets the threshold for inclusion.
After all inclusion and exclusion criteria have been met and confirmed, and disallowed 
medication stopped, the subject will be invited to return to the study center for Day 1 of the 
double-blind study period. The subject should be supplied with tubes and instructions for the 
collection of saliva at home. The subject should also be instructed to come to the study center on 
Day 1 in fasted condition when possible.
During the screening visit, the Q1.6-app will be downloaded and the date of Visit 2 should be 
entered in the dashboard when the subject is eligible and the date available.
8.2.2.
Baseline Visit (Visit 2) 
The study subject will be asked to come to the study center in fasted condition. Baseline blood 
collections should be completed first. Thereafter the subject will have a meal. followed by 
completion of all other study assessments planned for Day 1 (see TES).
If the subject still complies with the in- and exclusion criteria, the subject will be randomized 
and supplied with study medication. The subject will start taking the study medication from Day 
2 onwards.
8.2.3.
Double-blind Treatment Perioda
The double-blind treatment period will start on the day of first dosing. From Day 2 onwards, the 
subject will take the study medication at home in fasting condition at least 30 minutes before 
breakfast. The subject will visit the study center weekly or every 2 weeks (between visit 6 
and 7). At each study visit, the subject should come to the study center in fasted condition and 
will be dosed at the study center after predose blood collections. Dosing should be witnessed by 
the study staff. At each study visit, subjects should take their study medication with them and 
return used and partly used blisters. 
                                                
a This section has been amended by amendment INT-2


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At Visits 3, 4 and 5, the subjects will be re-randomized to blind subjects and investigators for the 
duration of the placebo lead-in period. At each visit new blisters with study medication will be 
supplied to the subject.
During the study visits, all assessments will be completed per the TES. For the sequence of 
assessments see Section 8.1.
Between visits the Q1.6-app will ask the subject about the self-assessment of treatment 
experience, compliance to intake of study medication and interest in the study. The Q1.6-app 
will ask the subjects also about their engagement to the study. This will be done at the start and 
the end of the study and up to 3 times during the study.
At their last study visit, each study participant will be invited to complete an IEC/IRB approved 
Experience Survey, to share to his/her experience as a volunteer in this study. The responses will 
be collected by an external party and anonymously provided to the sponsor.
8.2.4.
Early Withdrawal Visit
All subject will have to complete Visit 11 (final visit and early withdrawal visit). Subject who 
prematurely withdrawal from the study are encouraged to complete Visit 11. During Visit 11, all 
assessments will be completed per the TES. 
For the sequence of assessments, see Section 8.1.
8.3.
Efficacy Assessments 
8.3.1.
Rater Qualification
Only qualified raters will be allowed to perform rating scales and questionnaires during the 
study. This applies to the MADRS, ATRQ, MINI, C-SSRS and CGI-S. Each rater should comply 
with rater qualification criteria in terms of educational background and experience with MDD 
and the applicable scales. Also, each rater not having received the status of qualified rater in the 
past 2 years, should pass a training and certification process. The process of rater qualification, 
the rater qualification criteria and exceptions to it, are described in a separate qualification 
methodology document. 
8.3.2.
Primary
MADRS
The primary efficacy evaluation will be the MADRS total score. The MADRS will be performed 
by qualified raters during the study, using the SIGMA (Williams 1988) and will be completed at 
screening and during the visits indicated in the TES.
The MADRS is a clinician-rated scale designed to measure depression severity and detects 
changes due to antidepressant treatment. (Montgomery 1979). The scale consists of 10 items, 
each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence 
of the symptoms), for a total possible score of 60. Higher scores represent a more severe 
condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, 


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appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and
suicidal thoughts. The test exhibits high inter-rater reliability.
The typical recall period for the MADRS is 7 days and will be used for the primary efficacy
evaluation.
8.3.3.
Secondary
Evaluation of depression
CGI-S
The CGI-S provides an overall clinician-determined summary measure of the severity of
the subject’s illness that takes into account all available information, including knowledge
of the subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of
the symptoms on the subject’s ability to function (Guy 1976). The CGI-S evaluates the
severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, a
subject is assessed on severity of mental illness at the time of rating according to: 0=not
assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill;
5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a
global evaluation of the subject’s condition at a given time.
SMDDS 
The SMDDS (McCarrier 2016) is a 16-item PRO measure intended for use as an endpoint in 
MDD clinical trials. Each item will be rated by the subject according to a 5-point Likert scale. 
The SMDDS uses a 7-day recall period and verbal rating scales. It was developed in 
accordance with the US Food and Drug Administration (FDA)'s PRO Guidance and best 
practices.
SATE.
The Self-Assessment of Treatment Experience questionnaire is a 1- or 2-item self-report scale 
designed to provide additional information regarding the subject’s subjective experience while 
taking the treatment. This is an internal Janssen questionnaire and the questions will be asked to 
the subject weekly by the Q1.6-app. The Q1.6-app will send an alert to the investigator when the 
subject replies that her/his depression is much worse or very much worse. For details see 
Section 10.9.
Evaluation of Anhedonia
SHAPS
The SHAPS (Nakonezny 2010, Snaith 1995) is a self-report 14-item, instrument, developed for 
the assessment of hedonic capacity. It has excellent internal consistency, with construct validity, 
and is unidimensional in assessing hedonic capacity among adult patients with MDD. The 
SHAPS possesses excellent psychometric properties, is not influenced by participant 
demographic and clinical characteristics, and is appropriate for use in both clinical and research 
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Subjects score whether they experience pleasure in performing a list of activities or experiences. 
Subjects can rate the answers a “definitely/strongly agree”, “agree”, “disagree” or “strongly 
disagree”. Answers will be rated according to Franken (2007): “Definitely agree” will be rated 1, 
“Agree” will be rated 2, “Disagree” will be rated 3, and “Definitely disagree” will be rated 4. So, 
the score of the scale will range from 14 to 56. The mean score in a population of patients 
hospitalized for treatment of depression was 34.4 (Franken, 2007).
For more details see Section 10.8
Evaluation of anxiety
SIGH-A
The SIGH-A is included to determine the frequency and severity of signs and symptoms of 
anxiety and determine both their influence on treatment and their responsiveness to treatment.  
This original HAM-A scale assesses the severity of different anxiety-related symptoms 
(Hamilton 1959; Hamilton 1969) with a score range of 0 to 52. It is the most widely used 
symptom severity measure for anxiety. Each of the 14 items is rated by the clinician on a 5-point 
scale ranging from 0 (not present) to 4 (maximum degree). The HAM-A has an inter-rater 
reliability correlation of r = .74 (Maier 1988) and the internal consistency of the measure is 
reported to be high with a coefficient alpha of .86 (Clark and Donovan, 1994). The symptoms 
can be grouped into two clusters: psychic anxiety and somatic anxiety.
As the original HAM-A lacks instructions for administration and clear anchor points for the 
assignment of severity ratings, the structured interview guide version will be used in the current 
study (Shear 2001). The SIGH-A has been shown to have high inter-rater and test-retest 
reliability and produced similar but consistently higher (+ 4.2) scores compared to the original 
HAM-A. Correlation with a self-report measure of overall anxiety has also been shown to be 
high (Shear 2001). 
HAM-A6
The HAM-A6 is a 6-item subscale derived from the original HAM-A (Hamilton 1959; Hamilton 
1969). Because the HAM-A, like the Hamilton rating scale for depression-17 (HDRS17), is a 
multi-dimensional scale, Bech derived a 6-item subscale, the HAM-A6, comprising five psychic 
anxiety symptoms: anxious mood, psychic tension, fears, intellectual disturbances, and anxious 
behaviour observed at the interview, as well as one somatic item, muscular tension (Bech 2007), 
with a score range of 0 to 24. In an analysis of four pooled dose-response trials in GAD, a 
Mokken analysis of the HAM-A6 yielded Loevinger coefficients above 0.40 individually and
combined, indicating that unlike the full HAM-A, the HAM-A6 subscale is uni-dimensional. 
Given a fundamental requirement for a drug to be considered to have an anxiolytic effect is that 
it has shown efficacy in terms of symptom reduction in the core symptoms of anxiety, and as 
these symptoms are captured by HAM-A6 (which is more in accordance with the DSM-IV 
criteria for GAD than the full HAM-A), the total HAM-A6 score is considered a sufficient 
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8.3.4.
Exploratory
CPFQ 
The CPFQ is a brief self-report scale that provides additional information regarding the impact of 
adjunctive treatment on aspects of cognitive and executive function including attention, memory 
and mental acuity. Subjects with MDD are often reported to have difficulties with functioning in 
this area. For details see Section 10.10.
8.4.
Safety Assessments 
The collection of AEs and concomitant medications will start after the ICF has been signed and 
will continue until the final study visit. All safety assessments listed below will be performed as 
specified in the TES.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
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 endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TES:
8.4.1.
Physical and Neurological Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the 
physical examinations.
Body weight will be measured as per the TES. Body weight will be measured using a calibrated 
scale. Subjects will be weighed at approximately the same time of day on the same scale, 
wearing underwear and a gown and without shoes; they will be instructed to empty their bladders 
before being weighed. (Note: if disrobing for weighing is logistically impossible, the subject 
should be dressed as lightly as possible, with consistency from visit to visit). 
The neurological examination at minimum will include a mental status exam, an assessment of 
cranial nerves (III to VII: oculomotor, pupils, and facial muscles), the motor system (basic 
strength), and coordination (gait). Sensory testing if guided by history of change in sensation.
8.4.2.
Vital Signs
Blood pressure and pulse/heart rate measurements will be assessed in supine positions with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available.
Supine blood pressure and pulse/heart rate measurements should be preceded by at least 
5 minutes of rest in a quiet setting without distractions (e.g., television, cell phones). 
In addition, oral or tympanic temperature will be measured.


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Vital signs should be measured in nonfasting conditions whenever possible.
8.4.3.
Electrocardiogram (ECG)
Twelve-lead ECGs, intended for safety monitoring, will be recorded supine (following 5 minutes 
rest) so that the different ECG intervals (RR, PR, QRS, QT) can be measured at multiple time 
points at screening and during the study (see TES). The ECG will be recorded until 4 regular 
consecutive complexes are available in good readable quality. 
During the collection of ECGs, subjects should be in a quiet setting without distractions (e.g., 
television, cell phones). Subjects 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: ECG, vital signs, blood draw. Please note that 
fasting blood draw may precede the ECG and vital signs in this study.
Hot and cold drinks and food should be avoided 30 minutes before an ECG measurement 
whenever possible.
8.4.4.
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, Clinical Laboratory Tests. A central laboratory will be 
used for testing. 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 eCRF. 
8.4.5.
Suicidal Risk Monitoring
JNJ-67953964 is considered to be a central nervous system (CNS)-active compound. The 
sponsor considers it important to monitor for such events before and during this clinical study.
Columbia Suicide Severity Rating Scale (C-SSRS)
An interview to assess the risk of suicidal ideation and behavior will be conducted at screening,
through the double-blind treatment phase and at Week 11 / early withdrawal. The C-SSRS is a 
low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the 
National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess 
severity and track suicidal events through any treatment (Posner 2007). The C-SSRS is a clinical 
interview providing a summary of both ideation and behavior that can be administered during 
any evaluation or risk assessment to identify the occurrence and intensity of suicidal thoughts 
and suicidal behaviors. It can also be used during treatment to monitor for clinical worsening. 
See Section 10.11 for details.
8.4.6.
Other Safety Evaluations
ASEX
ASEX (McGahuey 2000) will be used to assess sexual dysfunction. The ASEX is a 5-item, self-
administered rating scale based on a 6-point Likert scale.


