Clinical trial NCT02498392
Conditions: Depressive Disorder Anxiety
Keywords: Major Depressive Disorder Depression Anxiety symptoms JNJ-42165279
Sponsor: Janssen Research & Development, LLC
Start date: 2015-10-07; Completion date: 2019-02-04
Enrollment: 161 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety and tolerability of JNJ-42165279 in participants with major depressive disorder (MDD) with anxiety symptoms who have had inadequate response to treatment with a selective serotonin reuptake inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI).

Detailed description:
This is a multicenter, double-blind (neither physician nor participant knows the treatment that the participant receives), placebo-controlled, randomized, parallel-group study in participants with Major Depressive Disorder (MDD) with Anxious Distress. Participants who had treatment initiated with a SSRI/SNRI allowed by the protocol will be evaluated at the investigation site. The site assessment will be reviewed and validated by an independent central rater. The review will include 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 Hamilton Depression Rating Scale (HDRS17). Enrolled participants will be maintained on SSRI/SNRI treatment throughout the study to determine whether additional treatment with JNJ-4216579 can reduce the symptoms of MDD with anxious distress.The study will consist of 3 phases: a Screening Phase of up to 4 weeks, an 11-week double-blind Treatment Phase, and a 3-week post-treatment (follow up) Phase. The double-blind treatment Phase of the trial will consist of 3 periods. The first period is a placebo lead-in of double-blind duration, after which participants will enter the treatment period when they will be randomly assigned to JNJ-42165279 or continuation on placebo for 6 weeks. Participants who successfully complete the treatment period prior to the end of Week 11, will be treated with placebo for the remaining time of the double-blind phase of the study, which will vary depending on the duration of the placebo lead-in for the specific participant. The total study duration for each participant will be approximately 18 weeks. Efficacy and safety of JNJ-42165279 will be evaluated. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants who responded in the placebo lead-in period will be administered with Matching Placebo orally. arm 2: Participants who responded in the placebo lead-in period will be administered with JNJ-42165279 orally at a dose of 25 milligrams (mg) tablets once daily for 6 weeks. arm 3: Participants who did not respond in the placebo lead-in period will be administered with Matching Placebo orally. arm 4: Participants who did not respond in the placebo lead-in period will be administered with JNJ-42165279 orally at a dose of 25 mg tablets once daily for 6 weeks.
Interventions: intervention 1: JNJ-42165279 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-42165279 will be administered orally at a dose of 25 milligrams (mg) tablet once daily for 6 weeks. intervention 2: Matching Placebo will be administered orally.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 24 October 2017
Janssen Research & Development *
Clinical Protocol
A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center 
Study Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Subjects with 
Major Depressive Disorder with Anxious Distress.
Protocol 42165279MDD2001; Phase 2a
Amendment INT-5
JNJ-42165279  
*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 Pharmaceutica NV; Janssen Biotech, Inc.; Janssen 
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious 
Diseases BVBA; 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:    2015-002007-29
     
Status:
Approved
Date:
24 October 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica N.V.  
EDMS number: EDMS-ERI-104283605, 7.0
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.
NCT02498392


JNJ-42165279
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Approved, Date: 24 October 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 13
TIME AND EVENTS SCHEDULE .............................................................................................................. 21
ABBREVIATIONS ...................................................................................................................................... 24
1.
INTRODUCTION................................................................................................................................ 26
1.1.
Background .................................................................................................................................... 26
1.2.
Overall Rationale for the Study...................................................................................................... 32
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 32
2.1.
Objectives ...................................................................................................................................... 32
2.2.
Hypothesis ..................................................................................................................................... 33
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 33
3.1.
Overview of Study Design.............................................................................................................. 33
3.2.
Study Design Rationale.................................................................................................................. 36
3.3.
Stopping Criteria ............................................................................................................................ 43
3.3.1.
Individual Stopping Criteria......................................................................................................... 43
3.3.2.
Protocol Stopping Criteria........................................................................................................... 43
4.
SUBJECT POPULATION.................................................................................................................. 43
4.1.
Inclusion Criteria ............................................................................................................................ 44
4.2.
Exclusion Criteria ........................................................................................................................... 46
4.3.
Prohibitions and Restrictions ......................................................................................................... 49
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 50
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 51
7.
TREATMENT COMPLIANCE............................................................................................................ 51
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 52
9.
STUDY EVALUATIONS .................................................................................................................... 53
9.1.
Study Procedures........................................................................................................................... 53
9.1.1.
Overview..................................................................................................................................... 53
9.1.2.
Screening Phase ........................................................................................................................ 54
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 55
9.1.4.
Posttreatment Phase (Follow Up)............................................................................................... 62
9.2.
Safety Evaluations ......................................................................................................................... 63
9.2.1.
Adverse Events........................................................................................................................... 63
9.2.2.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 63
9.2.3.
Vital Signs................................................................................................................................... 64
9.2.4.
Electrocardiogram....................................................................................................................... 64
9.2.5.
Physical and Neurological Examinations.................................................................................... 64
9.2.6.
Clinical Laboratory Tests ............................................................................................................ 64
9.3.
Efficacy........................................................................................................................................... 66
9.3.1.
Evaluations ................................................................................................................................. 66
9.3.2.
Endpoints.................................................................................................................................... 67
9.4.
Pharmacokinetics........................................................................................................................... 68


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9.4.1.
Evaluations ................................................................................................................................. 68
9.4.2.
Analytical Procedures................................................................................................................. 68
9.4.3.
Pharmacokinetic Parameters ..................................................................................................... 68
9.5.
Biomarker and Pharmacogenomic Evaluations............................................................................. 69
9.6.
Sample Collection and Handling.................................................................................................... 69
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 70
10.1.
Completion ..................................................................................................................................... 70
10.2.
Discontinuation of Study Treatment............................................................................................... 70
10.3.
Withdrawal from the Study............................................................................................................. 70
11.
STATISTICAL METHODS................................................................................................................. 71
11.1.
Sample Size Determination ........................................................................................................... 71
11.2.
Efficacy Analysis ............................................................................................................................ 72
11.3.
Safety Analysis............................................................................................................................... 73
11.4.
Interim Analysis.............................................................................................................................. 74
11.5.
Biomarker Analysis ........................................................................................................................ 74
11.6.
Pharmacogenomic Analyses ......................................................................................................... 74
11.7.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis ............................................ 75
11.8.
Data Review Committee (DRC)..................................................................................................... 75
12.
ADVERSE EVENT REPORTING ...................................................................................................... 75
12.1.
Definitions ...................................................................................................................................... 75
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 75
12.1.2.
Attribution Definitions.................................................................................................................. 76
12.1.3.
Severity Criteria .......................................................................................................................... 77
12.2.
Special Reporting Situations.......................................................................................................... 77
12.3.
Procedures..................................................................................................................................... 78
12.3.1.
All Adverse Events...................................................................................................................... 78
12.3.2.
Serious Adverse Events ............................................................................................................. 79
12.3.3.
Pregnancy................................................................................................................................... 80
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 80
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 80
13.1.
Procedures..................................................................................................................................... 80
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 80
14.
STUDY DRUG INFORMATION......................................................................................................... 80
14.1.
Physical Description of Study Drug(s) ........................................................................................... 80
14.2.
Packaging ...................................................................................................................................... 81
14.3.
Labeling.......................................................................................................................................... 81
14.4.
Preparation, Handling, and Storage............................................................................................... 81
14.5.
Drug Accountability ........................................................................................................................ 81
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 82
16.
ETHICAL ASPECTS ......................................................................................................................... 82
16.1.
Study-Specific Design Considerations........................................................................................... 82
16.2.
Regulatory Ethics Compliance....................................................................................................... 83
16.2.1.
Investigator Responsibilities ....................................................................................................... 83
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 83
16.2.3.
Informed Consent ....................................................................................................................... 84
16.2.4.
Privacy of Personal Data ............................................................................................................ 85
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 86
16.2.6.
Country Selection ....................................................................................................................... 86
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 86
17.1.
Protocol Amendments.................................................................................................................... 86
17.2.
Regulatory Documentation ............................................................................................................ 87


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17.2.1.
Regulatory Approval/Notification ................................................................................................ 87
17.2.2.
Required Prestudy Documentation............................................................................................. 87
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 88
17.4.
Source Documentation................................................................................................................... 88
17.5.
Case Report Form Completion ...................................................................................................... 88
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 89
17.7.
Record Retention ........................................................................................................................... 90
17.8.
Monitoring ...................................................................................................................................... 90
17.9.
Study Completion/Termination....................................................................................................... 91
17.9.1.
Study Completion ....................................................................................................................... 91
17.9.2.
Study Termination....................................................................................................................... 91
17.10.
On-Site Audits ................................................................................................................................ 91
17.11.
Use of Information and Publication................................................................................................ 91
REFERENCES............................................................................................................................................ 94
ATTACHMENTS......................................................................................................................................... 95
Attachment 1:
17-Item Hamilton Depression Rating Scale (HDRS17) ................................................. 95
Attachment 2:
Clinical Global Impression – Improvement (CGI-I)........................................................ 96
Attachment 3:
Clinically Useful Depression Outcome Scale (CUDOS-A) ............................................ 97
Attachment 4:
Cognitive and Physical Functioning Questionnaire (CPFQ).......................................... 98
Attachment 5:
Medical Outcomes Study (MOS) - 12-Item Sleep Scale Acute - Revised..................... 99
Attachment 6:
Perceived Stress Scale (PSS) ..................................................................................... 101
Attachment 7:
Snaith-Hamilton Pleasure Scale (SHAPS) .................................................................. 102
Attachment 8:
Self-Assessment of Treatment Experience ................................................................. 104
Attachment 9:
Columbia Suicide Severity Rating Scale – BASELINE................................................ 105
Attachment 10:
Columbia Suicide Severity Rating Scale – Since Last Visit......................................... 107
Attachment 11:
Anticipated Events ....................................................................................................... 109
Attachment 12:
Prohibited Cytochrome P450 Inhibitors and Inducers ................................................. 110
INVESTIGATOR AGREEMENT ............................................................................................................... 111
LAST PAGE.............................................................................................................................................. 111
LIST OF ATTACHMENTS
Attachment 1:
17-Item Hamilton Depression Rating Scale (HDRS17).............................................. 95
Attachment 2:
Clinical Global Impression – Improvement (CGI-I)..................................................... 96
Attachment 3:
Clinically Useful Depression Outcome Scale (CUDOS-A)......................................... 97
Attachment 4:
Cognitive and Physical Functioning Questionnaire (CPFQ) ...................................... 98
Attachment 5:
Medical Outcomes Study (MOS) - 12-Item Sleep Scale Acute - Revised ................. 99
Attachment 6:
Perceived Stress Scale (PSS).................................................................................. 101
Attachment 7:
Snaith-Hamilton Pleasure Scale (SHAPS)............................................................... 102
Attachment 8:
Self-Assessment of Treatment Experience.............................................................. 104
Attachment 9:
Columbia Suicide Severity Rating Scale – BASELINE ............................................ 105
Attachment 10:
Columbia Suicide Severity Rating Scale – Since Last Visit ..................................... 107
Attachment 11:
Anticipated Events.................................................................................................... 109
Attachment 12:
Prohibited Cytochrome P450 Inhibitors and Inducers.............................................. 110


JNJ-42165279
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Approved, Date: 24 October 2017
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
12 Jun 2015
Amendment INT-1
31 Aug 2015
Amendment INT-2
Amendment INT-3
Amendment INT-4
Amendment INT-5
03 July 2017
13 July 2017
25 August 2017
24 October 2017
Amendments below are listed beginning with the most recent amendment.
Amendment INT-5 (24 October 2017)
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.  
The overall reason for the amendment:

On regulator’s request, subjects with abnormal high liver function analytes will not be allowed in the 
study.

An exclusion criterion for breast feeding women was missing.

On request of investigators: Venlafaxine (immediate release) added to the list of allowed antidepressant 
drugs.

On request of investigators: added instructions on the use of PRN non-benzodiazepine sleep aids.

Added: more specific instructions of the calculation of QTc interval to determine stopping or exclusion 
criteria.
Applicable Section(s)
Description of Change(s)
Section 3.3.1
Individual stopping 
criteria
Section 4.2
Exclusion criteria
Changed:
QTc interval is higher than 500 msec
Into
QTc interval (QTcF; QTcB if ECG machine only shows QTcB) is higher than 500 msec
Exclusion criterion 9
Changed:
…such as QTc >450 msec…
Into
…such as QTcF (QTcB if ECG machine only shows QTcB) >450 msec…
Exclusion criterion 10
Changed: 
Subject has a history of or current liver or renal insufficiency; clinically significant 
cardiac, vascular, pulmonary, gastrointestinal, endocrine, hematologic, rheumatologic, 
psychiatric, or metabolic disturbances (e.g. unstable situation needing monitoring or 
regular dose adaptations).  Subjects with liver function analytes higher than the upper 
limit of normal at screening need to be reviewed with the sponsor for acceptability prior 
to enrollment.  
into
Subject has a history of or current liver or renal insufficiency; clinically significant 
cardiac, vascular, pulmonary, gastrointestinal, endocrine, hematologic, rheumatologic, 
psychiatric, or metabolic disturbances (e.g. unstable situation needing monitoring or 
regular dose adaptations). Subjects with renal or liver function analytes significantly 


JNJ-42165279
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Approved, Date: 24 October 2017
higher (more than 1.5 times the upper limit of normal) at screening are not eligible 
for the study.
Exclusion criterion 19
Changed:
Subject is a man who plans to conceive a child, while enrolled in this study or within 3 
months after the last dose of study.
into
Subject is a woman who is pregnant, or breast-feeding, or planning to become 
pregnant or is a man who plans to father a child, while enrolled in this study or 
within 3 months after the last dose of study.
Section 8,
Prestudy and 
concomitant 
medication
Added to list of allowed antidepressant medication: venlafaxine.
Changed:
Note: Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon and eszopiclone) are 
allowed on a PRN (as needed) basis during the study.
into
Note: Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon and eszopiclone) are 
allowed on a PRN (as needed) basis during the study, however, not more than 2 nights in 
a row and not more than a total of 3 nights weekly during the double-blind treatment 
period.
Amendment INT-4 (25 August 2017)
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.  
The overall reason for the amendment:

Based on a regulatory decision, to allow women of childbearing potential to participate in this study 
under conditions of pregnancy testing and the use of high quality contraception.

Add the optional use of a diary or electronic device to document the intake of study medication.
Applicable Section(s)
Description of Change(s)
Synopsis
Safety Evaluations
Added: 
In all women, serum and urine pregnancy test will be performed at Screening and at 
Visit 10. In women of childbearing potential (WOCBP), urine pregnancy test will be 
performed at all other timepoints. If the urine pregnancy test is positive, a serum β-hcg test 
will be performed.
Time & Events 
schedule
Added: pregnancy test for WOCBP at each visit.
Added: Footnote t: Urine pregnancy test In WOCBP only. If the urine pregnancy test is 
positive, a serum β-hcg test will be performed. Investigators may perform additional 
pregnancy testing at their discretion as clinically needed.
Changed: footnote k. Performed for all women. Serum and urine pregnancy test performed 
at Screening, urine pregnancy test at other time points, If the urine pregnancy test is 
positive, a serum β hcg test will be performed. Investigators may perform additional 
pregnancy testing at their discretion as clinically needed.


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Approved, Date: 24 October 2017
Section 3.2.
Population
Added:
Given the observation in the rat reproductive toxicology studies (see Section 1.1), WOCBP 
will only be included if they agree to ongoing use of a highly effective method of birth 
control (i.e. one that results in a less than 1% per year failure rate when used consistently 
and correctly). All WOCBP will have a pregnancy test at screening and each study visit 
during the double-blind phase. WOCBP constitute a large part of the target population in 
clinical practice. Safety and efficacy data in this population are important for future 
clinical studies.”
Removed: (of non-child bearing potential)
Section 4.1 
Inclusion criteria
Inclusion criteria 6 and 7 will be replaced by:
6.1. Before randomization, a woman must be either:

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 >40 IU/L); permanently sterilized (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy); or 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 (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.  

All women must have a negative pregnancy test at screening and a negative urine 
pregnancy test on study day 1.

All women 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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Approved, Date: 24 October 2017
7.1.
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 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.
Section 9.1.3
Added: urine pregnancy test at visits 2 to 9 for WOCBP and serum pregnancy test at 
Visit 10 for all women.
Section 9.2.6
Changed text on pregnancy test:

In all women: serum β-HCG and urine pregnancy test will be performed at Screening 
and at study visit 10. 

In WOCBP: serum β-HCG and urine pregnancy test will be performed at all other 
timepoints. 

If the urine pregnancy test is positive, a serum β-HCG test will be performed.
Rationale: Add the optional use of a diary or electronic device to document the intake of study medication.
Synopsis and 
Section 6 
Added: The sponsor may optionally develop tools to improve and/or document 
compliance to intake of study medication when locally feasible. This may include a diary 
or an electronic registration tool.
Amendment INT-3 (13 July 2017)
This amendment is considered to be non-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.  
The overall reason for the amendment:

Correction of wordings and inconsistencies.
Applicable Section(s)
Description of Change(s)
4.1
Time & Events 
schedule
Inclusion criterion 6: Replaced “Menstrual” by “Childbearing age”
Footnote b: replace “7 to 28 days” into “7 to 21 days”
Amendment INT-2 (03 July 2017)
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.  
The overall reason for the amendment:

To update the information on toxicology

Adaptation of the number of subjects participating in the study. This will be changed from 140 to 143 to 
replace 3 subjects who had to stop early when the study was put on hold.

To add neurological examinations to confirm the safety of participation in the trial and treatment with 
JNJ-42165279.

Change in allowed medication and control of drug intake.


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Approved, Date: 24 October 2017
Applicable Section(s)
Description of Change(s)
Rationale: To update the information on toxicology
Section 1.1
Text on 
 and 
 
added to reflect recent non-clinical study results.
Applicable Section(s)
Description of Change(s)
Rationale: Adaptation of the number of subjects participating in the study. This will be changed from 140 to 143
to replace 3 subjects who had to stop early when the study was put on hold
Synopsis and Sections 3.1 and 4.0 
Changed 140 subjects participating in this study into 143
subjects.
Synopsis and Section 11.1
Added sentence: To replace 3 subjects who prematurely 
stopped the study when the study was put on hold, the 
total number of subjects entering the study will be 
increased from approximately 140 to 143.
Rationale:
•
Better clarify that administration of study medication at the site needs to be witnessed by study site personnel.
•
Add melatonine and ramelteon as prohibited medication.
Section 6
Added in last paragraph:  ..which will be witnessed by 
designated study-site personnel at the study sites.
Section 9.1.3
Replaced:
Study medication will be self-administered on site as 
outlined in Section 6, Dosage and Administration. 
by:
Study medication will be self-administered on site as 
outlined in Section 6, Dosage and Administration, which 
will be witnessed by designated study-site personnel at 
the study sites.
Section 8
Replace 
Note: 
Nonbenzodiazepines 
sleep 
aids
(including: 
zolpidem, zaleplon, eszopiclone and ramelteon) are 
allowed on a PRN (as needed) basis during the study. 
With 
Note: 
Nonbenzodiazepines 
sleep 
aids 
(including: 
zolpidem, zaleplon and eszopiclone) are allowed on a 
PRN (as needed) basis during the study.
Added to list of “Other prohibited medication”:
- melatonine and ramelteon.
CCI
CCI


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Approved, Date: 24 October 2017
Applicable Section(s)
Description of Change(s)
Rationale:
To add neurological examinations to confirm the safety of participation in the trial and treatment with 
JNJ-42165279.
Applicable Section(s)
Description of Change(s)
Synopsis and 3.1 Overview of Study Design      
Synopsis
Screening
Screening will include obtaining informed consent,
assessment of study inclusion and exclusion criteria, 
medical history, physical examination, neurological 
examination and safety evaluations.
Safety Evaluations: Physical examination, neurological 
examination, vital signs, body temperature … …will be 
performed during the study to monitor subject safety.
Time & Events schedule.
-
Neurological examination added at screening, during 
the treatment phase and at the end of treatment visit
(or early withdrawal visit)
-
Footnote “s” added: A neurological examination will 
also be completed in case of adverse event of 
interest.
4.2 Exclusion criteria
9.1.2 Screening Phase
9.1.3 Double-Blind Treatment Phase
9.2.5 Physical and Neurological Examinations
11.3 Safety Analysis
12.2 Special Reporting Situations
Exclusion criteria 8 has been updated as follows:
8.1 Subject has clinically significant abnormal findings 
on physical examination, neurological examination or 
clinically significant abnormal vital signs indicative of 
untreated illness (such as infection or hypertension).
Neurological examination added
Neurological examination added at Week 5, Week 9 and 
Week 11 visits
Title updated and text added:
The neurological examination can be adapted as 
necessary but should include mental status (orientation 
and memory); oculomotor motion and vision for cranial 
nerve testing; limb strength and abnormal movements 
for motor function; and tests of cerebellar function: gait, 
finger-to-nose, heel-to-shin, and rapid alternating 
movements. Tests of sensation (e.g., pain, vibration) 
should be included only if indicated by clinical 
history/symptoms.
The neurological examination will be done at screening, 
during the treatment phase and at the end of treatment 
visit (or early withdrawal visit) for all subjects. In 
addition, neurological examinations will be completed 
when event driven. These events of interest include 
diplopia, vision impairment, gait disturbance and severe 
headache.


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Applicable Section(s)
Description of Change(s)
Sub title updated as follows: Physical and Neurological
Examinations.
Text added:
For this study safety events of interest include diplopia, 
vision impairment, gait disturbance and severe headache. 
These events will trigger a neurological examination and 
a narrative of the event.
Amendment INT-1 (31 Aug 2015)
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.  
The overall reason for the amendment: The overall reason for the amendment is to clarify the updated procedure 
performed by an independent central rater and to address FDA comments.
Applicable Section(s)
Description of Change(s)
Rationale: Updated procedure performed by an independent central rater at screening
Synopsis – Overview 
of Study Design –
Time & Events 
schedule.
3.1. Overview of 
Study Design
3.2. Study Design 
Rationale
9.1.2. Screening
Description of the updated procedure performed by an independent central rater at 
screening
Rationale: Clarification of the duration of the ongoing SSRI/SNRI antidepressant treatment and clarification of the 
procedures performed by an independent central rater at screening
Synopsis – Overview 
of Study Design
Synopsis – Overview 
of Study Design   
4.1. Inclusion 
Criteria.
Maximal duration of “no longer than 14 weeks” with their current antidepressant has been 
deleted to allow more flexibility.
Inclusion criteria 2, 3 and 4 updated


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Approved, Date: 24 October 2017
Rationale: Addition of vilazodone to the list of the allowed antidepressants as requested by FDA
Synopsis – Overview       Vilazodone added to the list of the allowed antidepressants
of Study Design –
3.1. Overview of 
Study Design
8. Prestudy and 
Concomitant Therapy
Rationale: Clarification of exclusion criteria # 19
4.2. Exclusion criteria
“father a child” replaced by “conceive a child”
Rationale: Administrative: correction content of Attachment 6 : Perceived Stress Scale (PSS)
Attachment 6
CPFQ questionnaire deleted


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Approved, Date: 24 October 2017
SYNOPSISa
A Phase 2a Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-center Study 
Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Subjects with Major 
Depressive Disorder with Anxious Distress.
JNJ-42165279 is a potent, selective, and orally bioavailable inhibitor of the enzyme fatty acid amide 
hydrolase (FAAH). FAAH is the enzyme primarily responsible for the degradation of a variety of fatty 
acid amides (FAAs), including the endocannabinoid N-arachidonoylethanolamine, or anandamide (AEA), 
the first identified endogenous cannabinoid receptor agonist. The endocannabinoid system is thought to 
play important roles in the regulation of the immune system, pain perception, and fear and anxiety 
responses. Modulation of fear and anxiety responses is the basis for testing JNJ-42165279 for therapeutic 
effect in subjects with mood disorders and clinically significant mood and anxiety symptoms.
This compound has been previously studied in six Phase 1 studies including a single ascending dose 
regimen up to 
 mg and a multiple dose regimen of 100 mg once-daily (q.d.) in healthy males, a 
multiple dose study with cohorts receiving 25, 75 or 100 mg for 10 days, a brain FAAH occupancy study 
using positron emission tomography (PET), a drug-drug interaction (DDI) study and an oral 
bioavailability study. A functional magnetic resonance imaging (fMRI) study with a dose of 100 mg 
once-daily over 4 days has recently been completed and analysis of the data is ongoing. A phase 2a study 
in patients with social anxiety disorders (SAD) is ongoing.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to evaluate the efficacy in terms of reduction of symptoms of 
depression and anxiety, as assessed by the change from baseline on a 17-item Hamilton Depression 
Rating Scale (HDRS17), and overall safety and tolerability of treatment with adjunctive JNJ-42165279 
compared to placebo in subjects with major depressive disorder (MDD) with anxiety symptoms who have 
had inadequate response to treatment with a selective serotonin reuptake inhibitor (SSRI) or 
serotonergic/noradrenergic reuptake inhibitor (SNRI).
Secondary Objectives
The secondary objectives of this study are:

To assess the efficacy of JNJ-42165279 on core symptoms of anxiety (HAM-A6).

To assess the efficacy of JNJ-42165279 using dimensional analyses of both anxiety and 
depression (HDRS17 and SIGH-A).

To assess the efficacy of JNJ-42165279 on the response and remission of depressive and anxiety 
symptoms (derived from HDRS17 and SIGH-A). 

To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as once daily 
(qd) in male and female subjects with MDD with anxious distress using a population PK 
approach and explore its relationship with efficacy and safety parameters.
                                                
a This section has been amended per Amendments INT-1, 2 and 4.
CC
I


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Exploratory Objectives
The exploratory objectives are:

To evaluate the impact of treatment with adjunctive JNJ-42165279 compared to placebo on 
Clinical Global Impression (CGI) and exploratory clinician-rated and patient-reported 
assessments (CUDOS-A, CPFQ, SHAPS, MOS Sleep-R, PSS and Self-Assessment of Treatment 
Experience).

To explore for differential efficacy in subjects with melancholic features and subjects with 
comorbid anxiety disorders, as reported on the Mini International Neuropsychiatric Interview 
(MINI) diagnostic interview and patient-reported assessments. 

To explore 
 (including but not limited to
 
 and 
that may be related to clinical response, nonresponse, or safety and 
tolerability parameters of JNJ-42165279.

To explore the relationship between plasma PK and plasma concentrations of FAAs (anandamide 
[AEA], palmitoylethanolamide [PEA] and oleoylethanolamide [OEA]) in subjects with MDD 
with anxious distress.
Hypothesis
The primary hypothesis is that 6-weeks of treatment with adjunctive JNJ-42165279 is superior to placebo 
in improving symptoms of depression and anxiety, as measured by the change from baseline in the 
HDRS17, in subjects with MDD with anxiety symptoms who have had an inadequate response to an 
SSRI/SNRI.
OVERVIEW OF STUDY DESIGN
This is a multi-center, double-blind, placebo-controlled, randomized, parallel-group study in subjects with 
MDD with anxious distress who have had inadequate response to SSRI/SNRI treatment. Subjects with 
MDD with anxious distress who have had treatment initiated with an SSRI/SNRI will be evaluated at the 
investigation site. Site assessments will be reviewed and verified by an independent central rater.  The 
review by a central rater will include 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 HDRS17. 
Assessments by qualified site personnel including the MINI, ATRQ, and HDRS17 will be recorded for 
review and validation of the suitability of the subject for enrollment into the study by an independent 
central rater contracted by the sponsor. Subjects who meet the inclusion and exclusion criteria and are 
enrolled will be maintained on the SSRI/SNRI treatment throughout the study to determine whether 
adjunctive treatment can reduce symptoms of MDD with anxious distress. For each subject, the study will 
consist of three phases: a screening phase of up to 4 weeks, double-blind treatment phase lasting up to 
11 weeks, and a 3-week post-treatment (follow up) phase. The double-blind treatment phase of the trial 
will consist of 3 periods. The first period is a placebo lead-in of double-blind duration, after which 
subjects will enter the treatment period when they will be randomly assigned to JNJ-42165279 or 
continuation on placebo for 6 weeks. Subjects who successfully complete the treatment period prior to the 
end of Week 11, will be treated with placebo for the remaining time of the double-blind phase of the 
study, which will vary depending on the duration of the placebo lead-in for the specific subject. The total 
study duration for each subject will be approximately 18 weeks. The end of study is defined as the date of 
the last visit of the last patient undergoing the trial. Investigators and subjects will remain blinded to the 
exact duration of the subject lead-in and withdrawal period during the entire study duration. 
CCI
CCI
CCI


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Approximately 143 subjects will enter the double-blind placebo lead-in period. At the end of the lead-in 
period, response status of the subjects will be assessed according to the double-blind response criteria 
based on reduction in HDRS17 relative to lead-in baseline. Both, lead-in placebo responders and lead-in 
placebo non-responders will be randomly assigned in a 1:1 ratio to either 25 mg of JNJ-42165279 or 
placebo in the treatment period. The primary efficacy analyses will be based on the treatment period data 
from the lead-in non-responders (94 subjects).
The study will be an outpatient study.
Screening
After giving written informed consent, subjects may be screened over a period of up to 4 weeks to assess 
their eligibility for the study according to the inclusion and exclusion criteria defined for this study. 
A critical element of the screening is determination that subjects must have (1) reached a pre-defined 
optimal dose based on the Antidepressant Treatment Response Questionnaire –ATRQ (Chandler 2010), 
(2) received treatment at the optimal dose for at least 6 weeks with their current antidepressant and (3) 
failed to respond to the current antidepressant therapy. The following antidepressants are permitted: 
citalopram, escitalopram, sertraline, paroxetine, venlafaxine XR, desvenlafaxine, duloxetine, 
milnacipram, vilazodone, and vortioxetine. Subjects will continue to take their SSRI/SNRI treatment at an 
adequate and tolerated dose (i.e. monotherapy) throughout the study provided it is one of the 
Adjunctive 
Placebo
Adjunctive
JNJ-42165279
Adjunctive
JNJ-42165279
Adjunctive 
Placebo
Adjunctive
Placebo
Lead-in Period
Double-blind
Screening
(up to 4 weeks)
MDD with Anxious 
Distress 
with an inadequate 
response to 
an SSRI/SNRI
HDRS17 total 18
HDRS17 anx/som
Factor ≥7
CONTRIBUTES TO PRIMARY ANALYSIS (circled in pink)
Treatment  Period
(Double-blind, 6 weeks)
Screening
Lead-in baseline
Treatment baseline
Week 0
Adjunctive
Placebo
Week 11
Withdrawal Period
Double-blind
Treatment endpoint
Subject-Specific Trial Scheme
Placebo NON-RESPONDER
Placebo RESPONDER
Criteria based on reduction from lead-in baseline in HDRS17


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antidepressants allowed by this protocol. No antidepressant dose changes are permitted from Screening 
through the end of the study, including the post-treatment phase. Subjects participating in this study must 
also fulfill the criteria for current/past/recurrent major depressive illness as per MINI). Furthermore, 
subjects with a primary psychiatric diagnosis other than MDD will be excluded (as per the MINI).
For inclusion, subjects must have a HDRS17 total score ≥18 and a HDRS17 anxiety/somatization factor 
score 7 while having been treated with one of the antidepressants approved in this protocol at an 
adequate dose and for at least 6 continuous weeks. The clinical history of the current episode of MDD 
will be assessed by the MINI and supplementary subject validation questions; the lack of response to 
antidepressant therapy symptom severity will be assessed by the HDRS17, and the antidepressant 
treatment history based on the subject’s report during the screening interview by the ATRQ. Each of these 
assessments will be conducted by qualified personnel at the site at screening and will be recorded to allow 
independent validation of the suitability of the subject for enrollment by an independent central rater 
contracted by the sponsor.
Screening will include obtaining informed consent, assessment of study inclusion and exclusion criteria, 
medical history, physical examination, neurological examination and safety evaluations. 
The screening visit may be split into 2 visits.
Adverse events will be collected starting after the informed consent form (ICF) has been signed until the 
final study procedure at the final visit.
Subjects who are deemed eligible for randomization will enter the double blind treatment phase.
Double Blind Treatment Phase
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1. 
Lead-in period
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1 and will be 
treated with placebo for the entire duration of the lead-in period. Investigators and subjects will be 
blinded to exact duration of each subject-specific lead-in period throughout 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 adjunctive placebo or JNJ-42165279 in a 1:1 ratio for a 6-weeks 
treatment period. Investigators and subjects will remain blinded to exact timing of the randomization and 
study drug treatment assignment for each subject.
Withdrawal period
Subjects who successfully complete the treatment period prior to the end of Week 11 will enter 
withdrawal period where they will be treated with placebo for the remaining time of the double-blind 
phase of the study, which will vary depending on the duration of the placebo lead-in for a given subject. 
Investigators and subjects will be blinded to exact duration of each subject-specific withdrawal period.
During the double-blind Treatment Phase, primarily safety and tolerability will be monitored at regular 
intervals (e.g. physical examination, suicidality risk assessment, vital signs, 12-lead electrocardiogram 
(ECG), safety labs, etc). Pharmacokinetics (plasma), and pharmacodynamic (PD) effects will be explored 
at the time points listed in the Time and Events Schedule (TES).


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The Time and Events Schedule summarizes the visits as well as the frequency and timing of assessments 
applicable to this study.
Follow Up
Minimally 7 and maximally 21 days following last dosing (Week 11), subjects will return to the clinical 
site for a safety follow up visit. The procedures to be completed during the follow up visit are listed in the 
Time and Events Schedule.
Any serious adverse event (SAE) must be reported to the sponsor by study-site personnel within 24 hours 
of their knowledge of the event as outlined in the protocol. 
SUBJECT POPULATION
The target population for this study is male subjects and female subjects who are not able to bear children 
with MDD with anxious distress who are between 18 and 64 years of age inclusive, with screening and 
baseline
symptom severity as measured by the total score HDRS17
≥18
and a HDRS17
anxiety/somatization factor score 7.   
Approximately 143 subjects with MDD with anxious distress will be enrolled in this proof-of-concept 
study.
The inclusion and exclusion criteria for enrolling subjects in this study are described in more detail in 
Section 4 of the protocol. 
DOSAGE AND ADMINISTRATION
Study medication will be provided as JNJ-42165279 tablets, strengths 25 mg and matching placebo, 
packaged in bottles. All tablets (JNJ-42165279 /placebo) are physically identical. 
A study-site investigational product manual including instructions for dispensing, storage (on site and at 
home) and intake of the study medication will be supplied to the study-site. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as indicated for this 
protocol. The sponsor may optionally develop tools to improve and/or document compliance to intake of 
study medication when locally feasible. This may include a diary or an electronic registration tool.
The selected 25 mg dose of JNJ-42165279 is expected to result in complete inhibition of FAAH enzyme 
in the brain throughout the dosing interval based on the outcome of the single ascending dose
(42165279EDI1001), multiple ascending dose (MAD) (42165279EDI1002) and PET occupancy 
(42165279EDI1003) studies.
SAFETY EVALUATIONS
Physical examination, neurological examination, vital signs, body weight, body temperature, clinical 
laboratory assessments, 12-lead ECG, urine drug screen, alcohol screening test, pregnancy testing, 
Columbia Suicide Severity Rating Scale (C-SSRS) assessments and evaluation of adverse events and 
concomitant medications will be performed during the study to monitor subject safety.
In all women, serum and urine pregnancy test will be performed at Screening and at Visit 10. In women 
of childbearing potential (WOCBP), urine pregnancy test will be performed at all other timepoints. If the 
urine pregnancy test is positive, a serum β-HCG test will be performed.
PHARMACOKINETIC EVALUATIONS
Venous blood samples for analysis of JNJ-42165279 will be collected at the time-points indicated in the 
Time and Events Schedule. 


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Concentration time data will allow estimation of individual pharmacokinetic (PK) parameters for 
JNJ-42165279 using a population PK modeling approach. It will also help to understand potential 
differences between healthy subjects and subjects with MDD. Time and days of JNJ-42165279 plasma 
concentration assessment were chosen to gather maximal information about the PK properties of 
JNJ-42165279 while minimizing subject burden regarding blood sampling.
EFFICACY EVALUATIONS
Primary
The 17-item Hamilton Depression Rating Scale (HDRS17) 
The HDRS17 is included as a means to determine the frequency and severity of signs and symptoms of 
depression and determine both their influence on treatment and their responsiveness to treatment.  
Secondary

Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A)
The SIGH-A is included here as a means to determine the frequency and severity of signs and symptoms 
of anxiety and determine both their influence on treatment and their responsiveness to treatment.  

HAM-A6 (derived from SIGH-A)

HDRS17 anxiety/somatization factor (derived from HDRS17)

HAM-D6  subscale (derived from HDRS17)

Clinical Global Impression Improvement (CGI-I)
Patient Reported Outcome Assessments
Patient reported outcomes are included to assess the effect of treatment on subjective symptoms of 
anxiety and depression which may occur in the population included in this study, the impact of treatment 
on sleep symptoms, and impairment in daily life. 

Clinically Useful Depression Outcome Scale (with anxious distress specifier) (CUDOS-A)

Cognitive and Physical Functioning Questionnaire (CPFQ)

Snaith-Hamilton Pleasure Scale (SHAPS)

Medical Outcomes Study Sleep-Revised (MOS Sleep-R)

Perceived Stress Scale (PSS)

Self-Assessment of Treatment Experience 
BIOMARKER AND PHARMACOGENOMIC (DNA) EVALUATIONS 
During the study, the following pharmacodynamics (PD) evaluations will be performed at the time points 
indicated in the Time and Events schedule: plasma concentrations of FAAs (AEA, PEA and OEA).










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Footnotes:
a
Visits should be conducted within +/-3 days of the scheduled day.
b
If a subject discontinues treatment before the end of the double-blind treatment phase, early withdrawal (EW) and post-treatment assessments should be obtained. 
Follow-up visit will take place 7 to 21 days after last dose intake or early withdrawal. 
c
Prestudy therapy will include all medications taken within the 30 days before screening. ATRQ verified by the independent rater will be used to document the 
current antidepressant used by the subjects and to determine the optimal dose of the antidepressant.
d
Triplicate ECG at Day 1 (predose)
e
Supine blood pressure, pulse, and oral temperature.
f
Body weight will be measured with subjects lightly clothed.
g
Serum chemistry, hematology, coagulation and urinalysis. TSH (all subjects) and FSH (only women) at screening only.
h
Only in case of any clinical significant abnormalities observed at Week 11.
i
ECG should be performed prior to study drug administration, and if possible, at approximately the same time of the day as the screening ECG.
j
Refer to study exclusion criteria for circumstances in which a repeat test during Screening is permitted.
k
Performed for all women. Serum and urine pregnancy test. Investigators may perform additional pregnancy testing at their discretion as clinically needed.
l
At each time point, a venous blood sample will be collected for PK analysis of JNJ-42165279 concentration at predose (i.e., prior to morning dose on Days 14, 35, 
63 and 77) and 2 to 4 hours postdose. 
m
Samples must be collected prior to dosing under fasting conditions whenever possible. 
n
Subjects will be asked to provide a small amount of saliva the night before and upon awakening the morning of the scheduled visit.
o
A venous blood sample will be collected for the FAAs (AEA, PEA and OEA). The Visit 2 sample must be taken before the first dose of JNJ-42165279 /placebo.
p
Concomitant therapies must be recorded throughout the study beginning with signature of the ICF to the final follow up visit (Visit 11).
q
Baseline version completed at screening.
r
HDRS17 anxiety/somatization factor score determined from the assessment.
s
A neurological examination will also be completed in case of adverse event of interest.
t.
Urine pregnancy test In WOCBP only. If the urine pregnancy test is positive, a serum β-hcg test will be performed. Investigators may perform additional pregnancy 
testing at their discretion as clinically needed.
ATRQ = Antidepressant Treatment Response Questionnaire; CGI-I=Clinical Global Impression – Improvement; CPFQ=Cognitive and Physical 
Functioning Questionnaire; C-SSRS = Columbia Suicide Severity Rating Scale; CUDOS = Clinically Useful depression Outcome Scale;       EW = 
Early Withdrawal; HAM-A6 = Hamilton Anxiety Rating scale; HDRS17 = Hamilton Depression Rating Scale; MINI = Mini International 
Neuropsychiatric Interview; MOS Sleep-R = Medical Outcomes Study Sleep-Revised; PSS = Perceived Stress Scale;            SHAPS = Snaith-Hamilton 
Pleasure Scale; SIGH-A = Structured Interview Guide for the Hamilton Anxiety Scale;  SIGH-D= Structured Interview Guide for the Hamilton 
Depression Scale


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Approved, Date: 24 October 2017
ABBREVIATIONS
Note: Pharmacokinetic Parameters are defined in Section 9.4.3 and questionnaires are 
defined after the Time and Events Schedule.
AEA
ALP
anandamide 
alkaline phosphatase
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance 
AST
Aspartate transaminase 
BMI
Body mass index 
CI
Confidence interval
CPK
CSF
Creatine phosphokinase 
Cerebrospinal fluid
CYP
cytochrome P450
DDI
DRC
DSM-5
Drug-Drug Interaction
Data Review Committee
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
ED
Effective Dose
(e)CRF
(electronic) case report form
eDC
Electronic data capture
FAAH
Fatty acid amide hydrolase 
FAAs
Fatty acid amides
FDA
Food and Drug Administration
fMRI
GAD
Functional magnetic resonance imaging 
Generalized anxiety disorder
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GGT
Gamma-glutamyltransferase 
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C antibodies 
hERG
Human Ether-à-go-go-Related Gene
HIV
Human immunodeficiency virus
IB
Investigators Brochure
IC
Inhibitory Concentration
ICF
Informed consent form  
ICH
International Conference on Harmonisation
ITT
Intention-to-Treat
IEC
Independent Ethics Committee
LC-MS/MS
Liquid chromatography/mass spectrometry/mass spectrometry
LDH
Lactic acid dehydrogenase 
MAD
Multiple Ascending Dose
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MINI
OEA
Mini International Neuropsychiatric Interview
Oleoylethanolamide
PD
PEA
PET
Pharmacodynamics
Palmitoylethanolamide
Positron emission tomography
PK
Pharmacokinetic
PQC
Product Quality Complaint
q.d.
Once-daily
RBC
SAD
Red blood cell 
Social anxiety disorder
SAE
Serious adverse event
SD
SNRI
SSRI
Standard deviation 
Serotonergic/noradrenergic reuptake inhibitor
Selective serotonin reuptake inhibitor
TEAE
TES
Treatment emergent adverse event
Time and Event Schedule


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ULN
Upper Limit of Normal
Vss
Volume of distribution at steady state 
WBC
White blood cell


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1.
INTRODUCTION
JNJ-42165279 is a potent, selective, and orally bioavailable inhibitor of the enzyme fatty acid 
amide hydrolase (FAAH). FAAH is the enzyme primarily responsible for the degradation of a 
variety 
of 
fatty 
acid 
amides 
(FAAs), 
including 
the 
endocannabinoid 
N-arachidonoylethanolamine, or anandamide (AEA), the first identified endogenous 
cannabinoid receptor agonist. The endocannabinoid system is thought to play important roles 
in the regulation of the immune system, pain perception, and fear and anxiety responses. 
Modulation of fear and anxiety responses is the basis for testing JNJ-42165279 for 
therapeutic effect in subjects with mood disorders and clinically significant mood and anxiety 
symptoms.
This compound has been previously studied in six Phase 1 studies including a single 
ascending dose regimen up to 
 mg and a multiple dose regimen of 100 mg once-daily 
(q.d.) in healthy males, a multiple dose study with cohorts receiving 25, 75 or 100 mg for 10 
days, a brain FAAH occupancy study using positron emission tomography (PET), a drug-
drug interaction (DDI) study and an oral bioavailability study. A functional magnetic 
resonance imaging (fMRI) study with a dose of 100 mg once-daily over 4 days has recently 
been completed and analysis of the data is ongoing.
A phase 2a study in patients with social anxiety disorder (SAD) is ongoing.
For the most comprehensive nonclinical and clinical information regarding JNJ-42165279, 
refer to the latest version of the Investigator's Brochure (IB) for JNJ-42165279.1
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Backgrounda
Nonclinical Studies
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of JNJ-42165279, refer to the latest version of the IB for JNJ-42165279.1
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
Nonclinical Pharmacology
JNJ-42165279 is a mechanism-based inhibitor of FAAH (IC50s of 26 ±4.9 nM [human] and 
500 ± 70 nM [rat] at native FAAH) with behavior consistent with a slowly turned-over 
enzyme substrate. Extensive in vitro profiling, including Cerep and kinase panels, radioligand 
binding, functional assays, and proteomics studies, has shown this compound to be highly 
selective. 
                                                
a This section has been amended per Amendment INT-2.
CCI


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Nonclinical effects of JNJ-42165279 have been demonstrated in three in vivo pain models in 
rats: the mild thermal injury model of acute burn pain, the formalin paw model of tonic pain, 
and the spinal nerve ligation model of neuropathic pain. Doses that produced maximal FAAH 
enzyme inhibition in white blood cells (WBCs) and brain corresponded to doses that 
produced maximal efficacy in the spinal nerve ligation model of neuropathic pain. Efficacy 
with JNJ-42165279 has also been demonstrated in the stress-induced anorexia rat model of 
anxiety. The estimated human efficacious plasma concentration (80 ng/mL, 0.2 M) was 
derived from the ED90 in the rat spinal nerve ligation model corrected for the 20-fold 
difference in human versus rat IC50 in the whole blood FAAH inhibition assay. This estimate 
is used for safety margin calculations in the rest of this document.
Safety Pharmacology
JNJ-42165279 had no adverse effect at  µM in the human ether-a-go-go related gene 
(hERG) patch clamp assay 
 and at 
 µM (the maximal dose assessed) in the 
rabbit Purkinje fiber assay.
In the Good Laboratory Practice (GLP) male conscious dog cardiovascular safety study, oral 
doses up to 
mg/kg (Cmax = 
ng/mL; 
-fold margin over the projected efficacious 
dose in humans of 
ng/mL) did not induce relevant changes in cardiovascular, 
electrocardiographic, or respiratory parameters. At the highest dose of 
mg/kg (mean 
plasma exposure of 
ng/mL), a 
% 
 in heart rate was observed in one dog, and 
a 
% 
 in another. No other relevant changes were recorded 
in the other cardiovascular, electrocardiographic, or respiratory parameters. There were no 
meaningful effects in the anesthetized guinea pig model.
In the neurobehavioral (Irwin) safety assessment study in rats,
 
 were noted from 
mg/kg, with changes 
in sensory-motor and affective responses at 
mg/kg. 
Pharmacokinetics and Product Metabolism in Animals
JNJ-42165279 has 
 oral bioavailability in rats (
%), dogs 
 