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The scale quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach 
orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher 
scores indicating more sexual dysfunction. See Section 10.12 for details.
KSS
The KSS is a subject-reported assessment used to rate sleepiness on a scale of 1 to 9, ranging 
from ‘extremely alert’ (1) to ‘very sleepy, great effort to keep awake, fighting sleep’ (9). See 
Section 10.13 for details.
8.5.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information 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.
AEs 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.
As with any CNS-active medication, investigators should monitor carefully and document any 
CNS-related AE including tremor, ataxia, abnormal sensation, confusion, or possibility of 
seizure.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality 
complaints (PQCs), refer to Section 10.4, Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.
Adverse Events of Special Interest
The following AEs are considered to be of special interest in this study:

Pruritus

GI complaints such as dyspepsia, abdominal pain, constipation, or diarrhea.
Investigators are instructed to inquire about the occurrence of such events during the collection 
of AEs at each visit. When reported and if these are of moderate or severe intensity (sufficient 
discomfort to cause interference with normal activity and/or warrant treatment), investigators 
should provide a narrative to describe the event. 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. 
Note: If the event meets the seriousness criteria (see Section 10.4), the Serious Adverse Event
Form must also be completed according to the SAEs reporting timeline described in 


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Section 10.4, ie, within 24 hours of having become aware of the event, even if all details are not 
available.
8.5.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Informationa
All Adverse Events
All AEs 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 AEs, including those 
spontaneously reported to the investigator within 30 days after the last dose of study medication, 
must be reported using the Serious AE Form. The sponsor will evaluate any safety information 
that is 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, without undue delay, under no circumstances later than 24 
hours after their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and the CRF, which must be completed and reviewed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a SAE should 
be transmitted electronically or by facsimile (fax).
8.5.2.
Follow-up of Adverse Events and Serious Adverse Events
AEs, including pregnancy, will be followed by the investigator as specified in Section 10.4,
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
8.5.3.
Regulatory Reporting Requirements for Serious Adverse 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 Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities 
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary, 
unless otherwise specified. 
8.5.4.
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 
                                                
a This section has been amended by amendment INT-3.


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event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious AEs and must be reported using the Serious Adverse Event Form. Any 
participant who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study medication.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.6.
Treatment of Overdose
For this study, any dose of JNJ-67953964 greater than 4 capsules within a 24-hour time period
will be considered an overdose. The sponsor does not recommend specific intervention for an 
overdose. 
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for
AE/SAE and laboratory abnormalities until 
JNJ-67953964 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 
medication 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.
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.
8.7.
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of JNJ-67953964 using a validated, 
specific and sensitive liquid chromatography-mass spectrometry/
mass spectrometry 
(LC-MS/MS) method. If required, some plasma samples may be analyzed to document the 
presence of circulating metabolites or to determine protein binding using a qualified research 
method. In addition, some samples may be used to measure plasma concentrations of the 
SSRI/SNRI used by the subject.
Venous blood samples of 6 mL will be collected for determination of JNJ-67953964 plasma 
concentrations when required specified in the TES. A PK blood sample will be collected at the 
same time as the blood samples for biomarkers when indicated in the TES.
The exact dates and times of blood sampling must be recorded in the laboratory requisition form.
Data will be listed for all subjects with available plasma concentrations per treatment and study 
day. All concentrations below the limit of quantification (LOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LOQ will be treated as zero 
in the summary statistics. 


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8.8.
Genetics
Blood samples (6 mL) will be collected to allow for the identification of pharmacogenomic
factors that may influence the PK, PD, safety and/or tolerability of JNJ-67953964, and to 
identify genetic and epigenetic factors associated with neuropsychiatric/neurodegenerative 
disorders. They may also be used to develop tests/assays related to JNJ-67953964 or 
neuropsychiatric/neurodegenerative disorders. 
Pharmacogenomic research may consist of the analysis of one or more candidate genes or of the 
analysis of (epi)genetic markers throughout the genome or analysis of the entire genome (as 
appropriate) in relation to JNJ-67953964 or neuropsychiatric/neurodegenerative disorders. All 
pharmacogenomic data obtained during this study may be included in ongoing cross-study 
analyses to investigate the relationship between depression severity and phenotypes and 
biomarkers. Participation in the genetic/pharmacogenomic part of this study is mandatory.
8.9.
Biomarkers
During the study, blood and saliva will be collected for the assessment of biomarkers at the time 
points indicated in the TES. Additional instructions for collection of biomarker samples: 

Blood biomarkers will be collected under fasting conditions – at least 4 hours, water 
permitted.

Subjects should be informed not to do strenuous sports or exercises within 24 hours before 
blood sample collection.

Food, drinks (except water) and oral care (brushing, flossing, mouthwash) are not permitted 
for 1 hour prior to saliva collection. 

Subjects should refrain from alcohol consumption for 12 hours prior to saliva sampling.

Subjects may receive a reminder via the smartphone to collect the saliva samples on time.
In blood and/or saliva, biomarkers related to the HPA axis activation including but not limited to
ACTH and cortisol, neurotropic factors, inflammation and metabolic factors may be investigated.
Biomarkers may be added or deleted based on scientific information or technical innovations 
under the condition that the total volume of blood collected will not be increased. The biomarker 
data obtained from this study may also be included in an ongoing cross-study analysis to 
investigate the relationship between depression severity and phenotypes and biomarkers.
Subject data
To evaluate the biomarker results, the following information needs to be documented on each 
day of collection of blood samples for biomarker analysis.

Diet (extremes during the previous week)

In WOCBP: Follicular phase by documenting first day of last menses.

Any sickness or allergy in the previous 2 weeks


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9.
STATISTICAL CONSIDERATIONS
9.1.
Sample Size Determination
The sample size for the study is determined based on the assumption of a treatment effect size of 
0.45 in the mean change from baseline in MADRS total score between JNJ-67953964 treatment 
group and placebo. The assumed effect size is based on review of the literature looking at the 
adjunctive treatment with ALKS 5461, a combination of buprenorphine (partial m-opioid 
receptor agonist and KOR antagonist) and samidorphan (a potent m-opioid receptor antagonist)
in MDD patients with an inadequate response to one or two courses of an antidepressant 
(Fava 2016 and Enrich 2015).
Using the data from the same studies, an estimate of 11 for standard deviation in the change in 
MADRS total score from baseline was made. Detection of 0.45 effect size with a power of 90% 
at an overall 1-sided significance level of 0.20, requires 45 subjects in each treatment group 
(90 subjects in total).
The choice of alpha and beta (1-power) for this Phase study was made in order to increase 
sensitivity for detecting a therapeutic signal while also maintaining a modest sample size. Thus, 
power was set to a high value (power=90%; beta=0.10) but the type 1 error rate was specified at 
1-sided alpha=0.20. This choice is supported by a publication by Lindborg et al (Lindborg 2014) 
in which authors note that type 1 and 2 error levels commonly employed in Phase 3 study 
designs (simple hypothesis tests with 2-sided alpha=0.05 and beta=0.2) are suboptimal for early 
phase studies and that switching these values (increasing alpha while decreasing beta) can 
increase Phase 2 productivity and reduce the risk of rejecting a compound with significant 
therapeutic potential. 
When adjusted for a drop-out rate of approximately 5% of subjects during the treatment period, 
the required number of subjects to be randomized is 96. To achieve this, the estimated number of 
subjects to enter the lead in period is 142, after adjusting for an estimated placebo response rate 
of 25% and drop-out rate of 10% during the lead-in period. 
A blinded sample size re-estimation is anticipated with 180 as the maximal number of subjects to 
be enrolled in the trial.
9.2.
Efficacy Analyses 
9.2.1.
Primary
Primary efficacy analyses will be based on the intention-to-treat analysis set from enriched
population (eITT) which consists of randomized lead-in placebo non-responders receiving at
least one dose of study medication and having at least one post-treatment baseline efficacy 
measurement.
The JNJ-67953964 treatment group will be compared with placebo using the primary efficacy
endpoint: change from treatment baseline in MADRS score during the treatment period. The 
comparison will be performed by means of a mixed-effects model for repeated measures 


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(MMRM), with time, treatment (placebo, JNJ-67953964) and time-by-treatment interaction as 
factors and baseline total MADRS score as a continuous covariate. Other covariates of interest 
may be included in the MMRM model. The treatment-placebo differences will be obtained using 
the appropriate contrast in the MMRM models at the 6-week endpoint.
Sensitivity analyses of the primary endpoint will be performed using an analysis of covariance 
(ANCOVA) model; these will be detailed further in the Statistical Analysis Plan.
In addition, same MMRM model will be fitted on full intention-to-treat analysis (fITT) set
consisting of all the randomized subjects receiving at least one dose of study medication and
having at least one post-treatment baseline efficacy measurement. 
Missing data mechanisms exploration and possible imputation methods for primary efficacy 
variable will be described in detail in Statistical Analysis Plan.
Descriptive statistics for actual values and changes from baseline for MADRS Score at each time 
point of the double-blind treatment phase will be provided by treatment group using both: eITT 
and fITT analysis sets. Mean differences between the treatments with corresponding confidence 
intervals (CIs) will be reported.
Frequency tables for response and remission of depressive symptoms (derived from the 
MADRS) will be provided by treatment group at each time point of the double-blind treatment 
phase using both: eITT and fITT analysis sets. Chi square test to test the overall differences 
between the treatment groups will be performed.
9.2.2.
Secondary
Evaluation of Anhedonia
Change from treatment baseline in SHAPS score during the treatment period will be analyzed 
with the same MMRM model as primary efficacy variable (MADRS) using both: eITT and fITT 
analysis sets. The JNJ-67953964 treatment group will be compared with placebo using the 
appropriate contrast in the MMRM model at the 6-week endpoint.
Descriptive statistics for actual values and changes from baseline for SHAPS total score at each 
time point of the double-blind treatment phase will be provided by treatment group using both: 
eITT and fITT analysis sets. Mean differences between the treatments with corresponding CIs 
will be reported.
The effect of JNJ-67953964 on depression symptoms across different baseline levels of 
anhedonia will be explored. Descriptive statistics for actual values and changes from baseline in 
MADRS Score within different anhedonia levels (no anhedonia, low level of anhedonia and high 
level of anhedonia; cutoff values will be provided in Statistical Analysis Plan) will be presented 
by treatment group using both: eITT and fITT analysis set.