%), and monkeys (
%). After intravenous administration, clearance was 
 in the dog 
and monkey 
mL/min/kg, respectively) and 
 in the rat (
 mL/min/kg); the 
volume of distribution at steady state (Vss) was 
; and the half-
life ranged from 
hours. JNJ-42165279 was highly bound (90% to 97%) to plasma 
proteins in all species with the highest binding in the dog. Brain-to-plasma ratios were 
consistent over time in the rat, and ranged from 
 in the rat and 
 in the dog.
JNJ-42165279 is primarily metabolized by 
 in liver microsomes 
with multiple metabolites observed in vitro and in vivo. 
 metabolites formed in 
 
 were 
 detected in vitro or in vivo in the 
toxicology species investigated. Currently no information is available about any 
pharmacology of any metabolites of JNJ-42165279.
Toxicology
The oral toxicity of JNJ-42165279 was characterized in 3-month toxicity studies in rats and 
dogs. In male rats at all doses, adverse effects on 
 
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JNJ-42165279
Amendment INT-5 42165279MDD2001
29
Approved, Date: 24 October 2017
A double-blind Phase 1 study (Study 42165279EDI1001) was completed with 29 healthy 
male subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic 
(PD) activity of JNJ-42165279 after single and repeated oral dosing. In Part 1, two cohorts 
(both n=9) received single ascending doses of JNJ-42165279 or placebo during each of 3 or 4 
dosing periods, separated by washout periods, using an alternating panel design. Two 
additional subjects participated in Panel 1 but withdrew from the study after the first dosing 
for reasons unrelated to safety or tolerability; 1 received placebo and 1 received JNJ-
42165279.
Doses studied in a fasted state were 2.5, 10, 30, 100, 175, and 250 mg. An additional 30-mg 
dose was also administered after intake of a regular meal. In Part 2, a separate cohort of 
9 subjects received either 100 mg JNJ-42165279 (n=6) or placebo (n=3) once-daily for 
6 consecutive days in a fed state. JNJ-42165279 was administered as an oral suspension 
(5 mg/mL or 50 mg/mL) throughout the study.
After a single dose, systemic exposure to JNJ-42165279, expressed as Cmax, AUClast, and 
AUC∞, increased with increasing dose. Plasma JNJ-42165279 concentrations declined in a 
 with mean t1/2 values of 
 to 
 hours for doses of 2.5 to 
250 mg.
The effect of 
 on the pharmacokinetics of JNJ-42165279 was 
investigated at the 
-mg dose level. The 
 was 
 based on median tmax
values of 
 hours and 0.5 hours in the 
, respectively. On average, the 
Cmax values were 
% 
 and AUC∞values were 
% 
 when JNJ-42165279 was 
. These 
 
.
JNJ-42165279 Cmax was reached at 0.5 to 2.5 hours postdose (median tmax value, 0.75 hours) 
following single-dose and once-daily administration of 100 mg. Based on the trough 
(i.e., predose) concentrations, steady-state conditions were achieved by the third 100-mg 
daily dose of JNJ-42165279. On average, the Cmax and AUCvalues were 1.13-times and 
1.44-times higher on Day 6 relative to Day 1. The similarity between the mean AUC∞
following the 100-mg dose during Part 1 (8,419 ng.h/mL) and the mean AUCon Day 6 
during Part 2 (8,644 ng.h/mL) further suggests that the pharmacokinetics of JNJ-42165279 is 
consistent after single-dose and once-daily repeated administration.
At a dose level of 30 mg or higher, FAAH activity in white blood cells (WBCs) showed a 
significant decrease with duration of at least 24 hours. At the same time the FAA plasma 
levels showed a significant increase. 
JNJ-42165279 was found to be well tolerated. There were no clinically significant changes in 
any safety measurements, including clinical laboratories, electrocardiograms (ECGs), vital 
signs, and physical and neurological examinations. There were no changes or abnormal 
findings in blood coagulation parameters. There were no deaths, serious adverse events
(SAEs), or discontinuations due to adverse events. All adverse events reported were mild in 
severity and had resolved by the time of the follow-up visit. The most frequently reported 
adverse events for subjects receiving JNJ-42165279 were headache, nasal congestion, and 
dizziness. 
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JNJ-42165279
Amendment INT-5 42165279MDD2001
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Approved, Date: 24 October 2017
In the second multiple ascending dose (MAD) study 42165279EDI1002, five cohorts were 
studied: healthy males at 10 mg, 25 mg, and 75 mg; healthy females (non-child bearing 
potential) at 100 mg, and healthy elders at 100 mg.  Six subjects were on active and two on 
placebo in each cohort.  All subjects were dosed during 10 days and cerebrospinal fluid 
(CSF) sampling was conducted prior to dosing and after 7 days of dosing in the healthy male 
cohorts. Concentrations of JNJ-42165279 in plasma, urine, and CSF were measured; and 
FAAH activity in leucocytes (WBCs), and anandamide (AEA), N-oleoylethanolamide 
(OEA), N-palmitoylethanolamide (PEA) in plasma, and AEA, OEA, and arachidonic acid 
(AA) in CSF were assayed. Tolerability, including effects on cognition and subjective 
ratings, were assessed. As dose related increases in coagulation parameters had been 
observed in male rats, blood coagulation parameters were also included.  
A preliminary analysis of data from study 42165279EDI1002 indicates that the plasma 
pharmacokinetics of JNJ-42165279 in female subjects and elderly subjects are similar to each 
other and to healthy male subjects enrolled in study 42165279EDI1001. These 3 subject 
groups received a single 100-mg dose of JNJ-42165279 and once-daily administration of the 
same dose until steady-state conditions were achieved.
Pharmacodynamic measures revealed that across the 25- to 100-mg JNJ-42165279 dose 
range, FAAH activity in WBCs was suppressed attaining a mean nadir of 7.85% to 10.4% 
(relative to predose values) after a single dose and a mean nadir of 0.58% to 10.5% after 
once-daily dosing for 10 days. At 96 hours after the last dose, mean FAAH activity remaining 
ranged from 28.3% to 58.2% of predose values. Single doses of JNJ-42165279 in the range of 
25 to 100 mg produced mean peak concentrations of AEA in plasma that were 5.5- to 10-
times higher than mean predose values, whereas mean peak OEA and PEA concentrations 
4.3- to 5.6-times higher. Similar changes in mean FAA concentrations were observed after 
daily administration of 25 to 100 mg for 10 days. Mean plasma AEA, OEA, and PEA 
concentrations were 1.3- to 3.1-times higher than mean predose values at 96 hours after the 
last JNJ-42165279 dose. Daily administration of JNJ-42165279 for 7 days increased mean 
OEA concentrations in CSF by approximately 6-fold in all dose groups while mean AEA 
increases were dose dependent. CSF AEA increased approximately 28-fold, 41 fold, and 77
fold while taking 10 mg, 25 mg, and 75 mg respectively, relative to predose. The 
concentrations of AA in CSF decreased slightly in all groups including placebo.
The most common treatment emergent adverse events (TEAEs) (≥3 subjects per dose group) 
in subjects dosed with JNJ-42165279 were headache, dizziness, and fatigue. Overall, more 
TEAEs were reported with JNJ-42165279 compared with placebo. All the TEAEs were either 
mild or moderate in intensity. None of the TEAEs was reported as severe and all were 
considered by the investigator as either doubtfully related or possibly related to the study 
drug. There were six TEAEs of hepatic enzymes elevated. One subject taking placebo, one
woman of non-child bearing potential, and two healthy elderly subjects taking 100 mg 
JNJ-42165279, had elevations of liver transaminases relative to baseline (up to 2.5 times the 
upper limit of normal[ULN]) that returned to normal after dosing stopped. No increases 
occurred in ALP or bilirubin.  Two out of six subjects taking 10 mg had elevations of ALT up 
to 1.5 times the ULN that returned to normal after dosing was stopped. No such increases 
were observed in the 25 mg or 75 mg male cohorts. There were no clinically significant 
changes in any safety measurements, including clinical laboratories, ECGs, vital signs, and 
physical and neurological examinations. There were no changes or abnormal findings in 


JNJ-42165279
Amendment INT-5 42165279MDD2001
31
Approved, Date: 24 October 2017
blood coagulation parameters. There were no deaths, serious adverse events, or 
discontinuations due to adverse events. Subjects receiving 100 mg reported slight similarity 
to sedatives and dissimilarity to stimulants on the Addiction Research Center Inventory-53; 
no groups reported similarity to cannabinoids.  No subjective effects were reported in any of 
the cohorts by Bond-Lader visual analogue scales.  
During the DDI study 42165279EDI1004 sixteen subjects received a single 30-mg 
JNJ-42165279 dose on Day 1. Thereafter, they received single oral doses of 
-mg 
 from Day 4 to Day 10 (inclusive). Subjects also received a dose of 30-mg 
JNJ-42165279 along with 
 mg 
 on Day 8.
Mean plasma JNJ-42165279 concentrations were 
 over the entire PK sampling period 
after co-administration of JNJ-42165279 with 
 compared with administration of 
JNJ-42165279 alone. Plasma JNJ-42165279 concentrations 
, with median 
tmax values of 
 hour following administration of JNJ-42165279 
 
.
Mean t1/2 was approximately 
% 
 after JNJ-42165279 was co-administered 
 
, compared with JNJ-42165279 administered 
 The estimated geometric 
mean ratios (GMRs) of JNJ-42165279 Cmax, AUClast, and AUC
 
 relative to JNJ-42165279 
 were 
%, 
%, and 
%, 
respectively. These results indicate that 
 in the 
 
 of JNJ-42165279 and that 
 is 
 of JNJ-42165279 in 
An analysis of brain FAAH occupancy by JNJ-42165279 using PET of 11C-MK-3168 has 
been conducted (study 42165279EDI1003). Analyses of PET scans after single doses of 
JNJ-42165279 ranging from 2.5 mg to 50 mg indicate that significant (85% to 95%) 
occupancy of FAAH in brain can be seen after pretreatment with doses as low as 10 mg and 
occupancy is completely saturated after higher doses. Other analyses including PK of JNJ-
42165279 and inhibition of FAAH activity in leukocytes at the time of brain occupancy 
measurements are ongoing.
The 
 of JNJ-42165279 administered as a 
-mg tablet relative to a 
-mg 
 was evaluated in healthy male subjects under 
 
(Study 42165279EDI1005). Mean plasma JNJ-42165279 concentrations 
 
 after administration of JNJ-42165279 as a 
 
 The mean AUC and Cmax values between the 
 
 The estimated geometric mean ratios (GMRs) of JNJ-42165279 Cmax, 
AUClast, and AUCfor the JNJ-42165279 administered as 
 
 were 
%, 
%, and 
%, respectively. The time to achieve maximum 
plasma concentration (tmax), terminal half-life values, and intersubject variability were 
.
A fMRI study with a dose of 100 mg once-daily over 4 days in healthy young males (study 
42165279ANX1001) has recently been completed and analyses of the data are in progress. 
For more details about the Phase 1 clinical data please refer to the IB.1
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JNJ-42165279
Amendment INT-5 42165279MDD2001
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Approved, Date: 24 October 2017
1.2.
Overall Rationale for the Study
The endocannabinoid system is thought to play important roles in the regulation of the 
immune system, pain perception, fear and anxiety responses and resilience to stress. 
Modulation of depression, fear and anxiety responses is the basis for testing JNJ-42165279 
for therapeutic effect in subjects with mood disorders and clinically significant mood and 
anxiety symptoms. The net effect of JNJ-42165279 is hypothesized to be a normalization of 
neurotransmission associated with states of hyper-arousal and chronic stress. JNJ-42165279
is being developed as a possible treatment of disorders of the central nervous systems (CNS), 
including anxiety disorders, post-traumatic stress disorder (PTSD), and major depressive 
disorder (MDD) with anxious distress. Based on nonclinical data, the compound is expected 
to show stress-reduction and anxiolytic activity and, therefore, may also be expected to be 
potentially effective in the treatment of MDD with anxious distress. The current study will be 
conducted 
to 
assess 
the 
efficacy, 
safety, 
tolerability, 
pharmacokinetics, 
and 
pharmacodynamics of treatment with adjunctive JNJ-42165279 in subjects with MDD with 
anxious distress.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy in terms of reduction of 
symptoms of depression and anxiety, as assessed by the change from baseline on a 17-item 
Hamilton Depression Rating Scale (HDRS17), and overall safety and tolerability of treatment
with adjunctive JNJ-42165279 compared to placebo in subjects with MDD with anxiety
symptoms who have had inadequate response to treatment with a selective serotonin reuptake 
inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI).
Secondary Objectives
The secondary objectives of this study are:
To assess the efficacy of JNJ-42165279 on core symptoms of anxiety (HAM-A6).
To assess the efficacy of JNJ-42165279 using dimensional analyses of both anxiety and 
depression (HDRS17 and SIGH-A).
To assess the efficacy of JNJ-42165279 on the response and remission of depressive and 
anxiety symptoms (derived from HDRS17 and SIGH-A). 
To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as once 
daily (qd) in male and female subjects with MDD with anxious distress using a population 
PK approach and explore its relationship with efficacy and safety parameters.
Exploratory Objectives
The exploratory objectives are:
To evaluate the impact of treatment with adjunctive JNJ-42165279 compared to placebo on
Clinical Global Impression (CGI) and exploratory clinician-rated and patient-reported 
assessments (CUDOS-A, CPFQ, SHAPS, MOS Sleep-R, PSS and Self-Assessment of 
Treatment Experience).




JNJ-42165279
Amendment INT-5 42165279MDD2001
34
Approved, Date: 24 October 2017
remain blinded to the exact duration of the subject lead-in and withdrawal period during the 
entire study duration.
Approximately 143 subjects will enter the double-blind placebo lead-in period. At the end of 
the lead-in period, response status of the subjects will be assessed according to the double-
blind response criteria based on reduction in HDRS17 relative to lead-in baseline. Both, lead-
in placebo responders and lead-in placebo non-responders will be randomly assigned in a 1:1 
ratio to either 25 mg of JNJ-42165279 or placebo in the treatment period. The primary 
efficacy analyses will be based on the treatment period data from the lead-in non-responders 
(94 subjects).
The study will be an outpatient study.
Screening
After giving written informed consent, subjects may be screened over a period of up to 4 
weeks to assess their eligibility for the study according to the inclusion and exclusion criteria 
defined for this study. 
A critical element of the screening is determination that subjects must have (1) reached a 
pre-defined optimal dose based on the Antidepressant Treatment Response Questionnaire –
ATRQ (Chandler 2010), (2) received treatment at the optimal dose for at least 6 weeks with 
their current antidepressant and (3) failed to respond to the current antidepressant therapy. 
The following antidepressants are permitted: citalopram, escitalopram, sertraline, paroxetine, 
venlafaxine XR, desvenlafaxine, duloxetine, milnacipram, vilazodone, and vortioxetine. 
Adjunctive 
Placebo
Adjunctive
JNJ-42165279
Adjunctive
JNJ-42165279
Adjunctive 
Placebo
Adjunctive
Placebo
Lead-in Period
Double-blind
Screening
(up to 4 weeks)
MDD with Anxious 
Distress 
with an inadequate 
response to 
an SSRI/SNRI
HDRS17 total 18
HDRS17 anx/som
Factor ≥7
CONTRIBUTES TO PRIMARY ANALYSIS (circled in pink)
Treatment  Period
(Double-blind, 6 weeks)
Screening
Lead-in baseline
Treatment baseline
Week 0
Adjunctive
Placebo
Week 11
Withdrawal Period
Double-blind
Treatment endpoint
Subject-Specific Trial Scheme
Placebo NON-RESPONDER
Placebo RESPONDER
Criteria based on reduction from lead-in baseline in HDRS17


JNJ-42165279
Amendment INT-5 42165279MDD2001
35
Approved, Date: 24 October 2017
Subjects will continue to take their SSRI/SNRI treatment at an adequate and tolerated dose 
(i.e. monotherapy) throughout the study provided it is one of the antidepressants allowed by 
this protocol. No antidepressant dose changes are permitted from Screening through the end 
of the study, including the post-treatment phase. Subjects participating in this study must also 
fulfill the criteria for current/past/recurrent major depressive illness as per Mini International 
Neuropsychiatric Interview (MINI). Furthermore, subjects with a primary psychiatric 
diagnosis other than MDD will be excluded (as per the MINI).
For inclusion, subjects must have a HDRS17
total score ≥18 and a HDRS17
anxiety/somatization factor score 7
while having been treated with one of the 
antidepressants approved in this protocol at an adequate dose and for at least 6 continuous 
weeks. The clinical history of the current episode of MDD will be assessed by the MINI and 
supplementary subject validation questions; the lack of response to antidepressant therapy 
symptom severity will be assessed by the HDRS17, and the antidepressant treatment history 
based on the subject’s report during the screening interview by the ATRQ. Each of these 
assessments will be conducted by qualified personnel at the site at screening and will be 
recorded to allow independent validation of the suitability of the subject for enrollment by an 
independent central rater contracted by the sponsor.
Screening will include obtaining informed consent, assessment of study inclusion and 
exclusion criteria, medical history, physical examination, neurological examination and 
safety evaluations. 
The screening visit may be split into 2 visits.
Adverse events will be collected starting after the informed consent form (ICF) has been 
signed until the final study procedure at the final visit.
Subjects who are deemed eligible for randomization will enter the double blind treatment 
phase.
Double Blind Treatment Phase
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1. 
Lead-in period
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1 and 
will be treated with placebo for the entire duration of the lead-in period. Investigators and 
subjects will be blinded to exact duration of each subject-specific lead-in period throughout 
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 adjunctive placebo or JNJ-42165279 in a 
1:1 ratio for a 6 week in treatment period.
Investigators and subjects will remain blinded to exact timing of the randomization and study 
drug treatment assignment for each subject.


JNJ-42165279
Amendment INT-5 42165279MDD2001
36
Approved, Date: 24 October 2017
Withdrawal period
Subjects who successfully complete the treatment period prior to the end of Week 11 will 
enter withdrawal period where they will be treated with placebo for the remaining time of the 
double-blind phase of the study, which will vary depending on the duration of the placebo 
lead-in for a given subject. Investigators and subjects will be blinded to exact duration of 
each subject-specific withdrawal period.
During the double-blind Treatment Phase, primarily safety and tolerability will be monitored 
at regular intervals (e.g.  physical examination, suicidality risk assessment, vital signs, 12-
lead electrocardiogram (ECG), safety labs, etc). Pharmacokinetics (plasma), and 
pharmacodynamic (PD) effects will be explored at the time points listed in the Time and 
Events Schedule (TES).
A pharmacogenomic blood sample will be collected to assess whether the subject is carrier of 
the A-allele variant for FAAH and to identify genetic and/or epigenetic factors that may 
influence the pharmacokinetics (PK), pharmacodynamics (PD), safety and/or tolerability of 
JNJ-42165279. 
The Time and Events Schedule summarizes the visits as well as the frequency and timing of 
assessments applicable to this study.
Follow Up
Minimally 7 and maximally 21 days following last dosing (Week 11), subjects will return to 
the clinical site for a safety follow up visit. The procedures to be completed during the follow 
up visit are listed in the Time and Events Schedule.
Any serious adverse event (SAE) must be reported to the sponsor by study-site personnel 
within 24 hours of their knowledge of the event as outlined in the protocol. 
3.2.
Study Design Rationalea
Blinding, Control, Study Phase/Periods, Treatment Groups
Double-blind 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. A placebo control will be used to establish the frequency 
and magnitude of changes in clinical endpoints that may occur in the absence of active 
treatment. 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. Placebo lead-
in responders will also be randomized to active or placebo during the treatment period in 
order to expose more subjects to JNJ-42165279 and to obtain the estimate of its effect in 
general population (not only in enriched). Withdrawal placebo period will be used to aid the 
blinding of the lead-in period duration and exact beginning and ending of the treatment 
                                                
a This section has been amended per Amendments INT-1 and 4.


JNJ-42165279
Amendment INT-5 42165279MDD2001
37
Approved, Date: 24 October 2017
period and will allow exploration for indication of symptoms of withdrawal from treatment
with JNJ-42165279 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 adverse events.  
The duration for random assignment to active treatment is 6 weeks.  Four weeks is accepted 
as the minimum time to demonstrate a response to adjunctive treatment of MDD for 
medications with known clinical effects such as atypical antipsychotics. Extending this to 6 
weeks allows for the possibility that a beneficial response to this untested mechanism of 
action accrues over time and limiting it to 6 weeks permits a period of observation after 
withdrawal of treatment while remaining under double-blind conditions.
Population 
The target population for this study is male or female subjects with MDD with anxious 
distress who are at least 18 years old but less than 65 years old and have had inadequate 
response to SSRI/SNRI treatment. The definition of inadequate response is similar to that 
used in the STAR*D study and adopted in the MGH Antidepressant Treatment History 
Questionnaire (ATRQ) namely, failure to have a 50% or greater reduction in symptom 
severity after at least 6 weeks of treatment with adequate doses of a medication which has 
demonstrated efficacy in clinical trials (Rush et al 2006, Chandler et al 2010). 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 adequate doses of SSRI/SNRI treatment for at least 6 weeks and 
manifest depressive symptom severity as measured by the total score HDRS17 ≥18. The 
presence of MDD with anxious distress will be defined by those subjects also having anxiety 
symptom severity as measured by the anxiety/somatization factor score of the HDRS17 ≥ 7 
(Fava 2008; Cleary 1977). 
Given the observation in the rat reproductive toxicology studies (see Section 1.1), WOCBP 
will only be included if they agree to ongoing use of a highly effective method of birth 
control (i.e. one that results in a less than 1% per year failure rate when used consistently and 
correctly). All WOCBP will have a pregnancy test at screening and each study visit during 
the double-blind phase. WOCBP constitute a large part of the target population in clinical 
practice. Safety and efficacy data in this population are important for future clinical studies.
Rationale for Dose Selection
Based on preclinical models of efficacy with adjustment for differences in affinity of 
JNJ-42165279 for human FAAH, the exposure predicted to provide 90% maximal effect was 
80 ng/mL (Investigator’s Brochure), and is hypothesized to be a function of complete (>90%) 
inhibition of FAAH. Mean steady state plasma concentrations above 80 ng/ml were sustained 
for up to 12 hours post-dose by 25 mg in the MAD study (42165279ED1002). Suppression of 
FAAH activity in WBC occurs rapidly after single doses as low as 2.5 mg, and shows dose 
dependent recovery. The lowest single dose completely suppressing FAAH WBC activity 
throughout the dosing interval in the single ascending dose study was 30 mg 
(42165279ED1001), and this was confirmed by complete suppression of FAAH WBC 


JNJ-42165279
Amendment INT-5 42165279MDD2001
38
Approved, Date: 24 October 2017
activity throughout the dosing interval during once-daily
dosing at 25 mg in 
42165279ED1002. In the same study, increases in concentrations of AEA and OEA in CSF 
were observed after 7 days of dosing with 10 mg, 25 mg, and 75 mg. Increases in AEA in 
CSF were dose dependent, increasing 28 fold during dosing with 10 mg, 41 fold with 25 mg, 
and 77 fold with 75 mg although the range of effects of 25 mg overlapped with those seen 
with 75 mg. 86% to 96% blocking of retention of the Merck FAAH tracer 11C-MK3168 in 
brain was observed in human PET studies after pretreatment with single doses of 10 mg and 
complete blocking of retention occurred after 25 mg and higher doses of JNJ-42165279 in 
42165279ED1003. In 42165279ED1002, mild increases in liver transaminases were observed 
in a few subjects, with up to 2.5-fold increases in ALT in 3 of 12 subjects taking 100 mg,
none of the subjects taking 25 mg or 75 mg, and 1.5 fold increases in 2 of 6 subjects taking 
10 mg  
 plays an important role in the metabolic elimination of JNJ-42165279. In the 
presence of 
, JNJ-42165279 Cmax, and AUCwere 
% and 
%, respectively (Study 42165219EDI1004). Polypharmacy is 
common in the clinical practice of mood disorders, and 
 
 in this study. While the 
 were 
observed with 
 mg, 
mg q.d. dose also appears to result in 
 
 
Based on these results, JNJ-42165279 25 mg q.d. is predicted to result in > 95% inhibition of 
FAAH activity without significant variability throughout the day and appears to offer the best 
balance between efficacy and safety. 
Efficacy Evaluation
Primary
Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of 
symptoms in subjects diagnosed with depression (Hamilton M 1960) with a score range of 0 
to 52. It is the most widely used symptom severity measure for depression. Each of the 17 
items is rated by the clinician on either a 3- or a 5-point scale. The HDRS has an inter-rater 
reliability correlation of r = .90 and the internal consistency of the measure is reported to be 
high with a coefficient alpha of 0.88. Criterion-related validity for this measure is high; 
Knesevich et al. found a high correlation between the Hamilton score and a psychiatrist’s 
global rating (r = 0.89, and between the change in these ratings during treatment (r = 0.68) 
(Knesevich J 1977).
An example of the HDRS17 is provided in Attachment 1.
Secondary
HAM-A6
The HAM-A6 is a 6-item subscale derived from the original Hamilton Anxiety scale (HAM-
A) (Hamilton 1959; Hamilton 1969). Because the HAM-A, like the 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 
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Amendment INT-5 42165279MDD2001
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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 DSM-IV criteria for GAD than the full HAM-A), the 
total HAM-A6 score is considered a sufficient statistic. 
HAM-D6 subscale
Over the years, the most consistent HDRS factor to measure the core symptoms of depression 
is the one identified using a clinical global severity measure as the index of validity (Bech 
1975). The six items are: depressed mood, guilt feelings, work and interests, psychomotor 
retardation, psychic anxiety, and general somatics (tiredness and pains), with a score range 
from 0 to 22. In psychometric studies using item response theory models it has consistently 
been shown that the sum score of these six items (HAM-D6), in contrast to the HDRS17, is a 
sufficient statistic (Bech 2002).
HDRS17 anxiety/somatization factor
The HDRS17 anxiety/somatization factor derived from Cleary and Guy’s factor analysis of the 
HDRS scale, includes six items from the original 17-item version: the items for psychic 
anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, 
hypochondriasis, and insight (Cleary 1977). Anxious depression is often defined as MDD 
with high levels of anxiety symptoms, as reflected in an anxiety/somatization factor score 
≥7 (Fava 2008).
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 et al, 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). 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.


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Clinical Global Impression – Improvement (CGI-I)
The CGI-I is a 7-point scale that requires the clinician to assess how much the subject’s 
illness has improved or worsened relative to a baseline state at the beginning of the 
intervention and rated as: 1=very much improved; 2=much improved; 3=minimally 
improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.
An example of the CGI-I is provided in Attachment 2.
Patient Reported Outcome Assessments
Clinically Useful Depression Outcome Scale (CUDOS-A)
The CUDOS contains 18 items assessing all of the Diagnostic and Statistical Manual of 
Mental Disorders (5th edition) (DSM-5) inclusion criteria for major depressive disorder and 
dysthymic disorder as well as psychosocial impairment and quality of life. The 16 symptom 
items are rated on a 5-point Likert scale in order to keep the scale brief. The CUDOS was 
designed to be brief (completed in less than 3 minutes), quickly scored (in less than 15 
seconds), clinically useful (fully covering the DSM-5 symptoms of major depressive disorder 
and dysthymic disorder), reliable, valid, and sensitive to change.
The content of the CUDOS-A subscale was based on the DSM-5 criteria for the anxious 
distress specifier. The 5 symptoms of the anxious distress specifier are as follows: feeling 
keyed up or tense, feeling restless, having difficulty concentrating because of worry, fearing 
that something awful might happen, and feeling that one might lose control. The items for the 
anxious distress specifier were drawn from a larger pool of 113 items assessing symptoms of 
anxiety. The pool of items was reviewed by clinicians experienced in treating mood and 
anxiety disorders, and consensus was reached regarding the items assessing the 5 criteria of 
the DSM-5 specifier. The respondent rated the 5 CUDOS-A items on the same 5-point ordinal 
scale used to rate the symptoms of depression (Zimmerman 2014). The CUDOS-A will be 
included in this trial to determine the correlation between endorsement of the DSM-5 criteria 
and other symptom assessments in this population and to explore for change as a function of 
time and/or treatment. 
An example of the CUDOS-A is provided in Attachment 3.
Cognitive and Physical Functioning Questionnaire (CPFQ) 
The CPFQ is a brief self-report scale that provides additional information regarding the 
impact of adjunctive treatment on aspects of cognitive function including attention, memory 
and mental acuity. Subjects with MDD are often reported to have difficulties with functioning 
in this area.
An example of the CPFQ is provided in Attachment 4.
Snaith-Hamilton Pleasure Scale (SHAPS)
An instrument developed for the assessment of hedonic capacity is the 14-item, self-report, 
Snaith–Hamilton Pleasure Scale (SHAPS; Snaith et al., 1995). The SHAPS was developed to 
minimize cultural, gender, and age biases in the evaluation of hedonic capacity. It not only 
measures hedonic tone, but also its absence, i.e. anhedonia. Anhedonia can be a core 


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symptom of depression. Four major domains are covered in the scale, namely 
interest/pastimes, social interaction, sensory experience, and food/drink.
An example of the SHAPS is provided in Attachment 7.
Medical Outcomes Study Sleep-Revised (MOS Sleep-R)
Symptoms of poor sleep commonly occur in anxiety and mood disorders. The Medical 
Outcomes Study Sleep-Revised (MOS Sleep-R) is a subject-completed scale containing 
12 items that addresses various dimensions of sleep. The instrument yields six subscales: 
sleep disturbance, snoring, shortness of breath or headache, sleep adequacy, sleep 
somnolence, and sleep quantity. Most items are answered on 5-point Likert scales for 10 of 
the items, where 1=“all of the time,” and 5=“none of the time,” 1 item on sleep latency is 
answered on a 5 point Likert scale from 1=“0-15 minutes” to 5=“more than 60 minutes.” The 
final item on the duration of sleep allows the subject to write in the number of hours slept per 
night. The version to be used in this study has a recall period of the 4 past weeks. Quantity of 
sleep is scored as the average number of hours slept per night. Other subscales scores are 
converted to a T-score with a mean of 50, standard deviation (SD) of 10 and range of 0 to 
100, where higher scores indicate fewer sleep-related problems.  The instrument has good 
data supporting its psychometric properties, and development history (Quick Start Guide for 
the MOS Sleep Scale-Revised 2010).
An example of the MOS Sleep-R is provided in Attachment 5.
Perceived Stress Scale (PSS)
The PSS is a brief, validated self-report scale that was selected to evaluate the impact of 
treatment with adjunctive JNJ-42165279 compared to placebo on perceived stress in this 
population. 
An example of the PSS is provided in Attachment 6.
Self-Assessment of Treatment Experience 
The Self-Assessment of Treatment Experience questionnaire is a 4-item self-report scale 
designed to provide additional information regarding the subject’s subjective experience 
while taking the treatment. This questionnaire is an internal Janssen scale.
An example of the Self-Assessment of Treatment Experience is provided in Attachment 8.
Safety Evaluations
Clinical Scales
Columbia Suicide Severity Rating Scale (C-SSRS)
An interview to assess the risk of suicidal ideation and behavior will be conducted at each 
study visit from Screening through the end of the double-blind treatment phase. 
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 


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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. 
If a suicide-related thought to behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be 
provided.
See Attachment 9 and Attachment 10 for examples of the C-SSRS (baseline) and C-SSRS 
(since last visit), respectively.
Pharmacokinetic Evaluations
During the study, the sparse blood samples will be collected at the time points indicated in 
the Time and Events Schedule for PK evaluation in patient population. Concentration time 
data will allow estimation of individual PK parameters for JNJ-42165279 using a population 
PK modeling approach. It will also help to understand potential PK differences between 
healthy subjects and subjects with MDD. Time and days of JNJ-42165279 plasma 
concentration assessment were chosen to gather maximal information about the PK properties 
of JNJ-42165279 while minimizing subject burden regarding blood sampling.
Pharmacodynamic Biomarkers
During the study, the following PD evaluations will be performed at the time points indicated 
in the Time and Events schedule: plasma concentrations of FAAs (AEA, PEA and OEA).
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to inter-
individual differences in drug distribution, metabolism 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 DNA for genotyping 
 which has been 
 
(Conzelman et al, 2012).
Approximately one quarter of the population carries the 
. Genotyping of 
this gene may 
 measured in this study. In addition, 
pharmacogenomics research may allow for the identification of 
 
factors that influence the 
 
 of JNJ-42165279 and for the identification of
 
. Specifically, 
 
known to be in 
 
will be evaluated.
Biomarker samples (blood, saliva) will be collected for the 
 
 (including but not limited to markers related to 
 
 
to allow for 
 and for an 
 
 evaluation.
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DNA and Biomarker samples may be used to help to explain 
 
 or may help to identify population subgroups that respond differently to a 
drug. DNA and Biomarker samples may be used to help address emerging issues and to 
enable the development of safer, more effective, and ultimately individualized therapies.
3.3.
Stopping Criteria
3.3.1.
Individual Stopping Criteriaa
In this phase 2a safety study, the following individual stopping rules will apply: 
The investigator or sponsor believes (e.g. that for safety or tolerability reasons such as a 
serious adverse event at least possibly related to the study drug) it is in the best interest of the 
subject to discontinue the study. 
The subject becomes pregnant
A subject will be discontinued from the study when the QTc interval (QTcF; QTcB if ECG 
machine only shows QTcB) is higher than 500 msec. ECG events should be confirmed by 
repeat twice as soon as possible after the initial ECG, and the average value of the QTcB
interval will be used to determine whether a subject should be discontinued. The subject will 
continue to be monitored by repeated 12-lead ECGs (at least every 60 min) until the ECG 
normalizes.
Because of limited information on the effects of JNJ-42165279 on the human liver function a 
subject will be discontinued from the study if either of the following occur:

Aspartate transaminase (AST) and/or alanine transaminase (ALT) >3 x ULN 
(confirmed by repeat),

Total bilirubin >2 x ULN (confirmed by repeat).  
3.3.2.
Protocol Stopping Criteria
Medical monitoring by the sponsor will occur on a continual basis including laboratory and 
ECG data.  A Data Review Committee (DRC) may be established to monitor data on an 
ongoing basis to ensure the continuing safety of the subjects enrolled in this study (see 
Section 11.8 Data Review Committee) if the frequency of discontinuations exceeds 10% of 
subjects or increases in liver transaminases of 5-fold over the ULN are observed. The 
committee will meet periodically to review interim data. After the review, the DRC will make 
recommendations regarding the safety and continuation of the study. The details will be 
provided in a separate DRC charter.
4.
SUBJECT POPULATIONb
Approximately 143 subjects with MDD with anxious distress will be enrolled in the proof-of-
concept study. Because it is of the interest to assess in this study the effect of FAAH 
inhibition on symptoms of anxiety and depression, additional assessments with anxiety and 
depression scales will be included. 
                                                
a This section has been amended per amendment INT-5
b This section has been amended per Amendment INT-2.
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The inclusion and exclusion criteria for enrolling subjects in this study and the prohibitions 
and restrictions are described in the following 3 subsections. If there is a question about the 
inclusion or exclusion criteria below, the investigator should consult with the appropriate 
sponsor representative before enrolling a subject in the study. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.1, 
Sample Size Determination.
4.1.
Inclusion Criteriaa
Each potential subject must satisfy all of the following criteria to be enrolled in the study
unless otherwise specified:
1.
Subject must be a man or woman between 18 and 64 years of age, inclusive.
2.
Subjects must have a primary DSM-5 diagnosis of MDD with Anxious Distress. 
Subjects with a diagnosis of comorbid Generalized Anxiety Disorder (GAD), Social 
Anxiety Disorder, or Panic Disorder may be included, if the investigator considers 
MDD with Anxious Distress to be the primary diagnosis (confirmed by an 
independent central rater through review of the MINI interview obtained by the site at
screening).
Subjects must have been treated with an SSRI/SNRI antidepressant approved in this 
protocol at an adequate dose, as defined by the ATRQ, and for at least 6 continuous 
weeks, validated by an independent central rater contracted by the sponsor. 
3.
A HDRS17 total score 18 at screening, assessed by a site rater and validated through
review by an independent central rater contracted by the sponsor; and on Day 1 by 
site rater.
4.
A HDRS17 anxiety/somatization factor score ≥7at screening, assessed by a site rater 
and validated through review by an independent central rater contracted by the 
sponsor; and on Day 1 by site rater.
5.
Subjects must have a body mass index (BMI=weight/height²) between 18 and 
35 kg/m2, inclusive, at screening.
6.
Criterion modified by Amendment 4.
6.1.Before randomization, a woman must be either:

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 >40 IU/L); permanently sterilized 
(e.g., tubal occlusion, hysterectomy, bilateral salpingectomy); or 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 
                                                
a This section has been amended per Amendment INT-1, 3 and 4.


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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 (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.  

All women must have a negative pregnancy test at screening and a negative urine 
pregnancy test on study day 1.

All women 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.
7.
Criterion modified by Amendment 4.
7.1.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 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.
8.
Subjects must be otherwise healthy for their age group or medically stable with or 
without medication on the basis of physical examination, medical history, vital signs, 
and 12-lead ECG performed at screening or at baseline. If there are abnormalities, 
they must be consistent with the underlying illness in the study population with 
written concurrence with the sponsor's medical monitor.
9.
Subjects must be otherwise healthy or medically stable on the basis of clinical 
laboratory tests performed at screening. If the results of the serum chemistry panel 
[including liver enzymes, other specific tests], hematology, or urinalysis are outside 
the normal reference ranges, the subject may be included only if the investigator 


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judges the abnormalities or deviations from normal to be not clinically significant. 
This determination must be recorded in the subject’s source documents and initialed 
by the investigator.
10.
Subject must be willing and able to adhere to the prohibitions and restrictions 
specified in this protocol.
11.
Subject must be willing and able to fill out self-administered questionnaires.
12.
Subject must be able to be compliant with self-administration of medication.
13.
Subject must be able to swallow the study medication whole with aid of water.
14.
Subject must sign an informed consent document indicating that they understand the 
purpose of and procedures required for the study and are willing to participate in the 
study.
4.2.
Exclusion Criteriaa
Any potential subject who meets any of the following criteria will be excluded from 
participating in the study unless otherwise specified:
1. 
Has any other current major psychiatric condition, including, but not limited to, 
MDD with psychotic features (lifetime), bipolar disorder (including lifetime 
diagnosis), 
obsessive-compulsive 
disorder, 
post-traumatic 
stress 
disorder, 
borderline personality disorder, eating disorder (e.g., bulimia, anorexia nervosa), or 
schizophrenia. 
The MINI will be conducted by the primary investigator/sub-investigator (either a 
psychiatrist or Ph.D. psychologist) at Screening to confirm MDD as the primary 
diagnosis. In addition, an independent rater will confirm that the current depressive 
episode is valid as well as verifying any comorbid psychiatric conditions validated 
in the MINI. As noted, subjects with a diagnosis of comorbid GAD, Social Anxiety 
Disorder, or Panic Disorder may be included.  
2.
3.
Has a length of current major depressive episode (MDE) >6 months.
Has initiated psychotherapy specific for MDD (such as cognitive behavioral, 
behavioral, or interpersonal therapy) for the current episode of depression within 6 
weeks prior to screening. Subjects receiving psychotherapy can continue receiving 
psychotherapy provided this therapy has been stable in frequency for the last 6 
months and will remain unchanged throughout the study treatment.
4.
Has more than 1 failed treatment with antidepressants of adequate dose and 
duration in the current major depressive episode, prior to and not including the 
inadequate response to the current SSRI/SNRI antidepressant.
                                                
a This section has been amended per Amendments INT-1, 2 and 5.


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5.
Has a history of resistance to medication treatment of major depressive episodes 
(≥3 lifetime treatment failures with approved antidepressants at adequate doses and 
duration).
6.
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 Columbia Suicide Severity Rating Scale (C-SSRS), 
or a history of suicidal behavior within the past year, as validated by the C-SSRS at 
screening or Day 1. Subjects with a prior suicide attempt, 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.
7.
Subject has a history of or current thyroid disease, thyroid dysfunction and is 
currently untreated for it. Subjects treated for thyroid disease may be enrolled 
following review of their records of diagnosis and treatment history by the 
investigator and with written concurrence with the sponsor's medical monitor to 
ensure disease/treatment stability and compliance.
8.
Criterion modified by Amendment 2.
8.1.
Subject has clinically significant abnormal findings on physical examination, 
neurological examination or clinically significant abnormal vital signs 
indicative of untreated illness (such as infection or hypertension).
9.
Criterion modified by Amendment 5.
9.1.
Subject has a clinically significant abnormal finding on 12-lead ECG such as 
QTcF (QTcB if ECG machine only shows QTcB) >450 msec for males and 
females, Left Bundle Branch Block, AV Block second degree or higher, 
permanent pacemaker or implantable cardioverter defibrillator (ICD) at 
screening or baseline (Day 1 predose), or any finding which in the opinion of 
the investigator is not appropriate and reasonable for the population under 
study. ECG recordings and vital signs may be repeated once and for questions 
on findings on the ECG a local cardiologist should be consulted. 
10. 
Criterion modified by Amendment 5.
10.1
Subject has a history of or current liver or renal insufficiency; clinically 
significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, 
hematologic, rheumatologic, psychiatric, or metabolic disturbances (e.g. 
unstable situation needing monitoring or regular dose adaptations). Subjects 
with renal or liver function analytes significantly higher (more than 1.5 
times the upper limit of normal) at screening are not eligible for the study.
11.
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 written concurrence with 
the sponsor's medical monitor, is considered cured with minimal risk of recurrence).


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12.
If a subject is using a drug with moderate/strong CYP3A4 inhibiting or inducing 
properties at, or prior to, screening it must be discontinued within the equivalent of 
at least 5 half-lives prior to Day 1. Note: an existing medication should not be 
stopped solely for the purpose of the subject entering the study. Use of moderate 
and strong inhibitors and inducers of CYP3A4 are prohibited during the study (See 
Attachment 12). 
13.
Subject has a history of positive tests for 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.
14.
Subject has a history of human immunodeficiency virus (HIV) antibody positive, or 
tests positive for HIV at Screening.
15.
Subject has a history of drug or alcohol use disorder according to Diagnostic and 
Statistical Manual of Mental Disorders (5th edition) (DSM-5) criteria within 
6 months before screening, or positive test result(s) for drugs of abuse (including 
barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) at 
screening. A positive screen for benzodiazepines is allowed if related to recent 
treatment.
16.
Subject has taken any disallowed therapies as noted in Section 8, Concomitant 
Therapy before the planned first dose of study drug.
17.
Subject has known allergies, hypersensitivity, or intolerance to JNJ-42165279 or its 
excipients (refer to Investigator's Brochure).
18.
Subject has received an investigational drug or used an investigational medical 
device within 3 months before the planned start of study or is currently enrolled in 
an investigational study.
19.
Criterion modified by Amendment 5.
19.1
Subject is a woman who is pregnant, or breast-feeding, or planning to 
become pregnant or is a man who plans to father a child, while enrolled in 
this study or within 3 months after the last dose of study.
20.
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.
21.
Subject has had major surgery, (e.g. requiring general anesthesia) within 8 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 or within 
4 weeks after the last dose of study drug administration. 
Note: subjects with planned surgical procedures to be conducted under local 
anesthesia may participate.