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Evaluation of Depression
Descriptive statistics for actual values and changes from baseline for CGI-S, SATE and SMDDS 
(total) scores at each time point of the double-blind treatment phase will be provided by 
treatment group using both: eITT and fITT analysis sets. In addition, for CGI-S, frequency tables 
will be provided by treatment and time-point.
Evaluation of Anxiety
Descriptive statistics for actual values and changes from baseline for SIGH-A total score as well 
as HAM-A6 score at each time point of the double-blind treatment phase will be provided by 
treatment group using both: eITT and fITT analysis sets. Mean differences between the 
treatments with corresponding CIs will be reported.
9.2.3.
Exploratory
Cognitive Functioning Analysis
The actual values of CPFQ and changes from baseline will be summarized at each scheduled 
time point by treatment. These analyses will be performed on both: eITT and fITT analysis sets.
9.3.
Biomarker Analyses
Biomarker levels will be tabulated for each time point and summary statistics will be calculated. 
Post-treatment changes in biomarker levels will be assessed by treatment group. Analysis of 
variance (ANOVA) and t-test will be used to assess differences across groups and time points. 
Correlations between biomarker levels and clinical endpoints will be evaluated.
The additional exploratory 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 may be 
explored. Additional exploratory analyses may also be performed. Results of all exploratory 
analysis (including the genetic/epigenetic results) will be presented in a separate report. 
All biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity, phenotypes, and biomarkers.
9.4.
PK analysis
Plasma concentrations for JNJ-67953964 will be analyzed. Based on the individual plasma 
concentration-time data from all subjects, exposure parameters of JNJ-67953964 will be derived 
using population PK (popPK) modeling. Potential baseline covariates (eg, demographics such as 
age, sex and race, body weight, laboratory variables such as creatinine clearance, etc.) may be 
included in the models, if relevant. The following exposure parameters will be derived using 
Bayesian feedback analysis: AUC24h and C0h. Results will be tabulated and summary statistics 
will be generated. Individual plasma concentrations per study visit will be listed. PK and PD
relationship will be explored, if feasible. Details of population PK analysis and PK/PD analysis 
will be given in an analysis plan and the results will be presented in a separate report.


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9.5.
Safety Analyses
Statistical analysis of the safety data will be done by the sponsor or under the authority of the 
sponsor. Specific details will be provided in the Statistical Analysis Plan.
All safety analyses will be performed based on the safety analysis set, which will include all 
randomized subjects who receive at least 1 dose of study drug. Safety summaries will be 
provided by treatment, unless specified otherwise.
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities 
(MedDRA) and tabulated by system organ class, by severity and relationship to study drug and 
will be presented by treatment. SAEs will be summarized separately.
The safety analysis will include the incidence of AEs, actual data and changes in blood pressure, 
pulse rate, laboratory safety data, 12-lead ECG and physical and neurological examination data 
from predose to all postdose assessments.
The suicidal ideation and suicidal behavior data collected from the C-SSRS will be summarized 
descriptively at each scheduled timepoint by treatment group. Sexual dysfunction (ASEX) and 
KSS data collected will be summarized descriptively at each scheduled timepoint by treatment 
group.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
MedDRA. All reported AEs with onset during the double-blind treatment phase (i.e., TEAEs, 
and AEs that have worsened since baseline) will be included in the analysis. For each AE, the 
percentage of subjects who experience at least one occurrence of the given event will be 
summarized by treatment group. Summaries will be provided for all subjects receiving at least 
one dose of study drug in this study, and will include AEs from this study. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who withdraw due to an AE, or who experience a severe AE or a SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and at each scheduled time point, and for 
changes from baseline.  
The number and percentage of subjects experiencing a laboratory result below or above normal 
reference ranges will be provided for each laboratory analyte by treatment group. Summaries 
will be provided for all subjects receiving at least one dose of study drug in this study. 
A listing of subjects with any laboratory result outside the reference ranges will be provided.


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ECG
Heart rate and ECG intervals (RR, PR, QRS and QT) as well as corrected QT intervals according 
to Bazett’s formula (QTcB) and Fridericia’s formula (QTcF) (Bazett 1920, Sagie 1992, Hodges 
1983, International Conference on Harmonization [ICH] 2005) from the 12-lead ECG will be 
summarized at baseline and at each scheduled time point and for changes from baseline using 
descriptive statistics. 
The number and percentage of subjects with at least one occurrence of a treatment-emergent 
potentially clinically important QTc measurement (QTc value >450, >480, or >500 msec) or 
with a change from baseline in QTc>30 msec or 60 msec, will be summarized by treatment 
group. 
Data listings of subjects with any potentially clinically important values or with a change from 
baseline in QTc will be provided.
Vital Signs
Descriptive statistics of temperature, pulse, and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized. 
Physical and Neurological Examinations
Subjects with abnormal findings will be presented in a data listing.
Other Safety Measures
C-SSRS
The suicidal ideation and behavior data collected from the C-SSRS will be summarized 
descriptively at each scheduled timepoint by treatment group. Data from the subjects with 
suicidal ideation and behavior will be presented in data listing.
ASEX and KSS
Sexual dysfunction and KSS data collected will be summarized descriptively at each scheduled 
timepoint by treatment group.
9.6.
Interim Analysis
An interim analysis may be executed. The procedures for the interim analysis will be described 
in a separate charter.
A blinded data review for purpose of sample size re-estimation may be performed during the 
study after minimally 50% of the subjects are randomized and have completed Week 6 of the 
double-blind treatment period. Sample size may be re-adjusted if the observed SD substantially
deviates from the hypothesized SD or if the lead-in response and dropout rate substantially 
deviate from the assumed values. The maximal number of subjects to be enrolled in the trial will 
not surpass 180.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
ABV
Alcohol-by-volume
ACTH
Adrenocorticotropic hormone
AE
Adverse Event
ALKS
Alkermes
ALT
alanine aminotransferase 
AMA
Anti-mitochondrial antibody
ANA
Antinuclear antibody
ANCOVA
Analysis of covariance
ANOVA
Analysis of variation
Anti-HAV (IgM)
Anti-hepatitis A virus (Immunoglobulin M)
Anti-HEV (IgM)
Anti-hepatitis E virus (Immunoglobulin M)
AP
Alkaline phosphatase
ASEX
Arizona sexual experiences scale
ASMA
Anti-smooth muscle antibody
AST
Aspartate transaminase 
ATRQ
Antidepressant Treatment History Questionnaire
AUC
Area under the plasma concentration-time curve (time period specified by 
subscript).
BBB
bundle branch block
BD
Bipolar disorder
BDNF
Brain-derived neurotropic factor
BMI
Body mass index 
BUN
Blood urea nitrogen
CBC
Complete blood count
CERC
Cerecor
CGI-S
Clinical Global Impression –  Severity
CHF
Congestive heart failure
CI
Confidence interval
Cmax
maximum drug concentration 
CMV
Cytomegalovirus
CNS
Central nervous system
CPFQ
Cognitive and Physical Functioning Questionnaire
CPK
Creatine phosphokinase 
CRP
C-reactive-protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variation
CYP
cytochrome P450
DILI
Drug induced liver injury
DM
Diabetes mellitus
DNA
desoxyribonucleic acid


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DRC
Data Review Committee
DSM-IV/5
Diagnostic and Statistical Manual of Mental Disorders fourth/fifth edition
EBV
Epstein-Barr virus
ECG
Electrocardiogram
(e)CRF
(electronic) case report form
eDC
Electronic data capture
EF
embryo/fetal 
eITT
Enriched intent-to-treat (population)
EOT
End-of-treatment
ERCP
endoscopic retrograde cholangiopancreatography
ESR
Erythrocyte sedimentation rate
FDA
Food and Drug Administration
fITT
Full intent-to-treat (population)
FSH
follicle stimulating hormone
FT4
Free thyroxine
G17
gastrin-17
GAD
General anxiety disorder
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase 
HAM-A
Hamilton Anxiety Scale
HAM-A6
6 item subscale from HAM-A
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C antibodies 
HDRS17
Hamilton rating scale for Depression-17
HIV
Human immunodeficiency virus
HPA
Hypothalamus pituitary adrenal
Hp IgG
helicobacter IgG antibodies 
hs-CRP
High-sensitivity C-reactive protein
IB
Investigator’s Brochure
ICD
International Classification of Diseases
ICF
Informed consent form  
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IGF1
Insulin-like growth factor 1
IL-X
Interleukin-X (1β, 2, 6, 10…)
INR
International normalized ratio
IUD
Intrauterine device
IUS
Intrauterine system
IWRS
Interactive web response system
KOR
kappa opioid receptor
KSS
Karolinska Sleepiness Scale
LC-MS/MS
Liquid chromatography/mass spectrometry/mass spectrometry


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LDH
Lactic acid dehydrogenase 
LFT
liver function test
LKM
Liver kidney microsomal antibody
LKM1
Liver kidney microsomal antibody type 1
LOQ
Limit of quantification
LT
Liver test
MADRS
Montgomery Asberg Depression Rating Scale
MAOI
Monoamine oxidase inhibitor
MDD
Major Depressive Disorder 
MDE
Maximum desired mean exposure
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effects model for repeated measures
MOS
Margin of Safety
MRCP
magnetic resonance cholangiopancreatography
MRI
Magnetic resonance imaging
MTD
Maximum tolerated Dose
NOAEL
no-observed-adverse-effect-level  
NSAID
Nonsteroidal anti-inflammatory drug
OCD
Obsessive compulsive disorder
OTC
Over the counter
pANCA
Anti-neutrophil cytoplasmic antibody
PD
pharmacodynamics(s)
PET
Positron emission tomography
PGI/II
pepsinogen I / II 
PK
Pharmacokinetic(s)
popPK
Population Pharmacokinetics
PPI
Proton pump inhibitor
PQC
Product Quality Complaint
PRN
As needed
PRO
Patient reported outcome
PT
Prothrombin time
PTSD
Post-traumatic stress disorder
PTT
Partial thromboplastin time
QD
Once daily
RBC
Red blood cell 
RNA
ribonucleic acid
SAD
Social anxiety disorder
SAE
Serious adverse event
SAMe
S-adenosyl methionine
SATE
Self-Assessment of Treatment Experience
SD
Standard deviation 
SHAPS
Snaith-Hamilton Pleasure Scale


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SIGH-A
Structured Interview Guide for the Hamilton Anxiety scale
SIGMA
The Structured Interview Guide for the MADRS 
SMDDS
Symptoms of Major Depressive Disorder Scale
SNRI
serotonin-norepinephrine reuptake inhibitor 
SRP
Study responsible physician
SSRI
Selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
Tbili
Total bilirubin
TEAE
Treatment-emergent adverse event
TES
Time and Events schedule
TIBC
Total iron binding capacity
TNFα
Tumor necrosis factor alpha
TSH
thyroid-stimulating hormone
ULN
Upper Limit of Normal
US
United States
VAS
Visual Analogue Scale
WBC
White blood cell 
WOCBP
women of childbearing potential 




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
For postmenopausal women only: Follicle stimulating hormone (FSH)

Serology (HIV antibody, HBsAg, and HCV antibody)

Thyroid function (TSH, FT4) at screening

HbA1c at screening in diabetic subjects only

Urine drug screen [opiates (including methadone), ecstasy, cocaine, 
(meth)amphetamines, cannabinoids, barbiturates].

Alcohol breath test.
The following biomarkers will be tested in this study. Biomarkers may be added or deleted based 
on the latest scientific insights without amending the protocol if the total volume of blood to be 
collected will not increase as a result of adding biomarkers.
analytes
saliva
cortisol
serum
High-sensitive C-reactive protein 
(hs-CRP)
serum
cortisol
serum
IL-6
serum
Tumor necrosis factor alpha (TNFα)
serum
IL-1b
serum
growth hormone
serum
adiponectin
serum
leptin
serum
Brain-derived neurotropic factor 
(BDNF)
serum
Insulin-like growth factor 1 (IGF1)
plasma
ACTH
plasma
Kynurenine metabolites
whole blood
genotyping/epigenetics


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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
Regulatory Ethics Compliance
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
Independent Ethics Committee/Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents:

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects).