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22.
Subject has a history of spontaneous, prolonged or severe bleeding.
23.
Subject has donated one or more units (approximately 450 mL) of blood or had 
acute loss of an equivalent amount of blood within 90 days prior to study drug 
administration.
24.
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
25.
Subject is unable to comply with the study-specific requirements.
4.3.
Prohibitions and Restrictions
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.
A man who is sexually active with a woman of childbearing potential and has not 
had a vasectomy must agree to use a barrier method of birth control e.g., either 
condom with spermicidal foam/gel/film/cream/suppository or partner with 
occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository, and all men must also agree not to donate sperm 
during the study and for 3 months after receiving the last dose of study drug. In 
addition, their female partners, if of childbearing potential, should also use an 
appropriate method of birth control for at least the same duration.
2.
Alcohol-containing products are not permitted from 24 hours before scheduled 
visits to the study site. The use of limited amounts of alcohol (up to 2 drinks daily) 
during the other days will be allowed.
3.
Subjects must abstain from using illegal drugs (including cannabis and marihuana) 
from Screening through the end of the post-treatment phase. While cannabis and 
marihuana use may be sanctioned in some regions, use of cannabanoids during this 
trial would prevent detection of an effect of JNJ-42165279 and therefore must not 
be used while participating in the trial.  If the subject has a positive urine drug 
screen during the study, he/she will be discontinued from the study.
4.
Subjects are prohibited from taking/consuming grapefruit, grapefruit juice, Seville 
oranges or poppy seeds from Screening through the end of the post-treatment phase.
5.
For a list of prohibited medications, please see Section 8 (Prestudy and 
Concomitant Therapy).


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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
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 (pooled)
center and lead-in response status. Exact timing of randomization for each subject will be 
blinded. The interactive voice/web response system (IVRS/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 IVRS/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 IVRS/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.
Under normal circumstances, the blind should not be broken until all subjects have completed
the study and the database is finalized. Otherwise, the blind should be broken only if specific
emergency treatment/course of action would be dictated by knowing the treatment status of 
the subject. In such cases, the investigator may in an emergency determine the identity of the
treatment by contacting the IVRS/IWRS. It is recommended that the investigator contact the 
sponsor or its designee if possible to discuss the particular situation, before breaking the 
blind. 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 case report form (CRF), and in the source document. The documentation received from 
the IVRS 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.
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 the DRC is specified (see 


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Section 11.3), 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.
DOSAGE AND ADMINISTRATIONa
Study medication will be provided as JNJ-42165279 tablets, strengths 25 mg and matching 
placebo, packaged in bottles. All tablets (JNJ-42165279 /placebo) are physically identical. 
A study-site investigational product manual including instructions for dispensing, storage (on 
site and at home) and intake of the study medication will be supplied to the study-site. 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol.
The selected 25 mg dose of JNJ-42165279 is expected to result in complete inhibition of 
FAAH enzyme in the brain throughout the dosing interval based on the outcome of the single 
ascending dose (42165279EDI1001), multiple ascending dose (42165279EDI1002) and PET 
occupancy (42165279EDI1003) studies.
During the treatment phase of this study dispensing and redispensing of their study 
medication will take place at the visits indicated in the Time and Events schedule. On Days 
of re-dispensing subjects will hand in their medication package dispensed previously and 
drug accountability will be performed.
Following last dosing, subjects will hand in their study medication received previously and 
final drug accountability will be performed.
During the entire blinded treatment period, subjects will self-administer once-daily (q.d.) 
study drug (JNJ-42165279/placebo) with a glass of non-carbonated water, after completion of 
breakfast or a light snack, during the morning hours, according to the instructions provided 
by the investigator. The sponsor may optionally develop tools to improve and/or document 
compliance to intake of study medication when locally feasible. This may include a diary or 
an electronic registration tool.
During scheduled visits, subjects will self-administer their study medication on site as 
described above, which will be witnessed by designated study-site personnel at the study 
sites. On Day 1 study drug administration will be administered following completion of all 
predose assessments and will not be limited to the morning hours.
7.
TREATMENT COMPLIANCE
The investigator or designated study-site personnel will maintain a log of all study drug 
dispensed and returned. Drug supplies for each subject will be inventoried and accounted for 
throughout the study. 
Study drug will be self-administered by subjects. As such the number of study drug dispensed 
will be recorded and compared with the number returned. 
                                                
a This section has been amended per Amendments INT-2 and 4.


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At study visits, study drug will be self-administered on site, which will be witnessed by 
designated study-site personnel at the study sites.
Subjects will receive instructions on compliance with study drug administration upon study 
medication (bottle) dispensing. During the course of the study, the investigator or designated 
study-site personnel will be responsible for providing additional instruction to re-educate any 
subject who is not compliant with taking the study drug. 
8.
PRESTUDY AND CONCOMITANT THERAPYa
Prestudy therapies administered up to 30 days before screening must be recorded at 
screening. 
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, venlafaxine XR, desvenlafaxine, duloxetine, 
milnacipram, vilazodone and vortioxetine. 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 through the end of the 
study, including the post-treatment phase. 
Concomitant therapies must be recorded throughout the study beginning with signing of the 
initial informed consent until the end-of-study visit (Follow-up visit). Concomitant therapies 
should also be recorded beyond this time only in conjunction with new or worsening adverse 
events until resolution of the event.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, 
herbal supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, 
special diets, exercise regimens) different from the study drug must be recorded in the CRF. 
Modification of an effective pre-existing therapy should not be made for the explicit purpose 
of entering a subject into the study.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Subjects are not allowed to participate if they have initiated psychotherapy specific for MDD 
(such as cognitive behavioral, behavioral, or interpersonal therapy) for the current episode of 
depression within 6 weeks prior to screening. Subjects who are otherwise receiving long-
standing psychotherapy can continue receiving psychotherapy provided this therapy has been 
stable in frequency for the last 6 months and will remain unchanged throughout the study 
treatment.
Prohibited Medications
Refer to Section 4.2 (Exclusion Criteria) for prohibited medications evaluated at Screening.
                                                
a This section has been amended per Amendments INT-1, 2 and 5.


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Subjects must agree not to use any of the following medications with psychotropic properties 
during study participation, including but not limited to:
Psychiatric medications other than the SSRI/SNRIs allowed in the protocol. Prohibited 
medications include mood stabilizers, antipsychotics, other antidepressants (e.g., MAOIs or 
TCAs), or medications to treat anxiety (including benzodiazepines: see below)
Sleep medications/medications to treat anxiety:

Benzodiazepines: Because concomitant use of benzodiazepines will confound the 
ability to interpret any potential anxiolytic efficacy signal, sleep aids and anxiolytics 
from the benzodiazepine class (e.g., lorazepam, temazepam, oxazepam, flurazepam, 
triazolam etc.) are prohibited from within 7 days prior to Screening and throughout 
the study duration.
Note: Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon and 
eszopiclone) are allowed on a PRN (as needed) basis during the study, however, not 
more than 2 nights in a row and not more than a total of 3 nights weekly during the 
double-blind treatment period.
Other Prohibited Medications include:

Sedating antihistamines

Melatonine and ramelteon

S-adenosyl methionine (SAMe), St. John’s wort, ephedra or kava kava

Opiates, including morphine, codeine hydrocodone, oxycodone, and methadone

Anticonvulsants

Moderate and strong CYP3A4 inhibitors or inducers (Attachment 12)
9.
STUDY EVALUATIONS     
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the visits as well as the frequency and timing of 
assessments applicable to this study. A visit window of +/- 3 calendar days will be allowed 
for all visits, unless otherwise indicated in the Time and Events Schedule. All visits are in 
principle single day visits however they may be performed over multiple days within the 
allowed visit window in case of logistical issues or subject’s preference.
In the event of abnormal safety findings during the conduct of the study, additional 
measurements may be made immediately and subsequently at a frequency considered 
appropriate by the attending physician.
The time points for individual measures may be changed (with or without affecting the 
overall frequency of these investigations) prior to and during the study based on newly 
obtained data (e.g., interim analysis, DRC) to allow for optimal fit to the actual safety or 
PK/PD profile of the study drug. This modification may result in a change in the overall 
frequency of the individual measures (e.g. safety measures, blood samplings) provided the 
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modifications, where performed only to allow optimal fit to the actual safety, PK/PD profile 
of the study drug, will not be considered to be an (substantial) amendment to the protocol.
Venous blood will be collected for all blood-based analysis. 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(s), vital signs, blood draw.
Blood may be drawn by using a cannula or by venipuncture. 
The order of multiple assessments within one protocol time point should also be the same 
throughout the study. 
Vital signs will be recorded from the opposite arm from which the blood samples are being 
taken.
Blood pressures and ECGs should be recorded approximately 5 to 10 minutes before PK 
blood samples are taken.
The volume of blood collected per subject will be detailed in a separate lab manual.
For each subject, the maximum amount of blood drawn in this study will not exceed 300 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
9.1.2.
Screening Phasea
Before any study specific procedures are conducted and following an explanation of the 
purpose and risks of the study, subjects will sign an informed consent form (ICF).
After giving initial written informed consent, subjects will be screened to assess their 
eligibility for the study according to the inclusion and exclusion criteria defined for this 
study.
Recording of adverse events/concomitant medication will start following consent and will 
continue until completion of the study.
During screening following assessments/procedures will be performed:
Physical examination
Neurological examination
Body weight
12-lead ECG 
Body temperature
Height
Supine vital signs (systolic and diastolic blood pressure and pulse)
                                                
a This section has been amended per Amendments INT-1 and 2.


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C-SSRS (baseline)
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
serology, hematology, serum chemistry, coagulation, TSH, FSH [women only] and 
urinalysis)
Urine drug screen
Alcohol screen
All women: Blood and urine pregnancy test
Review of inclusion and exclusion criteria
Complete/Review Medical History and Demographics
Complete/Review Prestudy Therapy (ATRQ) (reviewed and validated by an independent 
central rater)
Review preplanned surgery/procedures
Mini International Neuropsychiatric Interview (MINI) (reviewed and validated by an 
independent central rater)
HDRS17 using the SIGH-D (reviewed and validated by an independent central rater only at 
screening)
Record adverse events and concomitant medication
9.1.3.
Double-Blind Treatment Phasea
Day 1
Subjects who successfully complete the screening examination will visit the clinical site on 
Day 1 during the morning hours. 
Prior to dosing the following (baseline) assessments will be performed:
Body weight
12-lead ECG (triplicate)
Body temperature
Supine vital signs (systolic and diastolic blood pressure and pulse)
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
WOCBP: urine pregnancy test.
Blood and saliva collection for exploratory biomarkers
Urine drug screen
Alcohol screen
                                                
a This section has been amended per Amendment INT-2 and 4.
CCI


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Review of inclusion and exclusion criteria
Randomization
Dispense placebo
HDRS17 using the SIGH-D
SIGH-A
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
Study medication will be dispensed and administered as outlined in Section 6, Dosage and 
Administration. Subjects will self-administer their study medication q.d. as instructed.
On Day 1 dosing will not be time limited and will be performed following completion of the 
baseline (predose) assessments and will be witnessed by designated study-site personnel at 
the study sites.. 
During the double-blind treatment period, following Day 1, subjects will return to the 
investigational site at regular time points as indicated in the Time and Events Schedule and 
further described below.   
Week 1 (Day 7)
Subjects will visit the site at Day 7 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites.
The following assessments will be performed at Day 7 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
WOCBP: urine pregnancy test.
Randomization
Drug accountability/Treatment compliance will be assessed.
Dispense study drug


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HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
Week 2 (Day 14)
Subjects will visit the site at Day 14 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites. 
The following assessments will be performed at Day 14 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
Randomization
Dispense study drug
Drug accountability/Treatment compliance will be assessed.
C-SSRS 
WOCBP: urine pregnancy test.
Blood sample collection for PK of JNJ-42165279 (predose and 2 to 4 hours postdose)
HDRS17 using the SIGH-D
SIGH-A
CGI-I
Record adverse events and concomitant medication
Week 3 (Day 21)
Subjects will visit the site at Day 21 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites. 


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The following assessments will be performed at Day 21 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
Urine drug screen
WOCBP: urine pregnancy test.
Randomization
Drug accountability/Treatment compliance will be assessed.
Dispense study drug
HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
Week 4 (Day 28)
Subjects will visit the site at Day 28 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites. 
The following assessments will be performed at Day 28 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
Randomization
Dispense study drug
Drug accountability/Treatment compliance will be assessed.
C-SSRS 
WOCBP: urine pregnancy test.
HDRS17 using the SIGH-D


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SIGH-A
CGI-I
Record adverse events and concomitant medication
Week 5 (Day 35)
Subjects will visit the site at Day 35 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites. 
The following assessments will be performed at Day 35 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
Neurological examination
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
Blood sample collection for PK of JNJ-42165279 (predose and 2 to 4 hours postdose)
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
WOCBP: urine pregnancy test.
Blood sample collection for pharmacogenomics
Randomization
Drug accountability/Treatment compliance will be assessed.
Dispense study drug
HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
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Week 7 (Day 49)
Subjects will visit the site at Day 49 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites.
The following assessments will be performed at Day 49 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
Urine drug screen
WOCBP: urine pregnancy test.
Randomization
Drug accountability/Treatment compliance will be assessed.
Dispense study drug
HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
Week 9 (Day 63)
Subjects will visit the site at Day 63 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites.


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The following assessments will be performed at Day 63 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
Neurological examination
C-SSRS 
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
WOCBP: urine pregnancy test.
Blood sample collection for PK of JNJ-42165279 (predose and 2 to 4 hours postdose)
Blood sample collection for pharmacogenomics
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
Randomization
Drug accountability/Treatment compliance will be assessed.
Dispense study drug
HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Record adverse events and concomitant medication
Week 11 (Day 77)
Subjects will visit the site at Day 77 during morning hours. Study medication will be self-
administered on site as outlined in Section 6, Dosage and Administration, which will be 
witnessed by designated study-site personnel at the study sites.
The following assessments will be performed at Day 77 as specified in the Time and Events 
schedule. Assessments can be performed pre-or post dose unless otherwise indicated.
Physical examination
Neurological examination
C-SSRS 
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Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)
All women: Urine and serum pregnancy test
Urine drug screen
Blood sample collection for PK of JNJ-42165279 (predose and 2 to 4 hours postdose)
Blood sample collection for pharmacogenomics
Body temperature
Body weight
12-lead ECG
Supine vital signs (systolic and diastolic blood pressure and pulse)
Drug accountability/Treatment compliance will be assessed.
HDRS17 using the SIGH-D
SIGH-A
CGI-I
CPFQ
CUDOS-A
SHAPS
MOS Sleep-R
PSS
Self-assessment of treatment experience
Record adverse events and concomitant medication
9.1.4.
Posttreatment Phase (Follow Up)
Minimally 7 and maximally 21 days following last dosing (Week 11), subjects will return to 
the clinical site for a safety follow up visit. The procedures to be completed during the follow 
up visit are listed in the Time and Events Schedule.
Investigators may re-contact the subject to obtain long-term follow-up information to 
determine the subject's safety or survival status (refer to Section 16.2.3, Informed Consent).
The following assessments will be performed at the follow-up visit as specified in the Time 
and Events schedule:
Physical examination
Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis) – Only in case of any clinical 
significant abnormalities at Week 11
Body temperature
Body weight
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12-lead ECG (only in case of any clinical significant abnormalities at Week 11)
Supine vital signs (systolic and diastolic blood pressure and pulse)
Record adverse events and concomitant medication
9.2.
Safety Evaluations
During the blinded treatment phase regular safety assessments will be performed as listed in 
the Time and Events Schedule. These safety assessments include but are not limited to: vital 
signs, ECG, physical examination, adverse events, safety labs, pregnancy tests, suicidality 
risks (C-SSRS). 
The Data Review Committee (DRC) may decide to modify the frequency over time of 
specific safety assessments in case (newly obtained) data collected in this study would 
support this decision.
Details regarding the DRC are provided in Section 11.8.
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.
9.2.1.
Adverse Events
Adverse events will be reported by the subject for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
9.2.2.
Columbia Suicide Severity Rating Scale (C-SSRS)
Consistent with regulatory guidance, any occurrence of suicide-related thoughts and 
behaviors will be assessed. An interview to assess the risk of suicidal ideation and behavior 
will be conducted at the time points listed in the Time and Events Schedule. 
The C-SSRS is a 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)19. 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. 
If a suicide-related thought or behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be 
provided.
See Attachment 9 and Attachment 10 for examples of the C-SSRS (baseline) and C-SSRS 
(since last visit), respectively.


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9.2.3.
Vital Signs
Vital signs (body temperature, pulse/heart rate, supine blood pressure) will be collected at the 
time points indicated in the Time and Events Schedule.
9.2.4.
Electrocardiogram
Twelve-lead ECGs2 will be collected at the time points listed in the Time and Events 
Schedule.
Only at Day 1 triplicate ECGs are required, i.e., 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set 
of triplicates should be completed in less than 4 minutes. 
During the study, the clinical investigator will review the ECG for immediate management 
and to mark abnormalities. A description of the overall assessment (i.e., normal or abnormal 
plus reason) will be made and a copy of the trace will be placed with the source data. 
9.2.5.
Physical and Neurological Examinationsa
The study investigator or other authorized and appropriately qualified designee will perform 
the physical examination.
Height will be measured at screening only. Body weight will be measured as per the Time 
and Events schedule.
The neurological examination can be adapted as necessary but should include mental status 
(orientation and memory); oculomotor motion and vision for cranial nerve testing; limb 
strength and abnormal movements for motor function; and tests of cerebellar function: gait, 
finger-to-nose, heel-to-shin, and rapid alternating movements. Tests of sensation (e.g., pain, 
vibration) should be included only if indicated by clinical history/symptoms.
The neurological examination will be done at screening, during the treatment phase and at the 
end of treatment visit (or early withdrawal visit) for all subjects. In addition, neurological 
examinations will be completed when event driven. These events of interest include diplopia, 
vision impairment, gait disturbance and severe headache.
9.2.6.
Clinical Laboratory Testsb
Blood samples (under fasted conditions whenever feasible) for serum chemistry and 
hematology and a random urine sample for urinalysis will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the adverse event section of the CRF. The laboratory 
reports must be filed with the source documents. The following tests will be performed a 
central laboratory appointed by the Sponsor:
                                                
a This section has been amended per Amendment INT-2.
b This section has been amended per Amendment INT-4


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Hematology Panel 
-hemoglobin
- platelet count
-hematocrit
- mean corpuscular volume
- red blood cell (RBC) count
- mean corpuscular hemoglobin
- white blood cell (WBC) count with differential
Coagulation
-prothrombin time (PT)
-activated partial thromboplastin time (aPPT)
- mean corpuscular hemoglobin 
concentration
- International normalized ratio (INR)
Serum Chemistry Panel 
Urinalysis 
Dipstick
Flow Cytometry
-specific gravity
-RBC
-pH
-WBS
-glucose
-epithelial cells
-protein
-blood
-ketones
Sediment 
-bilirubin
-crystals
-urobilinogen
-casts
-nitrite
-bacteria
-leukocyte esterase
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be 
determined using a dipstick. RBC, WBC, epithelial cells, crystals, casts, and bacteria will be 
measured using flow cytometry. If there is discordance between the dipstick results and the 
flow cytometric results, the sediment will be examined microscopically.
-sodium
-alkaline phosphatase (ALP)
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
- phosphate
-glucose
-albumin
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-cholesterol
-gamma-glutamyltransferase (GGT)
-triglycerides
-total and direct bilirubin
-high density lipid protein
-low density lipid protein
-magnesium
TSH (all subjects) and FSH (only women) 
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Urine Drug Screen: opiates (including methadone), cocaine, amphetamines, cannabinoids, 
barbiturates, and benzodiazepines. 
Serology (hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV), HIV)
Alcohol breath test
Pregnancy tests:

In all women: serum β-HCG and urine pregnancy test will be performed at 
Screening and at study visit 10. 

In WOCBP: serum β-HCG and urine pregnancy test will be performed at all other 
timepoints. 

If the urine pregnancy test is positive, a serum β-HCG test will be performed.
The use of local laboratories is allowed in cases where initiation of treatment or safety 
follow-up is time-critical and the central laboratory results are not expected to be available 
before the need to begin dosing or if actions need to be taken for safety reasons (samples will 
be taken in parallel for the central laboratory).
9.3.
Efficacy
9.3.1.
Evaluations 
The nature and content of the primary and secondary clinician administered scales as well as 
the Patient Reported Outcome scales are described in Section 3.2.  Subscales derived from 
the principal scales are defined below. 
Primary
Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of 
symptoms in subjects diagnosed with depression (Hamilton M 1960) with a score range of 0 
to 52. It is the most widely used symptom severity measure for depression. Each of the 17 
items is rated by the clinician on either a 3- or a 5-point scale. The HDRS has an inter-rater 
reliability correlation of r = .90 and the internal consistency of the measure is reported to be 
high with a coefficient alpha of 0.88. Criterion-related validity for this measure is high; 
Knesevich et al. found a high correlation between the Hamilton score and a psychiatrist’s 
global rating (r = 0.89, and between the change in these ratings during treatment (r = 0.68) 
(Knesevich J 1977).
Secondary
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A)
The total and subscale scores for the SIGH-A and HDRS17 will be used to evaluation of 
efficacy on symptoms of anxiety and depression. 
HAM-A6
The HAM-A6 is a 6-item subscale derived from the original Hamilton Anxiety scale (HAM-
A) (Hamilton 195910; Hamilton 196912). Because the HAM-A, like the Hamilton Depression 
Rating Scale (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, 


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intellectual disturbances, and anxious behavior observed at the interview, as well as one 
somatic item, muscular tension (Bech 2007) 3, 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-5 criteria for GAD than the full HAM-
A), the total HAM-A6 score is considered a sufficient statistic. 
HAM-D6
A 6-item subscale from the HDRS17 (HAM-D6) will be analyzed as it has been shown to be a 
uni-dimensional scale that provides information to core depressive symptoms and is sensitive 
to treatment response (Bech 1975)4. 
HDRS17 Anxiety/Somatization factor score
In addition the anxiety-somatization factor total score from the HDRS17 will be included 
(Cleary 1977)7. A cut-off of ≥ 7 on this factor has been used to define subjects with anxious 
depression in prior clinical trials (Fava 2008)9.
Clinical Global Impression Improvement (CGI-I)
Patient Reported Outcome Assessments
Clinically Useful Depression Outcome Scale (CUDOS-A)
Cognitive and Physical Functioning Questionnaire (CPFQ) 
Snaith-Hamilton Pleasure Scale (SHAPS)
Medical Outcomes Study Sleep-Revised (MOS Sleep-R)
Perceived Stress Scale (PSS)
Self-Assessment of Treatment Experience
9.3.2.
Endpoints    
Primary endpoint
Efficacy will be based on the change from baseline of the HDRS17 total score with adjunctive 
JNJ-40411813 compared with placebo after 6 weeks of treatment. 
Secondary endpoints
Change from baseline in HAM-A6 score, HDRS17 Anxiety/Somatization factor score, HAM-
D6 score, SIGH-A total score, the distribution of remitters and responders based on HDRS17
and SIGH-A total score reduction from lead-in baseline definitions, will be compared with 
placebo after 6 weeks of treatment.
Exploratory endpoints
Other scales (CGI-I) and patient reported outcomes (CUDOS-A, CPFQ, SHAPS, MOS 
Sleep-R, PSS and Self-Assessment of Treatment Experience) will be used during the study.


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9.4.
Pharmacokinetics
9.4.1.
Evaluations 
Venous blood samples for analysis of JNJ-42165279 in plasma will be collected at the time-
points indicated in the Time and Events Schedule. 
Blood samples will be used to evaluate the plasma pharmacokinetics of JNJ-42165279. 
Samples collected for analyses of JNJ-42165279 plasma concentration may additionally be 
used to evaluate safety or efficacy aspects that address concerns arising during or after the 
study period or for the evaluation of relevant biomarkers. Genetic analyses will not be 
performed on these plasma samples. Subject confidentiality will be maintained.
9.4.2.
Analytical Procedures
Pharmacokinetics
Plasma will be analyzed to determine concentrations of JNJ-42165279 using a validated, 
specific, and sensitive LC-MS/MS method by or under the supervision of the sponsor. 
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. In addition, plasma samples may be stored for 
future analysis of protein binding and the metabolite profile.
9.4.3.
Pharmacokinetic Parameters
PK analyses of the plasma concentrations will be undertaken to estimate peak plasma 
concentration and systemic exposure of JNJ-42165279. Based on the individual plasma 
concentration-time data, if sufficient data are available, the following PK parameters of 
JNJ-42165279 will be estimated at steady state in subjects receiving a dose of JNJ-42165279
using population PK modeling:
Cmax
maximum plasma concentration
tmax
time to reach the maximum plasma concentration
AUC
area under the plasma concentration-time curve from 0 to hours post dosing 
(time is the dosing interval)
The parameters of interest for the statistical analysis will be the log-transformed estimated 
dose normalized AUC and Cmax. All ratios will be calculated as differences of least square 
means of the appropriate model on the log-scale, and will be presented after back-
transformation to the original sale with the corresponding 90% confidence intervals (CIs).
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of JNJ-42165279 will be 
derived using population PK modelling. Baseline covariates (e.g., body weight, age, sex, 
CrCL, race) may be included in the model, if relevant.


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9.5.
Biomarker and Pharmacogenomic Evaluations
During the study, the following PD evaluations will be performed at the time points indicated 
in the Time and Events schedule: plasma concentrations of FAAs (AEA, PEA and OEA).
Blood and saliva will be collected for the assessment of biomarkers at the time points 
indicated conditions (no food or drink except water for at least 8 hours/overnight) between 
08:00 and 10:00 am whenever possible. When fasting is not feasible subjects should be 
advised to follow a low-fat diet. Subjects should be informed to refrain from strenuous 
exercise and use of NSAID medications for 24 hours before blood collection (as the use of 
NSAIDs may impact biomarker measurements, specifically via altering circulating and 
inducible cytokine levels. In addition NSAIDs also have been reported to inhibit FAAH 
directly so there is a particular need in FAAH studies to restrict their use). Any exercise 
performed during 24 hours prior to visit and details of length of fast/food intake prior to 
collection should be recorded on the CRF or lab requisition form. 
In 
 (including but not limited to markers related to 
 
 
will be investigated to allow for 
 and 
for an 
 evaluation. 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. 
 for the measurement of 
 will be collected the evening 
before and upon awakening the morning of the visits indicated in the Time and Events 
schedule. Subjects will collect 
 
  Subjects should not 
 
  
DNA samples will be analyzed 
.8 Additional analyses may be conducted if 
it is hypothesized that this may help resolve issues with the clinical data. DNA samples may 
also be used for the identification of 
 that may influence the 
 of JNJ-42165279, and for 
.
DNA and biomarker samples will be used for research related to JNJ-42165279 or MDD. 
They may also be used to develop tests/assays related to JNJ-42165279 or MDD. 
Pharmacogenomic research may consist of the analysis of one or more candidate genes or of 
the analysis of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate) in relation to JNJ-42165279 or MDD clinical endpoints.
The biomarker and pharmacogenomics 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.
9.6.
Sample Collection and Handling
PK and PD (biomarker) sampling/assessment times and sampling volumes can be adapted 
without protocol amendment provided that the maximal volume collected per subject 
specified per protocol will not be exceeded.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Refer to the Time and Events schedule for the timing and frequency of all sample collections.
The exact dates and times of blood sampling must be recorded in the CRF or lab requisition 
form. 
Instructions for the collection, handling, storage, and shipment of samples will be provided in 
a separate lab manual. Collection, handling, storage, and shipment of samples must be under 
the specified, and where applicable, controlled temperature conditions as indicated in the lab 
manual.
All the assays and instruments used in this study will be performed by trained operators at the 
Sponsor or designated laboratories in Europe or the US on coded samples. 
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed 
assessments at Week 11 (Day 77) of the double-blind phase. Subjects who prematurely 
discontinue study treatment for any reason before completion of the double-blind phase will 
not be considered to have completed the study.
10.2.
Discontinuation of Study Treatment 
If a subject's study treatment must be discontinued before the end of the treatment regimen, 
this will not result in automatic withdrawal of the subject from the study. 
A subject's study treatment should be discontinued if:
The investigator believes that for safety reasons (e.g., adverse event) it is in the best interest 
of the subject to discontinue study treatment
A subject experiences a severe or serious adverse event while receiving treatment, that is 
considered at least possibly related to study drug
Noncompliance with study drug (i.e. less than 80% compliance) during the blinded treatment 
phase
If a subject discontinues study treatment before the end of the blinded phase the subject will 
be asked to complete the End-Of-Treatment Visit (Week 11 assessments) if not obtained 
earlier and the Follow-up visit as per Time and Events Schedule.
10.3.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:
It is not possible to obtain blood 
Serious violation of protocol procedures
Lost to follow-up
Withdrawal of consent
If a subject is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented.


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When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF 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 be asked, if not yet obtained, 
to have the Week 11 assessment performed. In addition, the subjects should have a follow-up 
evaluation as described in Section 9.1.4.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples 
will be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analyses will be conducted by the Sponsor or under the authority of the Sponsor. A 
general description of the statistical methods to be used to analyze the safety, tolerability, 
pharmacodynamic and pharmacokinetic data is outlined below. Specific details will be 
provided in the Statistical Analysis Plan.
11.1.
Sample Size Determinationa
The sample size for the study is determined based on the assumption of a minimally relevant 
treatment effect size of 0.45 in the mean change from baseline to the endpoint in HDRS17
total score between JNJ-42165279 treatment group and placebo. The assumed effect size is 
based on review of the literature looking at the treatments for MDD and MDD with anxious 
distress (Lee 2004 and McIntyre 2007) taking into account that the effect size in enriched 
population is expected to be higher. A standard deviation of 7.5 in the change in HDRS17
total score from baseline is estimated based on previously conducted clinical trial in similar 
patient population (40411813DAX2001) allowing for a higher variability.
The effect size of 0.45 (under SD assumption of 7.5) translates to a treatment difference 
between JNJ-42165279 and placebo at endpoint of 3.5 points. Detection of this magnitude of 
effect size with a power of 90% at an overall 1-sided significance level of 0.20, requires 
45 subjects in each treatment group. 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=10%) but the type 1 error rate was specified at 1-sided alpha=0.20. This choice is 
supported by a recent publication by Lindborg et al 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 Phase 2, 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.
                                                
a This section has been amended per Amendment INT-2.


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When adjusted for a drop-out rate of approximately 3% of subjects who will have no pre-
treatment baseline efficacy measurement, the required number of subjects to be randomized 
in the treatment period is 94. To achieve this, the estimated number of subjects to enter the 
lead in period is 140, after adjusting for an estimated placebo response rate of 25% and drop-
out rate of 10% during the lead-in period.
To replace 3 subjects who prematurely stopped the study when the study was put on hold, the 
total number of subjects entering the study will be increased from approximately 140 to 143.
Blinded sample size re-estimation is previewed with 180 as maximal number of subjects to be 
enrolled in the trial (Section 11.4).
11.2.
Efficacy Analysis
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-42165279 treatment group will be compared with placebo using the primary efficacy 
endpoint: change from treatment baseline in HDRS17 score during the double-blind treatment 
period.  The comparison will be performed by means of a mixed-effects model using repeated 
measures (MMRM), with time, treatment (placebo, JNJ-42165279) and time-by-treatment 
interaction as factors and lead-in baseline total HDRS17 score as a continuous covariate and a 
(pooled) center as categorical covariates. Other covariates of interest may be included in the 
MMRM model. An unstructured variance-covariance matrix will be used. The treatment-
placebo differences will be obtained using the appropriate contrast in the MMRM models at 
the 6-week endpoint.
The change from baseline for the key secondary continuous efficacy endpoints (HAM-A6
score, HDRS17 Anxiety/Somatization factor score, HAM-D6 score and SIGH-A total score)
will be analyzed in the same way as for the HDRS17 total score.
Sensitivity analyses of the primary endpoint will be performed using an ANCOVA model; 
these will be detailed further in the Statistical Analysis Plan. 
In addition, exploratory efficacy analyses will be performed on full intention-to-treat analysis 
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 (fITT). Treatment 
effect for fITT analysis set will be estimated in 2 manners: using the same MMRM model as 
for the primary efficacy analysis with and without lead-in response status as additional 
covariate. 
Descriptive statistics for values and changes from baseline for all efficacy measures including 
subscale scores for selected scales at each time point of the double-blind treatment phase will
be provided by treatment group and lead-in response status (where applicable) using both: 
eITT and fITT analysis sets.
Frequency tables for response of depressive and anxiety symptoms (derived from the HDRS17
and SIGH-A) will be provided by treatment group and lead-in response status (where 


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applicable) at each time point of the double-blind treatment phase using both: eITT and fITT 
analysis sets. Chi square test will be used to test the overall differences between the treatment 
groups. If deemed appropriate, Cochran–Mantel–Haenszel test with (pooled) center as 
stratification factor will be performed.
11.3.
Safety Analysisa
All subjects receiving at least one dose of study drug will be included in the safety analysis. 
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. 
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse 
events with onset during the double-blind treatment phase (i.e., treatment-emergent adverse 
events, and adverse events that have worsened since baseline) will be included in the 
analysis. For each adverse event, 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 adverse events from this study. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who withdraw due to an adverse event, or who experience a severe or a 
serious adverse event.
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.
12-Lead 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) 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 will be summarized by treatment group. 
                                                
a This section has been amended per Amendment INT-2.


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Summaries will be provided for all subjects receiving at least one dose of study drug in this 
study. 
Data listings of subjects with any potentially clinically important values (QTc value >450, 
>480, or >500 msec) or with a change from baseline in QTc >30 msec will be provided.
Vital Signs
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. 
Physical and Neurological Examinations
The number and percentage of subjects with a change from normal at baseline to abnormal at 
any post-baseline exam will be tabulated by treatment group. 
Subjects with abnormal findings will be presented in a data listing.
Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment group for all subjects receiving at 
least one dose of study drug in this study.
11.4.
Interim Analysis 
No interim analysis is foreseen. However, depending on the recruitment, an unblinded review 
of the data might be conducted for subjects who completed the treatment periods by an 
internal Data Review Committee (DRC). The DRC may decide to terminate the study after 
review of the safety data. If any such review is conducted it will be documented in an Early 
Medicine DRC charter prior to the unblinding. The constitution of the Data review committee 
will be documented in the Early Medicine Data Review Committee charter and may include 
sponsor study team members.
Blinded data review for purpose of sample size re-estimation may be performed after 75% of 
the subjects are randomized. Sample size may be re-adjusted if observed SD substantially 
deviates from the hypothesized or if the lead-in response and dropout rate substantially 
deviate from the assumed. Maximal number of subjects to be enrolled in the trial will not 
surpass 180.
11.5.
Biomarker Analysis
Changes in blood and saliva biomarkers over time will be summarized by treatment group. 
Associations between baseline levels and changes from baseline in selected biomarkers and 
clinical endpoints will be explored. Additional exploratory analyses may be performed and 
results of exploratory analyses may be presented in a separate Biomarkers report.
11.6.
Pharmacogenomic Analyses 
Results will be presented in a separate report.


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11.7.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis
Where appropriate, the relationship between plasma concentrations of JNJ-42165279 and 
corresponding biomarkers (plasma concentrations of FAAs [AEA, PEA, and OEA]) will be 
plotted to evaluate the relationships graphically. If deemed appropriate, suitable PK/PD 
population models will be applied to describe the exposure-effect relationships.
Population PK modeling of plasma concentrations of JNJ-42165279 will be undertaken. In 
view of the sparse sampling foreseen for this study, data may be combined with a selection of 
Phase 1 data (e.g. from studies 42165279EDI1001, 42165279EDI1002, and/or 
42165279EDI1004) in order to support a relevant structural model.
11.8.
Data Review Committee (DRC)
Based on the safety signal observed in six clinical studies in healthy subjects exposed to 
JNJ-42165279 to date, a DRC will be set up if any relevant additional safety findings are 
observed (like if the frequency of discontinuations exceeds 10% of subjects or increases in 
liver transaminases of 5-fold over the ULN are observed). 
To protect the integrity of the clinical study, the DRC members (medical and statistical 
experts, internal or external to J&J) will not be study team personnel or otherwise directly 
involved in the study conduct, data management, or statistical analysis for the study. 
The objectives and scope of the DRC and the operational and logistical procedures to perform 
the DRC activities will be documented in the DRC charter prior to the review of any data by 
the DRC. 
Only blinded information, conclusions, or recommendations will be communicated by the 
DRC chairperson while the study is ongoing.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects, investigators, and the sponsor, and are 
mandated by regulatory agencies worldwide. The sponsor has established Standard Operating 
Procedures (SOPs) 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.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered 
a medicinal (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonisation [ICH]).


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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 adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event 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 adverse event occurs for which there is evidence suggesting a 
causal relationship between the study drug and the event (e.g., death from anaphylaxis), the 
event must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (e.g., all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For JNJ-42165279, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure.1
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is 
possible, probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.


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Doubtful
An adverse event for which an alternative explanation is more likely, e.g., concomitant 
drug(s), concomitant disease(s), or the relationship in time suggests that a causal relationship 
is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
e.g., concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event 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 adverse event 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).
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (e.g., laboratory abnormalities).
12.2.
Special Reporting Situationsa
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
Overdose of a sponsor study drug
Suspected abuse/misuse of a sponsor study drug
Inadvertent or accidental exposure to a sponsor study drug
                                                
a This section has been amended per Amendment INT-2.


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Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, e.g., name confusion)
For this study safety events of interest include diplopia, vision impairment, gait disturbance 
and severe headache. These events will trigger a neurological examination and a narrative of 
the event.
Special reporting situations should be recorded in the CRF. Any special reporting situation 
that meets the criteria of a serious adverse event should be recorded on the serious adverse 
event page of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events 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 subject's 
last study-related procedure (which may include contact for follow-up of safety). Serious 
adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol.
All other events that meet the definition of a serious adverse event will be reported as serious 
adverse events, regardless of whether they are protocol-specific assessments. Anticipated 
events will be recorded and reported as described in Attachment 11.
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
drug, 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 adverse event to study therapy. All measures 
required for adverse event management must be recorded in the source document and 
reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events 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.
For all studies with an outpatient phase, including open-label studies, the subject 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


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Statement, in the local language(s), that the subject 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
Subject number
Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate 
sponsor contact person by study-site personnel within 24 hours of their knowledge of the 
event.
Information regarding serious adverse events will be transmitted to the sponsor using the 
Serious Adverse Event Form, which must be completed and signed by a physician from the 
study site, and transmitted to the sponsor within 24 hours. The initial and follow-up reports of 
a serious adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject'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 drug or to factors unrelated to study 
conduct
It becomes unlikely that any additional information can be obtained (subject 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 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a 
serious adverse event, except hospitalizations for the following:
Hospitalizations not intended to treat an acute illness or adverse event (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 serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
For convenience the investigator may choose to hospitalize the subject for (part of) the 
duration of the treatment period. 
The cause of death of a subject in a study, whether or not the event is expected or associated 
with the study drug, is considered a serious adverse event.


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12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) 
are considered serious adverse events and must be reported using the Serious Adverse Event 
Form. Any subject who becomes pregnant during the study must be promptly withdrawn 
from the study and discontinue further study treatment.
12.4.
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 on the Contact 
Information page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., 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 
subjects, 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 reporting of PQC information; all studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel as soon as 
possible after being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report 
the PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-42165279 solid dosage formulation will be supplied as 
-mg 
 
The JNJ-42165279 placebo will be supplied as 
, matching visually to the 
. JNJ-42165279/placebo will be manufactured and provided under the 
responsibility of the sponsor. 
C
CI
CCI
CCI
CCI


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Refer to the Investigator's Brochure1 for a list of excipients.
14.2.
Packaging
The study drug will be packaged in individual subject kits. Each kit will consist of 1 bottle 
containing 11 tablets.
All JNJ-42165279/placebo solid formulation study drug will be dispensed in child-resistant 
packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study medication will be stored in a secure area with restricted access.
The JNJ-42165279 and placebo solid dosage formulation 
 
 as indicated on the product specific labeling.
Additional guidance and detailed instructions for the clinical site dosing procedures and 
storage conditions are described in the Dose Preparation Instructions/ Pharmacy manual or 
equivalent document.
Refer to the Dose Preparation Instructions/Pharmacy Manual for additional guidance on 
study drug dispensing, dosing process, and handling.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. The dispensing of study drug to the 
subject, and the return of study drug from the subject (if applicable), must be documented on 
the drug accountability form. Subjects must be instructed to return all original containers, 
whether empty or containing study drug. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under 
appropriate environmental conditions. Unused study drug, and study drug returned by the 
subject, 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 drug, or used returned study drug 
for destruction, will be documented on the drug return form. When the study site is an 
authorized destruction unit and study drug supplies are destroyed on-site, this must also be 
documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not 
be retained for drug accountability purposes. 
Study drug 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 drug will be 
supplied only to subjects participating in the study. Returned study drug must not be 
CCI


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dispensed again, even to the same subject. Study drug may not be relabeled or reassigned for 
use by other subjects. The investigator agrees neither to dispense the study drug from, nor 
store it at, any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with, but not limited to, the following supplies:
Investigator Brochure for JNJ-42165279
Pharmacy manual/study site investigational product manual
Laboratory manual
IVRS/IWRS Manual
Electronic data capture (eDC) Manual
Sample ICF
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, 
during the study, subjects 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 subjects who are fully able to 
understand the risks, benefits, and potential adverse events of the study, and provide their 
consent voluntarily will be enrolled. The efficacy of JNJ-42165279 for treatment of MDD 
with anxious distress is not known and testing for evidence of benefit will require random 
assignment to active drug or placebo.  Introduction of other medication or psychotherapeutic 
treatment to augment response to their ongoing treatment with SSRI/SNRI monotherapy will 
not be allowed.  Subjects will be monitored for the severity of their major depressive episode 
including assessment of suicidality to ensure the safety of subjects and confirm whether 
continuation in the study is in their best interest.  
The study treatment duration in this study of subjects with MDD is supported by the available 
toxicology and clinical data (see Investigator’s Brochure)1. A safety signal of treatment 
emergent elevation of liver transaminases up to 2.5 times the upper limit of normal was 
identified in the Phase 1 multiple dose study, occurring in 5 out of 30subjects exposed to 
more than 4 days dosing of JNJ-42165279 and 1 out of 10 subjects on placebo, returning to 
normal values after dosing had ended.  To mitigate the risk to subjects participating in this 
trial, a dose of 25 mg was selected that should allow for testing of the pharmacology of the 
compound, all subjects will be screened and those with evidence of pre-existing liver 
dysfunction will not be enrolled, concomitant treatment with strong CYP3A inhibitors will 
not be allowed, and clinical safety labs will be collected at least every 2 weeks with results
available for ongoing monitoring by the investigator and sponsor.  ‘Stopping rules’ have been 
developed for stopping treatment in the event that subjects have an increase in transaminases 
to >3 x ULN or have an increase in total bilirubin to >2 x ULN, and a Data Review
Committee may be established to monitor the study data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study if the frequency of discontinuations 


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exceeds 10% of subjects or increases in liver transaminases of 5 fold over the ULN are 
observed. 
A placebo arm is warranted and necessary to allow for an accurate assessment of the safety 
and tolerability of the study drug. Treatment with placebo dosing is not equivalent to non-
treatment; study medication will be administered adjunctively to SSRI/SNRI therapy. All 
medication treatment will occur within the context of carefully supervised and supportive 
care. Only investigators experienced in the treatment of MDD will participate in the trial and 
can provide expert guidance on the alternatives for treatment if subjects elect to discontinue 
the study prior to the last visit or after the completion of the study.
Only experienced and qualified physicians are allowed to perform the applicable procedures.
The total blood volume to be collected will not exceed 300 mL, which is considered to be 
safe and acceptable in comparison to a Red Cross blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory 
and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human 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 study data are credible.
16.2.2.
Independent Ethics Committee or 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 (as required by local 
regulations):
Final protocol and, if applicable, amendments
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
Investigator's Brochure (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


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This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), 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 (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)
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
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable
New edition(s) of the Investigator's Brochure 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 study 
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
Development Safety Update Report and Line Listings, where applicable
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval 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 about 
the study completion [(if applicable, the notification will be submitted through the head of 
investigational institution)].
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative, if applicable) must give written consent 
according to local requirements after the nature of the study has been fully explained. The 


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ICF(s) must be signed before performance of any study-related activity. The ICF(s) that is/are
used must be approved by both the sponsor and by the reviewing IEC/IRB and be in a 
language that the 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 study-site 
personnel must explain to potential subjects (or their legally acceptable representatives, if 
applicable) the aims, methods, reasonably anticipated benefits, and potential hazards of the 
study, and any discomfort 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 the subject will 
receive for the treatment of his or her disease. 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 records may be accessed by health authorities and authorized sponsor 
personnel without violating the confidentiality of the subject, to the extent permitted by the 
applicable law(s) or regulations. By signing the ICF the subject (or legally acceptable 
representative, if applicable), is authorizing such access, including permission to obtain 
information about his or her survival status, 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, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
The subject (or legally acceptable representative, if applicable), 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 either the subject's (or 
his or her legally acceptable representative's) personally dated signature. After having 
obtained the consent, a copy of the ICF must be given to the subject.
Where local regulations require, a separate ICF may be used for the required DNA 
component of the study.
16.2.4.
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 subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable 
representative, if applicable) includes explicit consent for the processing of personal data and 
for the investigator/institution to allow direct access to his or her original medical records 
(source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory 


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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 biomarker and PK 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 or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will 
be protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-42165279, 
to understand MDD, to understand differential drug responders, and to develop tests/assays 
related to JNJ-42165279 and MDD.  The research may begin at any time during the study or 
the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not 
be labeled with personal identifiers. Subjects may withdraw their consent for their samples to 
be stored for research (refer to Section 10, Withdrawal From the Study (Withdrawal From the 
Use of Samples in Future Research).
16.2.6.
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 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal 
amendment by the sponsor. All protocol amendments must be issued by the sponsor, and 
signed and dated by the investigator. Protocol amendments must not be implemented without 
prior IEC/IRB approval, or when the relevant competent authority has raised any grounds for 
non-acceptance, except when necessary to eliminate immediate hazards to the 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. When the change(s) involves only logistic or 
administrative aspects of the study, the IRB (and IEC where required) 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 


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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 
CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
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.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to 
the study site:
Protocol and amendment(s), if any, signed and dated by the principal investigator
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.
Regulatory authority approval or notification, if applicable
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
Documentation of investigator qualifications (eg, curriculum vitae)
Completed investigator financial disclosure form from the principal investigator, where 
required
Signed and dated clinical trial agreement, which includes the financial agreement
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 
subject:


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Completed investigator financial disclosure forms from all subinvestigators
Documentation of subinvestigator qualifications (eg, curriculum vitae)
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
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 study-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 subject 
identification and date of birth. In cases where the subject is not randomized into the study, 
the date seen and date of birth will be used.
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.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: 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 adverse events and follow-up of adverse 
events; 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).
Inclusion and exclusion criteria not requiring documented medical history must be verified at 
a minimum by subject interview or other protocol required assessment (e.g., physical 
examination, laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
CRFs are provided for each subject in electronic format. 