IB (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects 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 subjects

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), the ICF, applicable recruiting materials, and subject 
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.
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

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor


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
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB
(at least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
investigational drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Annual Safety 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 subjects, data or trial 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 clinical study. The 
re-approval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB
about the study completion.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF must be signed before performance of any study-related 
activity. The ICF that is used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the subject can read and understand. The informed consent 
should 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 investigational 
staff must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort that participation in the study may entail. 
Subjects 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 that they will receive. Finally, they will be told that the investigator will maintain 
a subject identification register for the purposes of long-term follow-up if needed and that their 


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records may be accessed by health authorities and authorized sponsor staff without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF, form the subject is authorizing such access, and agrees to allow his or her 
study physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
The subject 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 should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the subject.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
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 study subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records 
for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject 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. 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.
Exploratory PK and DNA research is not conducted under standards appropriate for the return of 
data to subjects. 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 subjects or investigators, unless required by law. 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.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or less, according to local 
regulations) for additional research. Samples will be used to understand JNJ-67953964, 


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neuropsychiatric/neurodegenerative disorders, differential drug responders, and to develop 
tests/assays related to JNJ-67953964.  The research may begin at any time during the study or 
the poststudy storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 7.5, Withdrawal from the Use of Research Samples.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 4.2.1, Study-Specific Ethical Design Considerations.
Administrative requirements
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 nonacceptance, 
except when necessary to eliminate immediate hazards to the subjects, 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 or its designee. When the change(s) involves only logistic or administrative aspects of 
the study, the IEC/IRB only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all 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 eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
Regulatory Documentation
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
investigational site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed, written IEC/IRB approval of the protocol, amendments, 
ICF, any recruiting materials, and if applicable, subject compensation programs. This 
approval must clearly identify the specific protocol by title and number and must be signed 
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 investigational staff 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 (e.g., Form FDA 1572), if applicable

Documentation of investigator qualifications (e.g., 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 subject:

Completed investigator financial disclosure forms from all clinical subinvestigators

Documentation of subinvestigator qualifications (e.g., curriculum vitae)

Name and address of any local or central laboratory conducting tests for the study, and a 
dated copy of current laboratory normal ranges for these tests, if applicable

Local or central laboratory documentation demonstrating competence and test reliability 
(e.g., accreditation/license), if applicable
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. 
All reports and communications relating to the study will identify subjects by assigned number.


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The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject 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; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
Following the ICH/GCP guidelines, direct access to source documentation (medical records) 
must be allowed for the purpose of verifying that the data recorded in the eCRF are consistent 
with the original source data.
Case Report Form Completion
eDC will be used for this study. The study data will be transcribed by study-site personnel from 
the source documents onto an electronic CRF, and transmitted in a secure manner to the sponsor 
within the timeframe agreed upon between the sponsor and the study site. The electronic file will 
be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Study site personnel must complete the CRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
The responsible study monitor will check data at the monitoring visits to the clinical study site. 
The Investigator will ensure that the data collected are accurate, complete and legible.
All clinical work conducted under this protocol is subject to GCP regulations. This includes an 
inspection by the Sponsor and Competent Authority representatives at any time. The Investigator 
will agree to the inspection of study-related records by Competent Authority representatives and 
the audits of the Sponsor or third parties, named by the Sponsor.


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Every effort should be made to ensure that all subjective measurements (e.g., pain scale 
information or other questionnaires) to be recorded in the CRF are completed by the same 
individual who made the initial baseline determinations. The investigator must verify that all data 
entries in the eDC system are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or an authorized member of the investigational staff must adjust the eCRF 
(if applicable) and complete the query. 
If corrections to a eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

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)

Site manager can generate a query for resolution by the investigational staff

Clinical data manager can generate a query for resolution by the investigational staff 
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 
associated personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, preparation, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study personnel before the 
start of the study. 
The sponsor will review eCRFs 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 clinical study database, they will be 
verified for accuracy and consistency with the data sources. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP 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 


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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.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
Monitoring
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 site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents); a sample may be reviewed. The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the eCRF are known to 
the sponsor and investigational staff and are accessible for verification by the sponsor site 
contact. If electronic records are maintained at the investigational site, the method of verification 
must be discussed with the investigational staff. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the investigational staff. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will 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.
Study Completion/Termination
Study Completion
The study is considered completed with the last visit (Visit 11/Early withdrawal visit) for the last 
subject participating in the study. The final data from the investigational site will be sent to the 
sponsor (or designee) after completion of the final subject visit at that site, in the time frame 
specified in the Clinical Trial Agreement.


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Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed.
The investigator may initiate 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 an investigational 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 subjects by the investigator

Discontinuation of further drug development
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the 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 and comparison with the CRFs. Subject privacy 
must, however, be respected. The investigator and staff are responsible for being present and 
available for consultation during routinely scheduled 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 should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
Use of Information and Publication
All information, including but not limited to information regarding JNJ-67953964 or the 
sponsor's operations (e.g., 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 exploratory 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 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 clinical study will be used by 
the sponsor in connection with the continued development of JNJ-67953964, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 


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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 eCRF data from all investigational sites that participated in the study. 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. Results of pharmacogenomic or 
exploratory 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 subject identifiers will not be used in 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.
The sponsor shall have the right to publish such data and information without approval from the 
investigator. 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 not mandate 
modifications to scientific content and does not have the right to suppress information. For 
multicenter study designs and substudy 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 site until the combined results from the completed study have been submitted 
for publication, within 12 months of the availability of the final data (tables, listings, graphs), 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 Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which state that 
the named authors must have made a significant contribution to the design of the study or 
analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of, and the results of, clinical studies as 
required by law.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.


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Financial disclosure
Investigators and subinvestigators 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 course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have a 
causal relationship with the medication. 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 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 AEs under 
Section 8.5.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information, for time of last adverse event recording).
Serious Adverse Event
A 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 subject 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 should 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 subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 


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be reported as a SUSAR even if it is a component of the study endpoint (e.g., 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 JNJ-67953964, the expectedness of an AE will be 
determined by whether or not it is listed in the IB.
Adverse Event Associated with the Use of the Medication
An AE is considered associated with the use of the medication if the attribution is possible, 
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(e.g., confirmed by dechallenge). An alternative explanation is less likely, e.g., concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
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.


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Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (e.g., laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject exposure to the 
sponsor study drug, e.g., name confusion)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the Serious Adverse Event page of the CRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study medication, 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 (e.g., 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 staff only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind


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Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study medication 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)
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as a SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (e.g., 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.]
The cause of death of a participant in a study within 30 days of the last dose of study medication, 
whether or not the event is expected or associated with the study medication, is considered a 
SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
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, or reliability of a 
product, including its labeling or package integrity. A PQC may have an impact on the safety and 
efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC 
information from studies are crucial for the protection of participants, investigators, and the 
sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate 


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reporting of PQC information; all studies conducted by the sponsor or its affiliates will be 
conducted in accordance with those procedures.
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.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 8.5.1, Time Period and 
Frequency for Collecting Adverse Event and serious Adverse Event Information). A sample of 
the suspected product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.


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10.5.
Appendix 5: Drugs to be avoided
Examples of Concomitant Drugs to be Avoided (Moderate or Strong Inhibitor/Inducer of
CYP3A4)
Enzyme
Inhibitors
Inducers
Strong
Moderate
Strong
Moderate
CYP3A4
Boceprevir,
Amprenavir,
Avasimibe,
Bosentan,
clarithromycin,
aprepitant,
carbamazepine,
efavirenz,
conivaptan,
atazanavir,
phenytoin,
etravirine,
grapefruit juice,
ciprofloxacin,
rifampin, St.
modafinil,
indinavir,
crizotinib,
John’s wort
nafcillin.
itraconazole,
darunavir/ritonavir,
ketoconazole,
diltiazem,
lopinavir/ritonavir,
erythromycin,
mibefradil,
fluconazole,
nefazodone,
fosamprenavir,
nelfinavir,
imatinib, verapamil
posaconazole,
fluvoxamine
ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Notes:

This is not an exhaustive list.
Source: USFDA - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664 htm. Accessed 04 November 2015


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10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information
Participants must follow contraceptive measures as outlined in Section 5.2, Inclusion Criteria. In 
addition to the procedures described in Section 5.2, male subjects must also use a condom if their 
female partner becomes pregnant to avoid exposure to the unborn child.
Pregnancy information will be collected and reported as noted in Section 8.5.4, Pregnancy and 
Section 10.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.






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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 subject 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 subjects 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 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 medication 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 subject is <50 
years of age, ceruloplasmin should also be tested to screen for Wilson’s disease.  If subject is 
sick enough to be hospitalized and is under age 50, 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 screen 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 Alk Phosphatase 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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10.8.
Appendix 8: The SHAPS
This questionnaire is designed to measure your ability to experience 
pleasure in the last few days.  It is important to read each statement 
very carefully.
Tick one of the boxes to indicate how much you agree or disagree 
with each statement.
1.
I would enjoy my favourite television or radio programme
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
2.
I would enjoy being with my family or close friends
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
3.
I would find pleasure in my hobbies and pastimes
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
4.
I would be able to enjoy my favourite meal
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
5.
I would enjoy a warm bath or refreshing shower
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   


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6.
I would find pleasure in the scent of flowers or the smell of a 
fresh sea breeze or freshly baked bread
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
7.
I would enjoy seeing other people's smiling faces
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
8.
I would enjoy looking smart when I have made an effort with 
my appearance
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
9.
I would enjoy reading a book, magazine or newspaper
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
10.
I would enjoy a cup of tea or coffee or my  favourite drink
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
11.
I would find pleasure in small things e.g. a bright sunny day, a 
telephone call from a friend
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   


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12.
I would be able to enjoy a beautiful landscape or view
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
13.
I would get pleasure from helping others
Strongly disagree ..............................................   
Disagree...........................................................   
Agree...............................................................   
Strongly agree ..................................................   
14.
I would feel pleasure when I receive praise from other people
Definitely agree.................................................   
Agree...............................................................   
Disagree...........................................................   
Strongly disagree ..............................................   
Reproduced from: Snaith et al. (1995) A scale for the assessment of 
hedonic tone. The Snaith-Hamilton Pleasure Scale. British Journal of 
Psychiatry, 167, 99-103.
© 1995 The Royal College of Psychiatrists.  Written permission must be obtained 
from the Royal College of Psychiatrists for copying and distribution to others or for 
republication (in print, online or by any other medium).
This version may be different from the final version in study.


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10.9.
Appendix 9: Self-Assessment of Treatment Experience
Questions are asked once weekly from Day 1 of dosing until Visit 11.
Question 1:
Since starting this study medication, overall would you say your depression is: 
o
Improved
o
Not changed
o
Got worse
If the subject selects answer 1 (Improved), following question is asked:
Question 2:
How much did your depression improve?
o
Slightly improved
o
Much improved
o
Very much improved
If the subject selects answer 3 (Got worse), following question is asked:
Question 3:
How much did your depression worsen?
o
Slightly worse
o
Much worse
o
Very much worse


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10.10. Appendix 10: Cognitive and Physical Functioning Questionnaire (CPFQ)
This version may be different from the final version in study.