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Electronic Data Capture (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.
All subjective measurements (e.g., pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the CRFs are accurate and 
correct.
All CRF 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 study-site personnel must adjust the CRF (if applicable) and complete the 
query. 
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:
Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).
Study site manager can generate a query for resolution by the study-site personnel.
Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study sites, review of protocol procedures with the 
investigator and study-site personnel before the study, periodic monitoring visits by the 
sponsor, direct transmission of clinical laboratory and ECG data from a central laboratory 
into the sponsor's data base. Written instructions will be provided for collection, handling, 
storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel 
before the start of the study. 
The sponsor will review CRFs for accuracy and completeness during on-site monitoring 
visits and after transmission to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. After upload of the data into the study database they 
will be verified for accuracy and consistency with the data sources.


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17.7.
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 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/institution must permit access to such 
reports.
17.8.
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 study 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 CRFs with the hospital or clinic 
records (source documents). The nature and location of all source documents will be 
identified to ensure that all sources of original data required to complete the CRF are known 
to the sponsor and study-site personnel and are accessible for verification by the sponsor 
study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. 
Findings from this review of CRFs and source documents will be discussed with the study-
site personnel. The sponsor expects that, during monitoring visits, the relevant study-site 
personnel will be available, the source 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 
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17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines
Inadequate recruitment of subjects by the investigator
Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site 
at any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy. These audits will require access 
to all study records, including source documents, for inspection and comparison with the 
CRFs. Subject privacy must, however, be respected. The investigator and study-site 
personnel are responsible for being present and available for consultation during routinely 
scheduled study-site audit visits conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either 
as part of a national GCP compliance program or to review the results of this study in support 
of a regulatory submission. The investigator should immediately notify the sponsor if he or 
she has been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-42165279 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 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 


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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 study will be used by the 
sponsor in connection with the continued development of JNJ-42165279, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to 
provide the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor 
and will contain CRF data from all study sites that participated in the study, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's database. 
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.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes 
to publish information from the study, a copy of the manuscript must be provided to the 
sponsor for review at least 60 days before submission for publication or presentation. 
Expedited reviews will be arranged for abstracts, poster presentations, or other materials. If 
requested by the sponsor in writing, the investigator will withhold such publication for up to 
an additional 60 days to allow for filing of a patent application. In the event that issues arise 
regarding scientific integrity or regulatory compliance, the sponsor will review these issues 
with the investigator. The sponsor will 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 study 
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.


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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.


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REFERENCES
1.
Janssen Research & Development, L.L.C. Investigator's Brochure JNJ-42165279, Edition 3, February 
2015  and Addendum 1, June 2015.
2.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-370.
3.
Bech P. Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled 
analysis of four placebo-controlled trials. Pharmacopsychiatry 2007; 40(4): 163-168.
4.
Bech P, Gram LF, Dein E, Jacobsen O, Vitger J, Bolwig TG. Quantitative rating of depressive states. Acta 
Psychiatr Scand 1975; 51(3): 161-170.
5.
Bech P. The Bech-Rafaelsen Melancholia Scale (MES) in clinical trials of therapies in depressive 
disorders: a 20-year review of its use as outcome measure. Acta Psychiatr Scand 2002; 106(4): 252-264.
6.
Chandler G, Iosifecu D, Pollack M, Targum S, Fava M. Validation of the Massachusetts General Hospital 
Antidepressant Treatment History Questionnaire (ATRQ). CNS Neuroscience & Therapeutics 2010, 16(5): 
322-325.
7.
Cleary P, Guy W. Factor analysis of the Hamilton depression scale. Drugs Exp Clin Res 1977; 1: 115–120
8.
Conzelmann A, Reif A, Jacob C, et al. A polymorphism in the gene of the endocannabinoid-degrading 
enzyme FAAF (FAAH C385A) is associated with emotional-motivational reactivity. Psychopharmacology 
(Berl). 2012;224(4):573-579.
9.
Fava M, Rush AJ, Alpert JE et al, Difference in treatment outcome in outpatients with anxious versus 
nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165(3): 342–351.
10.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32(1): 50-55.
11.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62.
12.
Hamilton M. The diagnosis and rating of anxiety, In Studies of Anxiety , MM Lader, Ed., Meedley Bros., 
Kent, 1969. 
13.
Hamilton M. Standardised assessment and recording of depressive symptoms. Psychiatr Neurol Neurochir 
1969 Mar-Apr; 72(2): 201-205.  
14.
R. G. Heimberg, K. J. Horner, H. R. Juster, S. A. Safren, E. J. Brown, F. R. Schneier, M. R. Liebowitz.
Psychometric properties of the Liebowitz Social Anxiety Scale. Psychological Medicine, 1999, 29(1), 
199–212
15.
Knesevich JW, Biggs JT, Clayton PJ, Ziegler VE. Validity of Hamilton Rating-Scale for depression. Br J 
Psychiatry 1977; 131: 49-52. 
16.
Lee S. et al: Does elimination of placebo responders in a placebo run-in increase the treatment effect in 
randomized clinical trials? A meta-analytic evaluation; Depression and Anxiety 2004;19(1)10-19
17.
Lindborg S., Persinger C., Sashegyi A., Mallinckrodt C. and Ruberg S.;  Statistical refocusing in the design 
of Phase II trials offers promise of increased R&D productivity; Nature Reviews Drug Discovery 13, 638–
640
18.
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
19.
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. American Journal of Psychiatry. 2007;164(7):1035–1043.
20.
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.
21.
Shear MK, Brown TA, Barlow DH, et al.. Multicenter Collaborative Panic Disorder Severity Scale, Am J 
Psychiatry 1997; 154(11): 1571–1575.
22.
Sheehan DV: The Anxiety Disease. New York: Charles Scribner and Sons; 1983
23.
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. British Journal of Psychiatry. 1995;167(1):99–103.
24.
Zimmerman M, Chelminski I, Young D, Dalrymple K, Walsh E, Rosenstein L. A clinically useful self-
report measure of the DSM-5 anxious distress specifier for major depressive disorder. J Clin Psychiatry.
2014;75(6):601-607.




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Attachment 2: Clinical Global Impression – Improvement (CGI-I)
Rate total improvement whether or not, in your judgment, it is due entirely to drug treatment. 
Compared to his/her condition at admission to the project, how much has the patient 
changed?
0 = Not assessed
1 = Very much improved
2 = Much improved
3 = Minimally improved
4 = No change
5 = Minimally worse
6 = Much worse
7 = Very much worse
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 1976. 
Rockville, MD, U.S. Department of Health, Education, and Welfare


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Attachment 3: Clinically Useful Depression Outcome Scale (CUDOS-A)
INSTRUCTIONS
This questionnaire includes questions about symptoms of depression. For each item please 
indicate how well it describes you during the PAST WEEK, INCLUDING TODAY. 
Circle the number in the columns next to the item that best describes you.
RATING GUIDELINES
0=not at all true (0 days)
1=rarely true (1-2 days)
2=sometimes true (3-4 days)
3=often true (5-6 days)
4=almost always true (every day)
During the PAST WEEK, INCLUDING TODAY....
1. I felt keyed up or on edge because I was worried about 
things…………………….................................................................................................................0 1 2 3 
4
2. I felt very fidgety, making it difficult to sit still .............................................................................0 1 2 
3 4
3. I had difficulty concentrating because my mind was on my 
worries……………………………………………………....................................................................0 1 2 
3 4
4. I worried a lot that something bad might happen........................................................................0 1 2 
3 4
5. When I was extremely anxious, I was afraid I would lose 
control……………………….............................................................................................................0 1 2 
3 4


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Attachment 4: Cognitive and Physical Functioning Questionnaire (CPFQ)


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Attachment 5: Medical Outcomes Study (MOS) - 12-Item Sleep Scale Acute - Revised


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Attachment 6: Perceived Stress Scale (PSS)


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Attachment 7: Snaith-Hamilton Pleasure Scale (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 .........................................................................   
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......................................................................................   


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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 .............................................................................   
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).


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Attachment 8: Self-Assessment of Treatment Experience
These questions are about your overall experience while on the study medication.  Please 
answer each question by selecting the response that best describes you.
1. Considering all aspects of your depression, since starting this study medication, 
overall would you say your depression is: 
(Select one response)
Very much improved
Much improved
Improved (just enough to make a difference)
No change
Worse (just enough to make a difference)
Much worse
Very much worse
2. Please select your response to the following statements.
3. During the past week (7 days), how would you rate your appetite (your overall 
desire to eat)?
(Select one response)
Very good
Good
Fair
Poor
Very poor
4. How interested would you be in continuing to take the study medication if needed?
(Select one response)
Not at all interested
A little interested
Moderately interested
Very interested
Extremely interested
Yes
No
While taking the study medication:
  I felt more relaxed 
  My mood improved 
  I was better able to perform my daily activities 
  I felt more interested in social activities
  My sleep improved 
  I felt less distracted 


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Attachment 9: Columbia Suicide Severity Rating Scale – BASELINE


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Attachment 10:
Columbia Suicide Severity Rating Scale – Since Last Visit


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Attachment 11:
Anticipated Events
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events:
• Suicidal thinking, ideation/ behavior, 
• Sleep changes/difficulty sleeping, reduced sleep, abnormal sleep, abnormal sleep, tiredness,       
fatigue, reduced energy, 
• Difficulty in sexual desire, performance or satisfaction, 
• Reduced appetite, weight changes (loss or increase), 
• Activation or hypomania/ mania, 
• Excessive happiness 
• Irritability, anger, impulsive behavior, 
• Agitation, anxious/anxiety, tension, panic attacks, phobia 
Reporting of Anticipated Events
These events will be captured on the eCRF and in the database, and will be reported to the 
sponsor as described in Section 12.3.1, All Adverse Events. 
Any event that meets serious adverse event criteria will be reported to the sponsor within the 
appropriate timeline as described in Section 12.3.2, Serious Adverse Events. These 
anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities. However if based on an aggregate review, it is determined that an anticipated 
event is possibly related to study drug, the sponsor will report these events in an expedited 
manner.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and 
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan (ASMP).


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Attachment 12:
Prohibited Cytochrome P450 Inhibitors and Inducers
Inducers
Carbamazepine
Dexamethasone
Efavirenz
Ethosuximide
Isoniazid
Nevirapine
Phenobarbital
Phenytoin
Prednisone
Rifabutin/rifampicin
St. John’s Wort
Inhibitors
Amprenavir
Atazanavir
Clarithromycin
Clotrimazole
Darunavir
Delavirdine
Diltiazem
Elvitegravir/Cobicistat
Erythromycin
Fluconazole
Fluoxetine
Fluvoxamine
Fosamprenavir
Grapefruit
Indinavir
Itraconazole
Ketoconazole
Lopinavir
Metronidazole
Mibefradil
Miconazole
Nefazodone
Nelfinavir
Nifedipine
Norfloxacin
Omeprazole
Propoxyphene
Quinine
Ritonavir
Saquinavir
Seville oranges
Simeprevir
Tipranavir
Troleandomycin
Verapamil
Zafirlukast



SAP_001.pdf: 
1 
Approved, Date: 14 February 2019  
 
Janssen Research & Development 
 
 
Statistical Analysis Plan 
 
  A Randomized, Double-blind, Placebo-Controlled, Parallel-Group, Multi-Center Study 
Investigating the Efficacy, Safety, and Tolerability of JNJ-42165279 in Subjects with Major 
Depressive Disorder with Anxious Distress 
 
Protocol 42165279MDD2001; Phase 2a 
 
 JNJ-42165279    
 
 
Status: 
Approved   
Date: 
14 February 2019 
Prepared by: 
Janssen Research & Development, a division of Janssen Pharmaceutica NV   
Document No.: 
EDMS-ERI-180165119 
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
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. 
NCT02498392


JNJ-42165279      
 
 
 
Statistical Analysis Plan 42165279MDD2001  
2 
Approved, Date: 14 February 2019  
TABLE OF CONTENTS 
ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION.................................................................................................................................. 5 
1.1. 
Trial Objectives ................................................................................................................................ 5 
1.2. 
Trial Design ...................................................................................................................................... 6 
1.3. 
Statistical Hypotheses for Trial Objectives ....................................................................................... 7 
1.4. 
Sample Size Justification ................................................................................................................. 7 
1.5. 
Randomization and Blinding ............................................................................................................ 9 
1.5.1. 
Procedures for Randomization ..................................................................................................... 9 
1.5.2. 
Blinding ......................................................................................................................................... 9 
2. 
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9 
2.1. 
Pooling Algorithm for Analysis Centers .......................................................................................... 10 
2.2. 
Analysis Sets .................................................................................................................................. 10 
2.2.1. 
All Subjects Analysis Set ............................................................................................................ 10 
2.2.2. 
All Enrolled Analysis Set ............................................................................................................. 10 
2.2.3. 
Safety Analysis Set ..................................................................................................................... 11 
2.2.4. 
Efficacy Analysis Sets ................................................................................................................. 11 
2.2.5. 
Per Protocol Analysis Set ........................................................................................................... 11 
2.2.6. 
Biomarker Analysis Set ............................................................................................................... 11 
2.3. 
Study Day and Relative Day .......................................................................................................... 12 
2.4. 
Analysis Timepoints and Phases ................................................................................................... 12 
2.5. 
Visit Windows ................................................................................................................................. 13 
3. 
SUBJECT INFORMATION ................................................................................................................ 18 
3.1. 
Demographics and Baseline Characteristics ................................................................................. 18 
3.2. 
Disposition Information................................................................................................................... 18 
3.3. 
Treatment Compliance ................................................................................................................... 19 
3.4. 
Extent of Exposure ......................................................................................................................... 19 
3.5. 
Protocol Deviations ........................................................................................................................ 20 
3.6. 
Prior and Concomitant Medications ............................................................................................... 20 
4. 
EFFICACY ......................................................................................................................................... 21 
4.1. 
Analysis Specifications................................................................................................................... 21 
4.1.1. 
Level of Significance ................................................................................................................... 21 
4.1.2. 
Imputation Methods for Missing Items ........................................................................................ 21 
4.2. 
Primary Efficacy Endpoint – HDRS17 Total Score .......................................................................... 21 
4.2.1. 
Definition ..................................................................................................................................... 22 
4.2.2. 
Estimand ..................................................................................................................................... 22 
4.2.3. 
Analysis Methods ........................................................................................................................ 22 
4.2.3.1. 
Primary Analysis ...................................................................................................................... 22 
4.2.3.2. 
Additional Analysis .................................................................................................................. 23 
4.3. 
Secondary Efficacy Endpoints ....................................................................................................... 23 
4.3.1. 
Definition ..................................................................................................................................... 23 
4.3.2. 
Analysis Methods ........................................................................................................................ 25 
4.4. 
Patient Reported Outcomes ........................................................................................................... 26 
4.4.1. 
Definitions ................................................................................................................................... 26 
4.4.2. 
Analysis Methods ........................................................................................................................ 27 
5. 
SAFETY ............................................................................................................................................. 27 
5.1. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 28 
5.2. 
Adverse Events .............................................................................................................................. 28 
5.3. 
Clinical Laboratory Tests................................................................................................................ 29 
5.4. 
Vital Signs and Physical Examination Findings ............................................................................. 31 
5.5. 
Electrocardiogram .......................................................................................................................... 32 


JNJ-42165279      
 
 
 
Statistical Analysis Plan 42165279MDD2001  
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Approved, Date: 14 February 2019  
5.6. 
C-SSRS .......................................................................................................................................... 33 
6. 
PHARMACOGENOMIC ANALYSES ................................................................................................ 34 
7. 
BIOMARKERS................................................................................................................................... 34 
7.1. 
Summary of FAA Biomarker Values .............................................................................................. 34 
7.2. 
Relationship Between FAA Biomarker Analytes and 
 ................................... 34 
7.3. 
Relationship Between FAA Biomarker Analytes and 
 ....................... 34 
REFERENCES ............................................................................................................................................ 35 
 
 
 
 
CCI
CCI


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Statistical Analysis Plan 42165279MDD2001  
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Approved, Date: 14 February 2019  
ABBREVIATIONS 
AEA 
anandamide 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATRQ 
Antidepressant Treatment History Questionnaire 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CGI 
clinical global impression 
CPFQ 
Cognitive and Physical Functioning Questionnaire 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating scale 
CUDOS-A 
clinically useful depression outcome scale 
DBP 
diastolic blood pressure 
DRC 
Data Review Committee 
DSM 
Diagnostic and Statistical Manual 
ECG 
electrocardiogram 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
Hamilton Rating Scale for Depression 
HDRS 
Hamilton Depression Rating Scale 
HPA 
hypothalamic–pituitary–adrenal 
ITT 
intention to treat 
eITT 
enriched intention to treat 
fITT 
full intention to treat 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LLN 
Lower limit of normal 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI 
mini international neuropsychiatric interview 
MMRM 
mixed model for repeated measures 
MOS 
Medical Outcomes Study 
PEA 
palmitoylethanolamide 
PK 
pharmacokinetic(s) 
PSS 
Perceived Stress Scale 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SATE 
Self-Assessment of Treatment Experience 
SD 
standard deviation 
SE 
standard error 
SHAPS 
Snaith–Hamilton Pleasure Scale 
SI 
Standard international 
SIGH-A 
Structured Interview Guide For The Hamilton Anxiety Scale 
SNRI 
serotonergic/noradrenergic reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
SBP 
systolic blood pressure 
TEAE 
treatment-emergent adverse event 
TEMA 
Treatment-emergent markedly abnormal 
TFL 
Tables, figures and listings 
ULN 
Upper limit of normal 
ULQ 
under the limit of quantification 
 
 


JNJ-42165279      
 
 
 
Statistical Analysis Plan 42165279MDD2001  
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Approved, Date: 14 February 2019  
1. 
INTRODUCTION 
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for final analyses of efficacy, biomarker and safety data.  
1.1. 
Trial Objectives 
Primary Objectives: 
The primary objective of this study is to evaluate the efficacy in terms of reduction of symptoms 
of depression and anxiety, as assessed by the change from baseline on a 17-item Hamilton 
Depression Rating Scale (HDRS17), and overall safety and tolerability of treatment with adjunctive 
JNJ-42165279 compared to placebo in subjects with major depressive disorder (MDD) with 
anxiety symptoms who have had inadequate response to treatment with a selective serotonin 
reuptake inhibitor (SSRI) or serotonergic/noradrenergic reuptake inhibitor (SNRI). 
Secondary Objectives: 
• To assess the efficacy of JNJ-42165279 on core symptoms of anxiety (HAM-A6). 
• To assess the efficacy of JNJ-42165279 using dimensional analyses of both anxiety and 
depression (HDRS17 and SIGH-A). 
• To assess the efficacy of JNJ-42165279 on the response and remission of depressive and 
anxiety symptoms (derived from HDRS17 and SIGH-A). 
• To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as once 
daily (qd) in male and female subjects with MDD with anxious distress using a population 
PK approach and explore its relationship with efficacy and safety parameters. 
Exploratory Objective: 
• To evaluate the impact of treatment with adjunctive JNJ-42165279 compared to placebo 
on Clinical Global Impression (CGI) and exploratory clinician-rated and patient-reported 
assessments (CUDOS-A, CPFQ, SHAPS, MOS Sleep-R, PSS and Self-Assessment of 
Treatment Experience). 
• To explore for 
 in subjects with 
 features and subjects with 
, as reported on the 
 
. 
• To explore 
 (including but not limited to 
 
 and 
 that may be related to 
 
 of JNJ-42165279. 
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• To explore the relationship between plasma PK and plasma concentrations of FAAs 
(anandamide [AEA], palmitoylethanolamide [PEA] and oleoylethanolamide [OEA]) in 
subjects with MDD with anxious distress. 
1.2. 
Trial Design 
This is a multi-center, double-blind, placebo-controlled, randomized, parallel-group study in 
subjects with MDD with anxious distress who have had inadequate response to SSRI/SNRI 
treatment.  
Subjects who meet the inclusion and exclusion criteria and are enrolled will be maintained on the 
SSRI/SNRI treatment throughout the study to determine whether adjunctive treatment with JNJ-
42165279 can reduce symptoms of MDD with anxious distress.  
For each subject, the study will consist of three phases: a screening phase of up to 4 weeks, a 
treatment phase lasting up to 11 weeks, and a 3-week post-treatment (follow up) phase. The 
treatment phase of the trial will consist of 3 periods. The first period is a placebo lead-in of 3 weeks 
for all subjects, after which subjects will enter the double-blind treatment period when they will 
be randomly assigned to JNJ-42165279 or continuation on placebo for 6 weeks. Subjects who 
successfully complete the double-blind treatment period will be treated with placebo during a 2-
week withdrawal period. The total study duration for each subject will be approximately 18 weeks.  
The end of study is defined as the date of the last visit of the last subject undergoing the trial. 
Investigators and subjects will remain blinded to the exact duration of the subject lead-in and 
withdrawal period during the entire study duration. 
Approximately 143 subjects will enter the double-blind placebo lead-in period. At the end of the 
lead-in period, response status of the subjects will be assessed according to the double-blind 
response criteria based on reduction in HDRS17 relative to lead-in baseline. Both lead-in placebo 
responders and lead-in placebo non-responders will be randomly assigned in a 1:1 ratio to either 
25 mg of JNJ-42165279 or placebo in the treatment period. The primary efficacy analyses will be 
based on the treatment period data from the lead-in non-responders (94 subjects). 
An overall flow diagram of the study is shown in the figure below. 