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Appendix 11b: Columbia Suicide Severity Rating Scale (Since Last Visit)


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10.12. Appendix 12: Arizona sexual experiences scale (ASEX)©
Male: 


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Female:
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10.13. Appendix 13: The Karolinska Sleepiness Scale.
Please, indicate your sleepiness during the 5 minutes before this rating through circling the 
appropriate description:
1=extremely alert
2=very alert
3=alert
4=rather alert
5=neither alert nor sleepy
6=some signs of sleepiness
7=sleepy, but no effort to keep awake
8=sleepy, some effort to keep awake
9=very sleepy, great effort to keep awake, fighting sleep
(This version may be different from the final version in study)


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10.14. Appendix 14: Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment INT-3
28 August 2019
Amendment INT2, GER-1
04 July 2019
Amendment INT2, GBR-1
21 May 2019
Amendment INT-2
26 February 2019
Amendment INT-1
18-June-2018
Original Protocol
14-March-2018


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11.
REFERENCES
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4.
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Chandler G, Iosifecu D, Pollack M, Targum S, Fava M. Validation of the Massachusetts General Hospital 
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322-325.
7.
Clark DB, Donovan JE. Reliability and validity of the Hamilton Anxiety Rating Scale in an adolescent 
sample. J Am Acad Child Adolesc Psychiatry. 1994;33(3):354-360.
8.
DeWitt SJ, Bradley KA, Lin N, Yu C, Gabbay V. A pilot resting-state functional connectivity study of the 
kynurenine pathway in adolescents with depression and healthy controls. J Affect Disord. 2018;227:752-
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9.
Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modulation in major depressive disorder. 
Neuropsychopharmacology. 2015;40(6):1448-1455.
10. Fava M, Iosifescu DV, Pedrelli P, Baer L. Reliability and validity of the Massachusetts general hospital 
cognitive and physical functioning questionnaire. Psychother Psychosom. 2009;78(2):91-97
11. Fava M, Memisoglu A, Thase ME, et al. Opioid Modulation with Buprenorphine/Samidorphan as 
Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-
Controlled Trial. Am J Psychiatry. 2016;173(5):499-508.
12. Franken IH, Rassin E, Muris P. The assessment of anhedonia in clinical and non-clinical populations: 
further validation of the Snaith-Hamilton Pleasure Scale (SHAPS). J Affect Disord. 2007;99(1-3):83-89.
13. Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. Department of
Health, Education, and Welfare; 1976.
14. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32(1): 50-55.
15. Hamilton M. The diagnosis and rating of anxiety, In Studies of Anxiety, MM Lader, Ed., Meedley Bros., 
Kent, 1969.
16. Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for 
heart rate is better. J Am Coll Cardiol. 1983;1:694.
17. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
18. Janssen Research & Development, L.L.C. Investigators Brochure JNJ-67953964, Edition 3, January 2019.
19. Knoll AT, Carlezon WA Jr. Dynorphin, stress, and depression. Brain Res. 2010;1314:56-73.
20. Lindborg SR, Persinger CC, Sashegyi A, Mallinckrod C, Ruberg SJ. Statistical refocusing in the design of 
Phase II trials offers promise of increased R&D productivity. Nat. Rev. Drug Discov. 2014; 13(8), 638–
640.
21. Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity and sensitivity to 
change in anxiety and depressive disorders. J Affect Disord. 1988;14(1):61-68.


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22. McCarrier KP, Deal LS, Abraham L, et al. Patient-Centered Research to Support the Development of the 
Symptoms of Major Depressive Disorder Scale (SMDDS): Initial Qualitative Research. Patient. 
2016;9(2):117-134
23. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): 
Reliability and Validity. J Sex Marital Ther. 2000;26(1):25-40.
24. McIntyre A. Gendron A, McIntyre A. Quetiapine adjunct to selective serotonin reuptake inhibitors or 
venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: A 
randomized, placebo-controlled pilot study. Depress Anxiety.2007;24(7):487-494
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1979 Apr;134:382-9.
26. Nakonezny PA, Carmody TJ, Morris DW, Kurian BT, Trivedi MH. Psychometric evaluation of the Snaith–
Hamilton Pleasure Scale (SHAPS) in adult outpatients with major depressive disorder. Int Clin 
Psychopharmacol 2010;25(6):328-333.
27. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164(7):1035-1043.
28. Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ. Repeated Administration of Opra Kappa 
(LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine 
Dependence. Neuropsychopharmacology. 2017, preview online Aug 31.
29. Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D. An improved method for adjusting the QT 
interval for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70(7):797-801.
30. Shear MK, Vander Bilt J, Rucci P, et al. Reliability and validity of a structured interview guide for the 
Hamilton Anxiety Rating Scale (SIGH-A). Depress Anxiety. 2001; 13(4): 166–178.
31. Sorgdrager FJH, Doornbos B, Penninx BWJH, de Jonge P, Kema IP. The association between the 
hypothalamic pituitary adrenal axis and tryptophan metabolism in persons with recurrent major depressive 
disorder and healthy controls. J Affect Disord. 2017;222:32-39
32. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of 
hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167(1):99-103.
33. Syrjänen K. Role of Serological Biomarker Testing (GastroPanel®) in Diagnosis of Symptomatic 
Dyspepsia and in Screening of the Risks of Stomach Cancer. EC Gastroenterology and Digestive System. 
2017;1.6: 209-222.
34. Umehara H, Numata S, Watanabe SY, et al. Altered KYN/TRP, Gln/Glu, and Met/methionine sulfoxide 
ratios in the blood plasma of medication-free patients with major depressive disorder. Sci Rep. 
2017;7(1):4855. 
35. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research (CDER): 
Guidance for Industry: Guidelines for the clinical evaluation of antidepressant drugs, February 1977.
36. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research (CDER): 
Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical 
Trials, August 2012, Revision 1.
37. Williams JBW. A structured interview guide for the Hamilton Depression Rating Scale. Archives of Gen. 
Psych. 1988;45(8):742-747.



SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Final,  Date: 3 June 2020
Janssen Research & Development
Department of Global Clinical Pharmacology
Population Pharmacokinetics and Pharmacodynamics Analysis Plan
JNJ-67953964  (Aticaprant)
Status:
Final
Date:
3 June 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-66353, 1.0
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.
NCT03559192


JNJ-67953964  (Aticaprant)
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Status: Final,  Date: 3 June 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
1.
INTRODUCTION.................................................................................................................................. 3
2.
OBJECTIVES ...................................................................................................................................... 4
3.
DATA ................................................................................................................................................... 5
3.1.
Description of the Available Data..................................................................................................... 5
3.2.
Handling Missing Data ..................................................................................................................... 7
3.2.1.
Missing Concentration Values ...................................................................................................... 7
3.2.2.
Missing MADRS or SHAPS scores .............................................................................................. 7
3.2.3.
Missing Date and Time Records .................................................................................................. 8
3.2.4.
Missing Covariate Values ............................................................................................................. 8
3.2.5.
Missing Exposure Variable ........................................................................................................... 8
3.2.6.
BQL Data ...................................................................................................................................... 9
4.
DATA ANALYSIS................................................................................................................................ 9
4.1.
Preliminary Population PK model .................................................................................................... 9
4.2.
Analysis Overview.......................................................................................................................... 10
4.3.
Exploratory Analysis....................................................................................................................... 11
4.4.
Population PK Model Development ............................................................................................... 11
4.4.1.
External Evaluation of the Preliminary Updated Population PK Model ...................................... 11
4.4.2.
Identification of Outliers .............................................................................................................. 12
4.4.3.
Covariate Analysis ...................................................................................................................... 13
4.4.4.
Refining the Covariance Structure.............................................................................................. 14
4.5.
Determination of Individual Population PK Parameter Estimates.................................................. 14
4.6.
MADRS and SHAPS PK/PD Modelling.......................................................................................... 14
4.7.
Simulations..................................................................................................................................... 15
4.8.
Exploration of Exposure - Safety Parameters................................................................................ 16
4.9.
Model Evaluation/Qualification....................................................................................................... 16
4.9.1.
Statistical Considerations in Case of Model Update .................................................................. 16
4.10.
Computer Software ........................................................................................................................ 17
4.11.
Report............................................................................................................................................. 17
REFERENCES............................................................................................................................................ 19


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1.
INTRODUCTION
JNJ-67953964, previously known as Cerecor (CERC)-501 and LY2456302, is a small molecule, 
high-affinity, selective kappa opioid receptor (KOR) antagonist. JNJ-67953964 is orally 
bioavailable and suitable for once-daily (QD) administration. 
KORs and their native ligand dynorphin are localized in areas of the brain that effect reward and 
stress and may play a key role in mood, stress, and addictive disorders. Chronic stress, substance 
abuse, and acute withdrawal lead to increased dynorphin expression, activating KORs and 
subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to 
negative affective states. The behavioral pharmacology of KOR antagonism has been tested in 
animal models of anhedonia, depression, and anxiety and found to have meaningful effects that 
may translate to therapeutic benefit in humans. KOR antagonists may be effective for the treatment 
of patients with mood disorders, perhaps by modulating the negative affective state associated with 
stress response.
Only about 50% of patients with major depressive disorder (MDD) show a meaningful response 
(>50% improvement to a first line antidepressant treatment), leaving many patients with 
substantial persistent impairment. Therapeutic strategies such as switching antidepressants and 
using adjuvant drug treatments can improve response, however almost 40% of patients remain 
symptomatic and fail to achieve full remission. Recently, Alkermes (ALKS) 5461, a combination 
of buprenorphine, which is a partial -opioid receptor agonist and KOR antagonist, and 
samidorphan, a potent -opioid receptor antagonist, has been tested in Phase 2 trials in subjects 
with MDD who have had only a partial response to treatment with a selective serotonin reuptake 
inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Adjunctive treatment 
with ALKS 5461 was associated with greater symptom reduction compared to placebo, suggesting 
that a KOR antagonist could provide a meaningful clinical benefit for patients being treated for 
MDD. 
A Phase 2a investigator-initiated study (FAST-MAS), evaluated whether JNJ-67953964 engages 
neural circuitry related to hedonic response to a monetary reward task. Subjects with mood and/or 
anxiety disorders and anhedonia were randomized to 8 weeks of double-blind treatment with 10 
mg JNJ 67953964 (N=43) or placebo (N=44). The primary outcome measure was the functional 
MRI (fMRI) response to a Monetary Incentive Delay Task conducted at baseline and after 8 weeks 
of treatment. The activation of brain regions implicated with reward were evaluated with mixed-
model analysis of variance (ANOVA) in 68 subjects. Mixed-model analyses revealed a significant 
Group×Time interaction in reward gain anticipation (p=0.019) (a priori primary outcome) and loss 
anticipation (p<0.001), consistent with relatively greater ventral striatal activation during
anticipation of both gain and loss in the JNJ 67953964 group post treatment. The results of this 
study establish that KOR antagonism has the hypothesized effect on neural function, thereby 
establishing proof of concept that engaging this target can modulate neuronal circuits relevant to 
reward and hedonic response.
In the study 67953964MDD2001 the efficacy of JNJ-67953964 compared to placebo is evaluated 
when administered as adjunctive treatment in subjects with MDD partially responsive to 


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Status: Final,  Date: 3 June 2020
SSRI/SNRI treatment in terms of reduction of symptoms of depression. Depression in this study 
is primarily assessed by the change from baseline on the Montgomery Asberg Depression Rating 
Scale (MADRS) in non-responders during the placebo lead-in period.
The MADRS is a clinician-rated scale designed to measure depression severity and detects changes 
due to antidepressant treatment.8 The scale consists of 10 items, each of which is scored from 0 
(item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total 
possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates 
apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude,
inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. The test exhibits 
high inter-rater reliability.
The SHAPS10,15 is a self-reported 14-item, instrument, developed for the assessment of hedonic 
capacity. It has excellent internal consistency, with construct validity, and is unidimensional in 
assessing hedonic capacity among adult patients with MDD. Subjects score whether they 
experience pleasure in performing a list of activities or experiences. Subjects can rate the answers 
a “definitely/strongly agree”, “agree”, “disagree” or “strongly disagree”. Answers will be rated 
according to Franken5: “Definitely agree” will be rated 1, “Agree” will be rated 2, “Disagree” will 
be rated 3, and “Definitely disagree” will be rated 4. So, the score of the scale will range from 14 
to 56. The mean score in a population of patients hospitalized for treatment of depression was 
34.45.
2.
OBJECTIVES
The primary objectives of the population pharmacokinetic (PK) and pharmacodynamic (PD) 
analysis are as follows:

To characterize the pharmacokinetics of 10 mg qd JNJ-67953964 after oral administration, 
including

an exploratory analysis to determine if any relevant covariate could explain the variability 
in exposure of JNJ-67953964;

derivation of individual exposure parameters for JNJ-67953964 (i.e. area under the 
plasma concentration-time profile of JNJ-67953964 over 24 hours, AUC0-24h maximum 
plasma concentration, Cmax, and pre-dose plasma concentrations, C0h). Exposure metrics 
will be derived from the popPK model on the study days with MADRS and SHAPS 
assessments;

To explore the relationship of JNJ-67953964 exposure with efficacy using the change from 
baseline in Montgomery-Asberg Depression Scale (MADRS) total score and change from 
baseline in Snaith-Hamilton Pleasure Scale (SHAPS);

To explore potential relationship between JNJ-67953964 exposure and pre-defined safety 
parameters. AEs of special interest may include pruritus and gastrointestinal (GI) complaints.


JNJ-67953964  (Aticaprant)
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Status: Final,  Date: 3 June 2020
3.
DATA
The database for population PK analysis and a dataset for the ER analysis will be created by 
Janssen R&D and/or the external data management provider SGS or Quintiles PK Office based on 
the clinical databases and according to Janssen R&D specifications. For the three Phase 1 trials, 
databases are prepared per trial, and merged subsequently with the PK dataset prepared for 
MDD2001 to establish a pooled PK dataset. The dataset preparation step for the pooled PK dataset 
should be reviewed according to the internal Janssen Job Aid for Data Flow or Internal Data 
Preparation. If necessary, minor data management to assemble a suitable NONMEM dataset may 
be performed. Any modifications to the PK or ER dataset, as well as the merge of the derived 
individual exposure metrics to the ER dataset will be described in the final report, and the R script 
used for modification and merging of the data set will be included as an appendix to the final 
report.
3.1.
Description of the Available Data
General information about the studies to be included in the Population PK analysis is summarized 
Table 1, and for Exposure-Response analysis in Table 2. Further studies may be added as 
appropriate.
All plasma PK samples with available date and time of both blood collection as well as preceding 
JNJ-67953964 dose administration will be used for the analysis. Subjects who have not received 
at least 1 dose of study drug (either JNJ-67953964 or placebo) will not be included in the analysis 
dataset. PK, MADRS and SHAPS data from subjects with missing dosing information and/or with 
incomplete dosing may only be included up to the time point of first occurrence of the missing 
dosing information/incomplete dosing. In case of miss-dosing (e.g. subject took one 5-mg capsule 
instead of two) the records will be handled as such and not be excluded. Any JNJ-67953964
concentrations before the administration of the first dose of JNJ-67953964 will lead to the 
exclusion of the subject from the analysis (ie, included in the dataset but commented out).
Baseline is defined as the last observation before the first dose administration of the treatment 
period (i.e. Treatment baseline) for MADRS, SHAPS and safety parameters. Data from screening 
and the lead-in period will not be included in the analysis. The primary analysis will be performed 
on data from the treatment period only.
No records will be deleted from the datasets: records that, for any reason, are excluded from the 
analysis will be commented out (i.e., including the letter “C” at the beginning of each excluded 
record or using a designated flag column).


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Table 1:
Overview of Trials to be Included in the Population PK Analysis
Study No.
Study Title & Design 
Brief Description of PK Data
67953964MDD2001
Title: A Phase 2a Randomized, Double-blind, 
Placebo-Controlled, Parallel-Group, Multi-center 
Study Investigating the Efficacy, Safety, 
Tolerability and Pharmacokinetics of JNJ-67953964 
in Subjects with Major Depressive Disorder.
Design: The treatment phase of the trial will consist 
of 3 periods. A placebo lead-in period of concealed 
duration, after which subjects will enter the double-
blind treatment period when they will be randomly 
assigned to 10 mg JNJ-67953964 q.d. or continue 
placebo in a 1:1 ratio for 6 weeks. Subjects who 
complete the treatment period, will then enter the 
withdrawal period and be treated with placebo for 
the remaining time of the treatment phase of the 
study.
No. of subjects with PK data 
available/total no. in study: 71/142 
(Planned)
PK samples are collected for plasma 
concentrations of JNJ-67953964
before and 2 hours after dosing on 
Day 22 (Day 1 Treatment Period), 29
(Trt Week 1), 43 (Trt Week 3) and 64 
(Trt Week 6).
LAFA
Single Ascending Dose, Fasted
Cohort 1: 4, 25, 60 mg + placebo (15 subjects)
Cohort 2: 2 and 10 mg + placebo (9 subjects)
Cohort 3: 4, 10, 25, 60 mg + Fentanyl (10 subjects)
No. of subjects with PK data 
available/total : 30/31
PK samples are collected at 0, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96
h
LAFB
Multiple Ascending Dose, Fasted
Cohort 4: 2 mg q.d. (9 subjects)
Cohort 5: 35 mg q.d. (9 subjects)
Cohort 6: 10 mg q.d. + ethanol (10 subjects)
No. of subjects with PK data 
available/total : 28/37 
PK samples are collected at 0, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96.0, 
120, 144, 168, 192, 216, 264 h
LAFC
Receptor Occupancy (PET)
0.5 mg (1), 2 mg (4), 4 mg (2), 10 mg (4), 25 mg (1 
subject)
No. of subjects with PK data 
available/total : 12/12 
PK sample are collected at 0.5, 1.0, 
2.5, 4, 6, 8, 12, 22.5 h


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Table 2:
Overview of Trials to be Included in the Exposure-Response Analysis
Study No.
Study Title & Design
Brief Description of Exposure and 
Response Data
67953964MDD2001
Title: A Phase 2a Randomized, Double-blind, 
Placebo-Controlled, Parallel-Group, Multi-center 
Study Investigating the Efficacy, Safety, 
Tolerability and Pharmacokinetics of JNJ-67953964 
in Subjects with Major Depressive Disorder.
Design: The treatment phase of the trial will consist 
of 3 periods. A placebo lead-in period of concealed 
duration, after which subjects will enter the double-
blind treatment period when they will be randomly 
assigned to 10 mg JNJ-67953964 q.d. or continue 
placebo in a 1:1 ratio for 6 weeks. Subjects who 
complete the treatment period, will then enter the 
withdrawal period and be treated with placebo for 
the remaining time of the treatment phase of the 
study.
No. of subjects with Exposure data 
available/total no. in study : 71/142 
(Planned)
Exposure metrics derived from popPK 
on Day 22, 29, 43, 50, 57 (Trt Week 
0, 1, 3, 4, 5 and 6) and 78 (EOS).
No. of subjects with MADRS and 
SHAPS data
available/total no. in study : 142/142 
(Planned)
MADRS and SHAPS assessment at 
Screening (Week -5 to 0) and on Day 
1, 8, 15 (Lead-in Week 0, 1, 2), 22, 
29, 43, 50, 57 (Trt Week 0, 1, 3, 4, 5 
and 6) and Day 78 (EOS).
Safety assessments: All AEs 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.
3.2.
Handling Missing Data
3.2.1.
Missing Concentration Values
Missing plasma concentration values will be treated as missing and will not be replaced with 
estimated (imputed) values. In the event of duplicate concentrations (samples from the same 
subject taken at the same time), all duplicated original values will be retained in the dataset but 
commented out and an additional data record will be included with the median concentration of 
the excluded duplicated samples.
3.2.2.
Missing MADRS or SHAPS scores
Missing on-treatment MADRS total or SHAPS scores will be treated as missing and will not be 
replaced with estimated (imputed) values. If the baseline MADRS or SHAPS is missing in the 
source data, its value in the analysis dataset will be populated with median of the treatment baseline 
for the corresponding lead-in response group (placebo-responder or placebo-non-responder.


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3.2.3.
Missing Date and Time Records
Concentration records with the following missing information will generally be excluded from the 
analysis: 1) recorded sampling date and time; 2) dosing information immediately prior to the 
sample collection time; 3) irresolvable discrepancy between recorded sampling date/time or 
dosing date/time.
MADRS or SHAPS total score values with the following missing information will generally be 
excluded from the analysis: 1) recorded assessment date; 2) dosing information on the assessment 
day; 3) irresolvable discrepancy between recorded MADRS or SHAPS assessment date or dosing 
date.
3.2.4.
Missing Covariate Values
If only limited covariates from a subject are missing, data can be imputed with one of the following 
methods:

For a given covariate, if no more than 10% of all subjects in the analysis population have 
missing values, then these missing values will be imputed with the median or mean (for 
continuous covariates) or mode (for categorical covariates) of the non-missing values from 
appropriate populations (studies), or

If predictors are correlated, then the missing data will be imputed based on the model that 
describes the relationship of each predictor to all other predictors.
In cases where the baseline value of a covariate is missing:

If the covariate value was recorded for the individual at an earlier assessment period, that 
earlier value will be carried forward.

If the covariate was not recorded for the individual at an earlier assessment period, but is 
available from a later assessment, that later value will be carried backward wherever 
appropriate.
For categorical covariates values which are missing, a special category may also be assigned which 
indicates that the covariate is unknown. If necessary other methods for missing covariate 
imputation may be considered. Any additional methods for handling missing covariates will be 
described in the final report.
3.2.5.
Missing Exposure Variable
If the individual PK parameters cannot be derived due to a lack of consistent or sufficient data, the 
typical values of PK parameters, taking the individual demographic values into account, will be 
used to derive the corresponding exposure metrics. If the number of subjects with missing exposure 
is relatively high (higher than 10%), a sensitivity analysis will be conducted by excluding the 
subjects with missing exposure.


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3.2.6.
BQL Data
The BQL data may initially be excluded from the estimation of the parameters (the M1 method) 
but retained in the NONMEM data set. If the amount of BQL is greater than 10%, the likelihood 
based (M3) method may be considered to evaluate the impact of BQL data on analysis results. 3
4.
DATA ANALYSIS
4.1.
Preliminary Population PK model
The sparse PK samples collected in Study 67953964MDD2001 will be evaluated with an existing 
population PK model, developed on a selection of Phase 1 data, in order to derive individual 
exposure metrics as per analysis objectives. 
A population PK model was published as part of the analysis of receptor-occupancy (RO) data 
obtained in the clinical study LAF-C using positron emission tomography (PET)9. The PK of JNJ-
67953964 in the PET study was described by a two-compartment distribution model with a first 
order absorption including 9 transit compartments. As the PK data in the PET study was limited 
to 24 hours, it was clear that the elimination was not captured well with this data. Therefore, this 
model was then updated with the data of the two phase 1 studies available, LAF-A (single doses
of 2 to 60 mg) and LAF-B (daily doses of 2, 10 or 35 mg up to 14 days). The preliminary updated 
model consisted of 6 transit-absorption compartments and inter-individual variability on relative 
bioavailability F. Parameter estimates of the preliminary updated population PK model are 
summarized in Table 3. Due to the limited dataset (n=71 subjects, 56 males and 15 females), no 
covariate analysis was performed. In case a further updated population PK model becomes 
available by the time of conducting the analysis, the updated model may be used and the details of 
the model will be provided in the report.
Table 3: Parameters Estimates of Preliminary Updated
Population PK Model
Updated model 
6 transit-cmt
(data LAF-A,-B,-C)
Parameter (Units)
Estimate (RSE,%)
IIV (%)
CL/F (L/h)
37.6 (4.81)
28.6
Vc/F (L)
399 (5.54)
22.4
Q/F (L/h)
48.6 (6.46)
-
Vp/F (L)
847 (6.16)
-
KA (/h)
5.36 (3.25)
23.6
F
1 FIX
26.3
RUV (CV%)
0.161 (10.5)
40.1
IIV= inter-individual variability (%); RSE= residual standard error; CV = coefficient of variation; CL/F = apparent 
clearance; Vc/F = apparent central volume of distribution; Q/F = apparent intercompartmental clearance; Vp/F = 
apparent peripheral volumes of distribution; KA = absorption rate constant; RUV = residual unexplained 
variability.


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4.2.
Analysis Overview
The analysis will consist of the following steps:
1.
Exploratory Analysis: A graphical analysis will be initially performed to explore baseline 
covariates and their correlations, JNJ-67953964 plasma concentration data, and change from 
baseline MADRS and SHAPS total score data collected in Study 67953964MDD2001
stratified by lead-in placebo response;
2.
External Evaluation of the Population PK Model: An external evaluation of the preliminary 
updated population PK model will be performed to assess the predictive performance of this
population PK model for the patient population in 67953964MDD2001. GoF plots, VPC’s, 
and pcVPC’s will be used as external evaluation methods. Refinements of the preliminary
population PK model structure may be performed in case the external evaluation is 
unsuccessful and therefore modifications to the model are required to adequately describe the 
both the Phase 1 and the current 67953964MDD2001 data;
3.
Determination of Individual Population PK Parameter Estimates: The individual 
population PK parameter estimates will be obtained from the population PK model obtained 
from the previous steps. A graphical covariate analysis will be performed to explore potential 
parameter-covariate relationships. Covariates that become significant and clinically relevant 
will be incorporated into the model.;
4.
Derivation of Individual Exposure Parameters: Using the individual population PK 
parameter estimates, the individual estimates of the area under the plasma concentration time 
profile of JNJ-67953964 over 24 hours (AUC0-24h), maximum JNJ-67953964 plasma 
concentration (Cmax) and the pre-dose JNJ-67953964 plasma concentration (C0h) will be 
derived for each visit in all subjects from Study 67953964MDD2001;
5.
Exploration of Relationship between Exposure and MADRS and SHAPS: Exploratory 
analyses will be performed to graphically inspect the response variables. During the analyses, 
at minimum, the following graphs will be explored: individual AUC0-24h versus MADRS and 
SHAPS total score, both absolute and change from baseline. Correlation between MADRS 
and SHAPS total scores. Exploratory plots will be stratified by lead-in placebo-response and 
by visit. The exposure-response analysis (step 6 and 7) will be performed for the efficacy 
endpoints if the exploratory analysis shows a relationship in exposure-efficacy;
6.
MADRS and SHAPS PK/PD Modelling: The change from baseline MADRS and SHAPS 
total score will be modelled separately using specific parameters for placebo effect, and drug 
effect, using individual JNJ-67953964 exposure estimates in the drug effect sub-model. 
Baseline scores, co-medication, gender, race and age at baseline will be tested as potential 
covariates. Primary analysis on MADRS will be performed on the enriched population (lead-
in non-responders). In case no effect on MADRS is found, change from baseline SHAPS total 
scores will be analyzed on the full dataset. If appropriate, the analysis on MADRS may be 
repeated on the full dataset, where both lead-in placebo response as well as baseline SHAPS 
total score will be tested as covariate in the model;
7.
Simulations of change in MADRS and SHAPS: Based on the final PK/PD model (including 
covariates, if any), model based simulations of the drug effect on MADRS and SHAPS change 
from baseline (i.e. net MADRS/SHAPS change from baseline after correction for placebo 
response) will be generated;


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8.
Exploration of Exposure versus Safety Parameters: Exploratory bar plots of AE grade 
versus exposure quantiles will be generated for the AE’s of interest: pruritis and GI 
complaints. Other AE’s with one or more observations of grade 3 or higher may be included 
in the exploratory analysis as well. If appropriate, a logistic regression may be used to describe 
the relationship between exposure and the occurrence of an AE.
9.
Reporting: Prepare the report in accordance with the FDA and EU guidance on population 
PK.1,2
4.3.
Exploratory Analysis
The aim of the exploratory data analysis will be twofold: (i) graphical presentation of the data in 
order to define the range of concentrations, guide the structural model considerations, and facilitate 
outlier identification; (ii) examination of covariate correlations which may help in building a 
covariate sub-model and avoid confounding bias.
Individual, and mean or median, plasma concentration – time profiles will be plotted on linear-
linear and logarithmic-linear scales after stratification by lead-in placebo response, SSRI or SNRI 
co-medication and other appropriate covariates. Data points will be considered as potential outliers 
if they substantially deviate from adjacent points in the concentration-time profiles and may be 
omitted from the model building (Section 4.4.2).
In addition, the exploratory graphical analysis of every quantitative covariate will consist of a 
histogram, box plots and plots of quartiles of covariate distributions and quantiles of standard 
normal distribution (QQ plot). Summary statistics of each quantitative covariate by study will be 
provided. Moreover, correlations between quantitative covariates and boxplots for every 
quantitative covariate against every categorical covariate will be explored.
4.4.
Population PK Model Development
4.4.1.
External Evaluation of the Preliminary Updated Population PK Model
An external model evaluation will be performed to assess the predictive performance of the 
preliminary updated population PK model for the current analysis dataset. For this purpose, the 
following diagnostics will be used:

Visual Predictive Check (VPC) and Prediction Corrected Visual Predictive Check 
(pcVPC). The VPC will be performed to provide visual comparison between distributions 
of simulated data using the previously developed model with the analysis dataset. The 
pcVPCs differs from traditional VPC in that the dependent variable has been subjected to 
a prediction correction before the statistics are calculated. Prediction correction aims to 
correct for the differences within a bin coming from different independent variables in the 
model and hence, clearly diagnose model misspecifications in both fixed and random 
effects. In the VPC, the 5th, 50th, and 95th percentiles of the observed data will be 
compared with the model-based predicted percentiles for each bin across time and 
replicates. A total of 1,000 replicates of the analysis dataset will be generated from the 
preliminary population PK model. Uncertainty in parameters estimates will not be 
considered in this analysis.


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
Goodness-of-fit (GoF) plots: A maximum a posteriori (MAP) estimation using the 
preliminary population model as prior information will be used to estimate the individual 
population PK model parameters for subjects included in Study 67953964MDD2001. This
analysis will be conducted using the MAXEVAL=0 option in NONMEM. The following 
goodness-of-fit plots will be generated in order to assess the deviation of population and 
individual predictions from the observed data:
o
Observations vs population predictions (PRED);
o
Conditional weighted residuals vs PRED and vs time since last dose;
o
Observations vs individual predictions (IPRED);
o
Individual weighted residuals vs IPRED and vs time since last dose;

Numerical Predictive Check (NPC). The NPC will be performed on the mean and the 
standard deviation (SD) of the exposure metrics (AUC24h and C0h), since these reflect the 
central tendency and the variability of the exposure metrics. Within each replicate, the 
mean and SD of the exposure metrics to be used in the ER analysis will be computed. 
The model-based distribution of the mean and SD of the exposure metrics across 
replicates will be obtained and its 2.5th and 97.5th percentile will be used to calculate the 
lower and upper limit of the 95% confidence interval (CI) of the model-based predicted 
mean and SD of the exposure metrics, which will be then compared to the actual metric 
of exposure obtained from the Study 67953964MDD2001. Based on the parameter 
estimates of the previously developed model, 1000 replicates of the analysis dataset will 
be simulated.
Adequacy of the model will be assessed by the ability of the model to capture the central tendency 
and the variability of the data (as attested by the VPC/pcVPC plots) and to provide population and 
individual predictions without significant bias (confirmed by the GoF plots).
If the external evaluation is unsuccessful, potential refinements of the preliminary population PK 
model (e.g. modifications of the model structure, re-estimation of population parameters, addition 
of study-specific factors, etc) will be evaluated in order to adequately describe the data from Study 
67953964MDD2001 and the three Phase 1 studies, LAF-A, LAF-B and LAF-C. If a model update 
is performed, the criteria described in Section 4.9 may be used to compare different candidate 
models.
4.4.2.
Identification of Outliers
An outlier is defined as an aberrant observation that significantly deviates from the rest of the 
observations in a particular subject or as a subject when all observations for that subject are 
aberrant. Outliers may be excluded from the analysis as they are known to have negative impact 
on the convergence and/or introduce bias in parameter estimates. The outlier detection in the full 
PK profiles will be based primarily on visual examination of individual and pooled concentration-
time profiles. Data points will be considered as potential outliers if they substantially deviate from 
adjacent points in the concentration-time profiles and if their conditional weighted residual is large, 


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eg, greater than +/- 6 units. Only the observations that meet both criteria will be identified as 
outliers. The observations will be excluded from the analysis by flagging them with “C” in the 
NONMEM dataset. In a subsequent step, it may be investigated if the outliers influence the 
population and individual population PK model parameter estimates.
4.4.3.
Covariate Analysis
The model described above (i.e. previously developed preliminary PK model or updated PK 
model) may constitute the base model for covariate model development. The basis of the covariate 
model should be the clinical significance of the covariate effects rather than their statistical 
significance. The model building will consist of a number of steps based on the guidance by 
various regulatory authorities1,2,16;
1.
A list of covariate/parameter pairs that are physiologically plausible are selected from 
exploratory plots of EBE vs covariates and based on generalized additive models (GAM)6 on 
the regression between each EBE and the covariates. Only covariates that are statistically 
significant (p < 0.001) with model parameters will be considered as potentially clinically 
relevant and will be further evaluated. Covariates will include gender, race, age, body weight, 
albumin and creatine clearance at baseline. If a candidate covariate can be represented as either 
a categorical or continuous covariate, the continuous covariate is usually preferred.
2.
Trim the list using the following criteria:
a.
When two or more covariates have correlation greater than 0.3 the most physiologically 
plausible should be retained and the others discarded because retaining them gives rise to 
the co-linearity problem.
b.
Remove covariates having insufficient sample sizes, ie, represented by less than 
20 subjects per parameter.20,21
c.
Overall number of subjects vs. number of covariate evaluations (number of covariate 
parameters) ≥ 10.19
3.
Fit the full model.20,21 If the full model does not converge, then the forward stepwise selection 
method can be taken based on a p-value < 0.01.
4.
The full covariate model from step 3 may be reduced based on the point estimates of the 
magnitude of the effect of the covariate on the PK parameter using a clinically meaningful
threshold (if available), to obtain the final covariate model. If deemed necessary, this step may 
be preceded by backward elimination using a more stringent nominal p-value of 0.001.
5.
A diagnostic plot should be made. It is useful to generate a forest plot7 or equivalent for the 
final covariate model to assist identification of clinically relevant covariates. Statistical tests 
on empirical Bayes' estimates (EBE's) are preferred over exploratory plots of EBE’s versus 
the covariates if the shrinkage is large (eg, >35%).17,18
A discussion of the physiological plausibility and clinical relevance of the final covariate model 
may be included in the discussion section of the report. We must take into consideration that the 
model is based on an association between the PK parameters and the covariates which can only be 
interpreted as causative if there are good scientific reasons for doing so.


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4.4.4.
Refining the Covariance Structure
Correlation between PK parameters may be tested after all significant fixed covariate effects have 
been included in the model. The individual ETAs will be examined graphically by plotting each 
ETA against all others. If visual inspection of plots reveals any correlation, the corresponding 
block may be introduced into the OMEGA matrix to test its significance using the likelihood ratio 
test. If implementing a correlation significantly improves the fit, the block will be kept in the 
model. The process will be repeated until no further improvement of the fit can be achieved. A
model with a full block of correlations between random effects will be used as a reference to 
determine the maximum possible improvement by optimizing covariance structure.
4.5.
Determination of Individual Population PK Parameter Estimates
The individual population PK parameter estimates of AUC0-24h, Cmax and the pre-dose 
JNJ-67953964 plasma concentration (C0h) will be calculated for each subject at each visit either 
by fixing the population parameters of the full covariate population PK model. 
Correlation between population PK parameters will be assessed. 
4.6.
MADRS and SHAPS PK/PD Modelling
Exploratory plots of individual AUC0-24h versus MADRS and SHAPS total score, both absolute 
and change from baseline, stratified by lead-in placebo-response and by visit will be created. The 
exposure-response analysis will only be performed for the efficacy endpoints if the exploratory 
analysis shows a relationship in exposure-efficacy.
The MADRS and SHAPS total score data will be modelled using specific parameters for baseline 
response, placebo effect, and drug effect, according to the following general equation:
 = (	

 + 	 + 	 + 	 + 	 + ) + ,  + 
where yij represents the change from baseline MADRS or SHAPS total score for the i-th subject at 
the j-th time point (j=1..5 for the 5 post-baseline visits in Week 1, 3, 4, 5 and 6), θ1-5 represent the 
fixed effects for the placebo response at the post-baseline visits, i.e. j=1..5 (with v1-5 denoting 
indicator variables with value 1 when j is equal to Treatment Week 1, 3, 4, 5 and 6),  i represents 
the random effect parameter for non-drug-related response, fi(vj, Ci) representing the 
concentration-effect relationship for JNJ-67953964 in the i-th subject at the post-baseline visits, 
i.e. j=1..5 as a function of the exposure metric Ci, and ij represents the residual variability 
associated to measurement yij. Baseline is defined as treatment baseline, i.e. last observation before 
the first dose.
The inter-individual variability (IIV) random effect i, and any random effect within fi will be 
assumed to be normally-distributed, zero-mean, uncorrelated random variables. The residual 
variability random effects ij will be assumed to be normally-distributed, zero mean, uncorrelated 
random variables that are also uncorrelated with respect to i, and any random effect within fi. 
Alternative distributions for the IIV and the residual variability random effects may be considered 
if needed. If warranted by the data, parametric functions of time (e.g. linear, exponential) may be 
used to describe the placebo effect.
The exposure metrics to be used in the PK/PD model will be AUC24h (see Section 4.5). Additional 
exposure metrics may be tested if the R2 of the correlation between PK parameters is less than 0.8.


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In case of C0h, observed pre-dose exposure may be used as an alternative to the model-estimated 
C0h.
The drug effect sub-model may be parametrized as a linear, or if the exposure range allows, Emax, 
sigmoid Emax, or exponential function, as determined by model building criteria (Section 4.9). In 
case a delay in onset of drug effect will be observed during the exploratory analysis, the delay will 
be fit using an appropriate delay function, such as a sigmoid13. Additional functional forms of the 
drug effect sub-models may be tested. Baseline MADRS or SHAPS will be tested as covariate on 
both drug-related and drug-non-related response in order to assess the potential influence of 
higher/lower baseline disease severity on MADRS and SHAPS change. Gender, race, and age at 
baseline will also be tested. Lead-in placebo response will be tested as covariate on models based 
on the full dataset for change from baseline MADRS scores. Lead-in placebo response will not be 
tested as covariate for change from baseline SHAPS models, as no effect was observed on SHAPS 
during the lead-in period based on blinded data. Additional parameter-covariate relationships may 
be tested if required.
Primary analysis on MADRS will be performed on the enriched population (lead-in non-
responders). In case no effect on MADRS is found, change from baseline SHAPS total scores will 
be analyzed on the full dataset. If appropriate, the analysis on MADRS may be repeated on the full 
dataset, where both lead-in placebo response as well as baseline SHAPS total score will be tested 
as covariate in the model.
Change from baseline MADRS or SHAPS total scores obtained during the withdrawal period 
(Day 78) may be explored and included in the model as function of exposure if deemed 
appropriate.
4.7.
Simulations
Based on the final PK/PD model (including covariates, if any), model-based simulations of placebo 
corrected change from baseline in MADRS/SHAPS will be generated. The following simulations 
will be performed:
a) Population distribution of the MADRS and SHAPS change from baseline and of the drug effect 
on MADRS and SHAPS at Week 6 vs AUC;
b) Probability to achieve a drug effect on MADRS and SHAPS of at least 1, 2, or 3 points drop 
at Week 6 in the population;
c) Point estimate and 90% confidence interval (CI) for the MADRS and SHAPS change from 
baseline and for the drug effect on MADRS and SHAPS at Week 6 vs AUC for the population 
studied;
d) Model-based MADRS and SHAPS change from baseline vs time by lead-in placebo-response.
Simulations (a), (b) and (d) will be performed using 10,000 subjects per dose level in order to 
adequately reflect PK and PD variability in a large population. For this purpose, interindividual 
variability in PK and in PD parameters, as well as residual variability in MADRS and SHAPS, 
will be included in the simulations. Uncertainty of model parameter estimates will not be included.
Simulations will be performed at the 10 mg qd dose level. Other dosing regimen may be included 
if deemed appropriate. The simulations will be summarized as median, 5th and 95th percentiles of 
the population. Simulations (a), (b) and (c) may be repeated for additional treatment days of 


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interest. When appropriate, simulations will be performed in sub-populations based on specific 
selection criteria, such as lead-in-placebo-response or baseline SHAPS scores.
4.8.
Exploration of Exposure - Safety Parameters 
Based on the clinical relevance, the AE data for gastrointestinal disorders will be dichotomized 
into presence or absence of an AE grade ≥ 3 at any visit postdose up to the last treatment day, 
while for pruritus and specific subclasses of gastrointestinal AE’s (e.g. diarrhea, constipation, 
abdominal pain) dichotomization will be based on any occurrence at any visit postdose up to the 
last treatment day (Day 22 to Day 64). JNJ-67953964 exposure metrics will be classified into 3 or 
4 categories dependent on the number of subjects per quantile. Similarly, an additional category 
will be included for the placebo-randomized subjects; in this case the exposure metrics will be 
assigned to a value of zero. Exploratory bar plots of number of subjects with an AE versus exposure 
groups will be generated for the AE’s of interest pruritis and GI complaints. If appropriate 
additional plots may be generated for other AE’s with at least one observation of grade 3 or higher.
If appropriate, a logistic regression may be used to describe the relationship between exposure and 
the occurrence of an AE. The exposure metrics to be used in the PK-safety evaluation will be Cmax
(see Section 4.5). Additional exposure metrics may be tested if the R2 of the correlation between 
PK parameters is less than 0.8.
4.9.
Model Evaluation/Qualification
Model evaluation/qualification assesses the extent of any mismatch between the model and the 
data that it is describing. The exact procedures employed depend on the data and models and can 
therefore not be prescribed.
The following plots may be examined to assess model evaluation/qualification:

Plots with predicted versus observed values of the response variable(s);

Plots with predicted values superimposed on plots of the data;

Various plots of residuals;

Plots of random effects versus covariates;

Visual or/and numerical predictive checks (VPC or/and NPC);

Other plots may be examined as required.
4.9.1.
Statistical Considerations in Case of Model Update
The principle of parsimony will be applied, meaning that the simplest model that adequately fulfils 
the analysis objective will be preferred. The statistical criteria described below will be used to 
compare different candidate models by NONMEM: 


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
To accommodate for multiple comparisons testing, inherent in population PK model 
development, a 6 points reduction of the objective function value for one additional parameter 
(either structural or random) in nested models, theoretically coinciding with P ≤ 0.01 in a Chi-
square (χ²) test, will be deemed significant during model development. 

For non-nested models, the appropriate Akaike’s Information Criterion (AIC) or alternative 
model selection criteria such as the Bayesian Information Criterion (BIC) may be used.4
The statistical criteria outlined below will be used for model assessment

The standard error of a structural parameter estimates reported by NONMEM should 
preferably be less than 50% of the estimated parameter value. This would imply that zero is 
excluded from the 95% CI of the parameter estimate, assuming normality.

The correlation between parameter estimates (structural and stochastic) reported by 
NONMEM in the correlation matrix of the model output, should lie between -0.95 and 0.95

The values estimated for η should be adequately centered around zero (reported p-value in the 
NONMEM output file should be larger than 0.05).

Shrinkage of the random effects should preferably be below 30% (η-shrinkage and 
ε-shrinkage).14
4.10.
Computer Software
Plasma concentration-time data will be used for non-linear mixed effect modeling using 
NONMEM (ICON plc).11 The first-order conditional estimation method (FOCE) estimation 
method will be used. The INTERACTION option will be used when appropriate. However, other 
estimation methods available in NONMEM may be used if deemed necessary. The NONMEM 
analysis is performed in a validated environment, the High Performance Pharmacometric Platform 
(HP3) based on Good Automated Manufacturing Practice (GAMP) and in accordance with 21 CFR 
Part 11 and Good Clinical Practice (GCP) regulations.
Post-processing of the NONMEM analysis results will be carried out in R (Version 3.3.1 or 
higher)12 or any other validated software.
4.11.
Report
A final report will be prepared in accordance with the FDA and EU guidances1,2 on population PK 
using the internal Janssen R&D report template. The final analysis report should always be 
reviewed according to the Overarching PM SOP and the internal Janssen R&D QC templates for 
analysis and report.
Per the internal Janssen R&D Job Aid for e-Submission, Janssen R&D will provide the NONMEM 
datasets in .xpt format. Janssen R&D will supply the NONMEM control streams and outputs in 
.pdf format.


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Wade JR, Edholm M, Salmonson T. A guide for reporting the results of population pharmacokinetic analyses: 
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Xu S, Yuan M, Zhu H, Yang Y, Wang H, Zhou H, Xu J, Zhang L, Pinheiro J, Full Covariate Modeling 
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