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1.3. 
Statistical Hypotheses for Trial Objectives 
The primary efficacy endpoint is the change from baseline in the HDRS17 total score at Week 6. 
The null hypothesis is that there is no difference between treatment with adjunctive JNJ-42165279 
and placebo in the improvement of symptoms of depression and anxiety, in subjects with MDD 
with anxiety symptoms who have had an inadequate response to an SSRI/SNRI, based on the 
primary efficacy endpoint. 
1.4. 
Sample Size Justification 
The sample size for the study is determined based on the assumption of a minimally relevant 
treatment effect size of 0.45 in the mean change from baseline to the endpoint in HDRS17 total 
score between JNJ-42165279 treatment group and placebo. The assumed effect size is based on 
review of the literature looking at the treatments for MDD and MDD with anxious distress (Lee 
2004 and McIntyre 2007) taking into account that the effect size in enriched population is expected 
to be higher. A standard deviation of 7.5 in the change in HDRS17 total score from baseline is 
estimated based on previously conducted clinical trial in similar patient population 
(40411813DAX2001) allowing for a higher variability. 
The effect size of 0.45 (under SD assumption of 7.5) translates to a treatment difference between 
JNJ-42165279 and placebo at endpoint of 3.5 points. Detection of this magnitude of effect size 
with a power of 90% at an overall 1-sided significance level of 0.20, requires 45 subjects in each 
treatment group.  


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Justification of alpha and beta 
The choice of alpha and beta (1-power) for this Phase 2 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 10%) but the type 1 error rate was specified at 
1-sided alpha 0.20. This choice is supported by a recent publication by Lindborg et al 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 Phase 2, 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. 
Adjusting for dropouts 
When adjusted for a drop-out rate of approximately 3% of subjects who will have no post treatment 
baseline efficacy measurement, the required number of subjects to be randomized in the treatment 
period is 94. To achieve this, the estimated number of subjects to enter the lead in period is 140, 
after adjusting for an estimated placebo response rate of 25% and dropout rate of 10% during the 
lead-in period. 
To replace 3 subjects who prematurely stopped the study when the study was put on hold, the total 
number of subjects entering the study will be increased from approximately 140 to 143. 
Unblinded Data Review 
In January 2016, Janssen decided to suspend the 42165279MDD2001 study because of severe 
safety issues that occurred for several healthy volunteers in a phase 1 study sponsored by Bial, in 
which a FAAH inhibitor had been administered. The FDA placed a clinical hold on all trials being 
conducted with a FAAH inhibitor. The 42165279MDD2001 study was unblinded and the 
randomization codes were provided to the investigators so that the subjects could be informed 
about their treatment. Two subjects had been randomized into the double-blind treatment; one to 
placebo and one to JNJ-42165279, and one subject was still in the lead-in period when the study 
was suspended. Safety information was listed for these 3 subjects. Following an investigation of 
the Bial compound, it was determined that the serious adverse events were not related to FAAH 
inhibition.  The FDA lifted the hold on 22 September 2016 and Janssen senior management 
approved resuming study 42165279MDD2001 in December 2016. The protocol was amended to 
replace the 3 subjects who prematurely stopped the study when it was put on hold. 
Interim Analysis 
No interim analysis is foreseen. However, depending on the recruitment, an unblinded review of 
the data might be conducted for subjects who completed the treatment periods by an internal Data 
Review Committee (DRC). The DRC may decide to terminate the study after review of the safety 
data. If any such review is conducted it will be documented in an Early Medicine DRC charter 
prior to the unblinding. The constitution of the Data review committee will be documented in the 
Early Medicine Data Review Committee charter and may include sponsor study team members. 
Sample Size Re-Estimation 
Blinded data review for purpose of sample size re-estimation may be performed after 75% of the 
subjects are randomized. Sample size may be re-adjusted if observed SD substantially deviates 
from the hypothesized or if the lead-in response and dropout rate substantially deviate from the 
assumed. Maximal number of subjects to be enrolled in the trial will not surpass 180. 


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1.5. 
Randomization and Blinding 
1.5.1. 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 (pooled) center and lead-in response 
status.  
Exact timing of randomization for each subject will be blinded. The interactive voice/web response 
system (IVRS/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 IVRS/IWRS 
and will then give the relevant subject details to uniquely identify the subject. 
1.5.2. 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 IVRS/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. 
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 the DRC is specified, 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. 
2. 
GENERAL ANALYSIS DEFINITIONS 
The statistical analysis will be performed using SAS® version 9.3 or higher. 
The analysis will include descriptive statistics, frequency tabulations, statistical analyses, 
graphical presentations and data listings. 
Unless otherwise specified, descriptive statistics of continuous parameters will be summarized 
using the following statistics: number of observations, mean, standard deviation (SD), standard 
error (SE), minimum, median and maximum. Frequency tabulations will display the number of 
subjects and corresponding percentage, where the incidence is based on the number of subjects in 
each treatment group.  
 


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Treatment Group Names 
The treatment group names will appear in the tables, figures and listings (TFLs) as: 
• Placebo 
• JNJ-42165279 25mg 
Lead-In Placebo Responders 
Lead-in placebo responders are defined as subjects with ≥40% improvement from lead-in baseline 
in the HDRS17 total score at the end of the lead-in period.  
Data from eCRF will be used to determine if subjects are lead-in placebo responders, since this 
reflects the final, clean data. For some subjects, incorrect HDRS17 total scores were fed into the 
IWRS system, and these scores were updated afterwards in the eCRF system (after randomization 
had occurred, and source data verification revealed that data had been wrongly entered into the 
IWRS system). A listing will be created with subjects who have HDRS17 total score discrepancies 
between the IWRS system and the eCRF system at lead-in baseline and at the end of the lead-in 
period. Data from the eCRF system will be used for the analysis.  
Initially, at the time of protocol development, the lead-in placebo response definition was set at 
≥50% improvement. However, when subject enrollment had started, it became apparent that the 
expected number of lead-in placebo responders was lower than what was anticipated (0 out of 14 
subjects, while it was predicted to have 2-3 subjects). It was clear that out of the first set of 14 
subjects, two subjects showed substantial improvement (40% and 41%) but they did not meet the 
≥50% improvement threshold. In order to make sure that the enrichment strategy would work, it 
was decided to update the definition of lead-in placebo response from ≥50% improvement to ≥40% 
improvement. In the analysis, we will apply the 40% improvement definition to all subjects, and a 
listing will be created to identify the two subjects who were randomized using the 50% 
improvement definition. Section 3.2 describes how lead-in placebo response will be summarized. 
2.1. 
Pooling Algorithm for Analysis Centers 
Centers will be pooled by country for the statistical analysis. 
2.2. 
Analysis Sets 
2.2.1. 
All Subjects Analysis Set 
The All Subjects Analysis Set will include all subjects who were screened.  
This analysis set will be used for all listings and for calculating and listing the study execution 
period. 
2.2.2. 
All Enrolled Analysis Set 
The All Enrolled Analysis Set will include all subjects who were enrolled into the Lead-in period, 
regardless of whether treatment was received.  


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This analysis set will be used for summarizing study disposition. 
2.2.3. 
Safety Analysis Set 
The Safety Analysis Set will be defined for both enriched and full study populations. 
• The Safety Analysis Set is defined as all enrolled subjects who received at least one dose 
of study medication in the Lead-in Period.  
• The Enriched Safety Analysis Set is defined as all enrolled subjects who received at least 
one dose of study medication in the Lead-in Period and who were lead-in placebo non-
responders. 
The safety analysis set will be used for summarizing safety information. In addition, the enriched 
safety analysis set will be used for summarizing adverse events. 
2.2.4. 
Efficacy Analysis Sets 
The ITT Analysis Set will be defined for both enriched and full study populations. At the time of 
study suspension, two subjects who were randomized had to withdraw early from the study 
(1 placebo subject, 1 JNJ-42165279 subject, both placebo non-responders). These two subjects 
will not be included in the ITT analysis sets. 
▪ The Enriched ITT (eITT) Analysis Set is defined as all enrolled subjects who were 
randomized into the double-blind treatment period, who were lead-in placebo non-
responder, who received at least one dose of double-blind study medication and have at 
least one post-baseline HDRS17 assessment during the double-blind treatment period.  
▪ The Full ITT (fITT) Analysis Set is defined as all enrolled subjects who were 
randomized into the double-blind treatment period, who received at least one dose of 
double-blind study medication and have at least one post-baseline HDRS17 assessment 
during the double-blind treatment period.  
Efficacy analyses will be summarized for both the eITT and fITT analysis sets. 
2.2.5. 
Per Protocol Analysis Set 
The Per Protocol Analysis Set will include all eITT subjects who did not have a major protocol 
deviation during the study. A sensitivity analysis of the primary efficacy parameter will be 
performed for the per protocol analysis set. 
2.2.6. 
Biomarker Analysis Set 
The Biomarker Analysis Set will include all enrolled subjects who were randomized in the 
double-blind treatment period, who received at least one dose of double-blind study medication 
and have biomarker data available in the double-blind treatment period. The biomarker analysis 
set will be used for summarizing biomarker results. 
 




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If the subject does not enter the Double-
blind Treatment Period then use 23:59 
of the day before the date of the first 
Follow-Up visit 
Double-Blind 
Treatment Period 
Date/time of the first study medication 
administration in the Double-Blind 
Treatment Period 
If the subject takes the morning dose 
on the day of randomization prior to 
the randomization (i.e. a dose of the 
lead-in medication), the time of 
morning intake of the next day is not 
known. The start date of the double-
blind treatment period will be the day 
after the day of randomization, and the 
time of intake will be imputed as 0:00. 
1 minute before the first study 
medication administration in the 
Withdrawal Treatment Period.  
If the subject does not enter the 
Withdrawal Treatment Period then use 
23:59 of the day before the start of the 
Follow-Up period. 
Withdrawal 
Treatment Period 
Date/time of the first study medication 
administration in the Withdrawal 
Period 
Day 77 visit or early withdrawal visit 
for subjects who dropout early. 
Follow-up 
00:00 of the date after the Day 77 visit 
or early withdrawal visit for subjects 
who dropout early. 
23:59 of the day of study termination 
(date of last contact) 
The last phase, whichever it is for a subject, always ends on 23:59 of the day of study termination 
(last contact). 
In case of a dropout during a treatment phase: the dropout subject will have a follow-up phase after 
this phase only if a follow-up visit (as defined in the protocol) was performed. 
The number of days per phase will be defined as: day of phase end – day of phase start + 1. 
2.5. 
Visit Windows 
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. Listed in Table 1 are visit windows and the target days for 
each visit. The reference day is Study Day 1 for each of the lead-in, the double-blind treatment and 
the withdrawal period.  
If a subject has 2 or more actual visits in one visit window, the visit closest to the target day will 
be used as the protocol visit for that visit window. The other additional visit(s) will not be used in 
the summaries or analyses. If 2 actual visits are equidistant from the target day within a visit 


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window, the later visit is used. If a visit window has no scheduled visits but does have unscheduled 
visits, then the unscheduled visit closest to the scheduled visit will be used. 
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the endpoint. Listed below (Table 
1) are the visit windows and the target days (if applicable) for each visit defined in the protocol. 


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Table 1 – Visit Windows 
Parameter 
Scheduled 
Visit Number 
Time Interval 
(label on output) 
Time Interval 
(Day)1 
Target Time Point (Day) 
by Period 
 
Analysis Phase 
HDRS17, C-SSRS 
1 
Screening 
< 1 
-28 to -1 
Screening 
2 
Lead-in Baseline 
<=1 
1 
Lead-in 
3 
Lead-in Week 1 
2 to 10 
7 
Lead-in 
4 
Lead-in Week 2 
11 to 17 
14 
Lead-in 
5 
Lead-in Week 3 
18 to 24 
21 
Lead-in 
5 
DB Treatment Baseline 
<=1 
1 
DB Treatment 
6 
DB Treatment Week 1 
2 to 10 
7 
DB Treatment 
7 
DB Treatment Week 2 
11 to 21 
14 
DB Treatment 
8 
DB Treatment Week 4 
22 to 35  
28 
DB Treatment 
9 
DB Treatment Week 6 
36 to 49 
42 
DB Treatment 
 
DB Treatment End Point2 
 
 
DB Treatment 
9 
Withdrawal Baseline 
<=1 
1 
Withdrawal 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
CPFQ, CUDOS-A, 
SHAPS, MOS Sleep-R, 
PSS 
2 
Lead-in Baseline 
<=1 
1 
Lead-in 
3 
Lead-in Week 1 
2 to 14 
7 
Lead-in 
5 
Lead-in Week 3 
15 to 28 
21 
Lead-in 
5 
DB Treatment Baseline 
<=1 
1 
DB Treatment 
7 
DB Treatment Week 2 
2 to 21 
14 
DB Treatment 
8 
DB Treatment Week 4 
22 to 35 
28 
DB Treatment 
9 
DB Treatment Week 6 
36 to 49 
42 
DB Treatment 
 
DB Treatment End Point2 
 
 
DB Treatment 
9 
Withdrawal Baseline 
<=1 
1 
Withdrawal 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
SATE 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
SIGH-A 
2 
Lead-in Baseline 
<=1 
1 
Lead-in 
3 
Lead-in Week 1 
2 to 10 
7 
Lead-in 
4 
Lead-in Week 2 
11 to 17 
14 
Lead-in 
5 
Lead-in Week 3 
18 to 24 
21 
Lead-in 
5 
DB Treatment Baseline 
<=1 
1 
DB Treatment 
6 
DB Treatment Week 1 
2 to 10 
7 
DB Treatment 
7 
DB Treatment Week 2 
11 to 21 
14 
DB Treatment 


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Parameter 
Scheduled 
Visit Number 
Time Interval 
(label on output) 
Time Interval 
(Day)1 
Target Time Point (Day) 
by Period 
 
Analysis Phase 
8 
DB Treatment Week 4 
22 to 35  
28 
DB Treatment 
9 
DB Treatment Week 6 
36 to 49 
42 
DB Treatment 
 
DB Treatment End Point2 
 
 
DB Treatment 
9 
Withdrawal Baseline 
<=1 
1 
Withdrawal 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
CGI-I 
3 
Lead-in Week 1 
2 to 10 
7 
Lead-in 
4 
Lead-in Week 2 
11 to 17 
14 
Lead-in 
5 
Lead-in Week 3 
18 to 24 
21 
Lead-in 
5 
DB Treatment Baseline 
<=1 
1 
DB Treatment 
6 
DB Treatment Week 1 
2 to 10 
7 
DB Treatment 
7 
DB Treatment Week 2 
11 to 21 
14 
DB Treatment 
8 
DB Treatment Week 4 
22 to 35  
28 
DB Treatment 
9 
DB Treatment Week 6 
36 to 49 
42 
DB Treatment 
 
DB Treatment End Point2 
 
 
DB Treatment 
9 
Withdrawal Baseline 
<=1 
1 
Withdrawal 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
Physical Examination 
1 
Screening 
< 1 
-28 to -1 
Screening 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
11 
Follow Up 
> DB or 
>Withdrawal 
7 to 21 
Follow Up 
Neurological 
Examination 
1 
Screening 
< 1 
-28 to -1 
Screening 
7 
DB Treatment Week 2 
2 to 21 
14 
DB Treatment 
9 
DB Treatment Week 6 
22 to 49 
42 
DB Treatment 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
Vital Signs, Body 
Temperature, Body 
Weight, Clinical 
Laboratory Assessments, 
12-lead ECG 
1 
Screening 
<1 
-28 to -1 
Screening 
2 
Lead-in Baseline 
<=1 
1 
Lead-in 
3 
Lead-in Week 1 
2 to 14 
7 
Lead-in 
5 
Lead-in Week 3 
15 to 28 
21 
Lead-in 
5 
DB Treatment Baseline 
<=1 
1 
DB Treatment 
7 
DB Treatment Week 2 
2 to 21 
14 
DB Treatment 
8 
DB Treatment Week 4 
22 to 35 
28 
DB Treatment 
9 
DB Treatment Week 6 
36 to 49 
42 
DB Treatment 


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Parameter 
Scheduled 
Visit Number 
Time Interval 
(label on output) 
Time Interval 
(Day)1 
Target Time Point (Day) 
by Period 
 
Analysis Phase 
 
DB Treatment End Point2 
 
 
DB Treatment 
9 
Withdrawal Baseline 
<=1 
1 
Withdrawal 
10 
Withdrawal Week 2 
2 to 20 
14 
Withdrawal 
11 
Follow Up3 
> DB or 
>Withdrawal 
7 to 21 
Follow Up 
1 Relative to Study Day 1 in each of the Lead-in, the double-blind treatment and the withdrawal period 
2 End Point is defined as the last non-missing post-baseline measurement during the double-blind treatment period. 
3 For clinical laboratory assessments and ECG, the follow up visit is performed only in case of any clinical significant abnormalities observed at Week 11. 
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3. 
SUBJECT INFORMATION 
Subject information will be summarized for the Safety Analysis Set and listings will be created for 
the All Subjects Set. 
3.1. 
Demographics and Baseline Characteristics 
The following demographic and baseline characteristics variables will be listed and summarized 
by treatment group and overall:  
- age at screening (years) 
- sex 
- race and ethnicity 
- country 
- lead-in response status 
- height at baseline (cm) 
- weight at baseline (kg)  
- BMI at baseline (kg/m²)  baseline weight (kg) / (baseline height (m))²      
- duration of prior antidepressant treatment (in days)  
Baseline disease characteristics will be summarized at lead-in baseline and at double-blind 
treatment baseline for the following assessments: HDRS17 total score, SIGH-A total score, HAM-
A6 subscale score, HAM-D6 subscale score and HDRS17 anxiety/somatization factor score. 
The summary of demographic and baseline characteristics and baseline disease characteristics will 
be presented for the Safety analysis set, the Enriched Safety analysis set, the Enriched ITT set and 
the Full ITT set. In addition, the summary for the Safety analysis set will be presented by country 
and by enrollment prior to/after study suspension. 
The following screening and/or pre-dosing test results will be listed:  
- urine drug screen abnormalities 
- positive serology results  
- serum FSH results that are ≤40 IU/L (females only)  
- positive alcohol results  
If no abnormalities or positive results, an empty listing will be produced stating “No data to report”. 
If a subject has an abnormal finding, all related results will be listed (e.g. all serology results, or 
all drug screening results). 
All medical history data will be presented in a listed. 
Results from the Mini-international neuropsychiatric interview (MINI) will be listed.  
3.2. 
Disposition Information 
The number of subjects in each analysis set will be presented, and the number of subjects by 
country and center will be presented for the Safety analysis set and for the Enriched ITT set. 


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Study completion/withdrawal information will be summarized by treatment group and overall and 
will be listed. The distribution of study termination reasons will also be summarized.  
The distribution of time to study discontinuation will be presented graphically using Kaplan-Meier 
estimates. The time to discontinuation will be calculated as the duration (in days) from Study Day 1 
of the lead-in period (defined in Section 2.4) to study discontinuation. Subjects who complete the 
study will be censored at the study disposition date. 
Study completion and withdrawal information will be presented for the Safety analysis set and the 
Enriched ITT set and the information for each subject will also be presented in a listing. 
The number and percentage of subjects who enter lead-in period, the double-blind treatment period 
and the withdrawal period and who complete the lead-in period, the double-blind treatment period 
and the withdrawal period will be summarized. 
The number and percentage of lead-in placebo responders will be summarized overall, by country 
and by site. A cumulative distribution plot of the percent reduction in HDRS17 total score from 
lead-in baseline at the end of the lead-in period will be provided overall and by country. To explore 
the duration of response for lead-in placebo responders, a Kaplan-Meier plot will be presented for 
the distribution of time to worsening (i.e. no longer meeting ≥40% improvement) after the lead-in 
period. Time to worsening will be calculated as the duration (in days) from Study Day 1 of the 
double-blind treatment period (defined in Section 2.4) to the first visit where <40% improvement 
in HDRS17 total score is observed. Subjects who do not reach the worsening criterion will be 
censored at the study disposition date. 
3.3. 
Treatment Compliance 
The number of tablets dispensed and returned at each visit will be listed.  
3.4. 
Extent of Exposure 
Study drug administration information will be presented for each subject in a data listing. 
Treatment duration is defined as the number of days between the first and last day of study drug 
in the treatment phase (including lead-in, double-blind treatment and withdrawal): last day of study 
drug administration – first day of study drug administration + 1.  
Descriptive statistics of treatment duration will be presented. A frequency distribution for the 
treatment period only will also be provided using the following categories: <1 week (<7 days), 1-
<2 weeks (7-<14 days), 2-<3 weeks (14-<21 days), 3-<5 weeks (21-<35 days), 5-<7 weeks (35-
<49 days), 7-<9 weeks (49-<63 days), 9-<11 weeks (63-<77 days) and ≥11 weeks (≥77 days). 


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3.5. 
Protocol Deviations 
All major protocol deviations will be listed.  
3.6. 
Prior and Concomitant Medications 
Prior therapies and concomitant medications (relative to the double-blind treatment period) will 
be tabulated in 3 separate summaries:  
1. Prior medication – any medication which starts and ends before the date/time of 
first study drug administration in the Double-blind Treatment Period 
2. Prior and concomitant medication – any medication which starts before the 
date/time of first study drug administration in the Double-blind Treatment Period 
and ends after the date/time of first study drug administration in the Double-blind 
Treatment Period 
3. Concomitant medication – any medication which starts after the date/time of first 
study drug administration in the Double-blind Treatment Period 
If a prior or concomitant therapy record is missing components of its start and/or stop dates (day 
and/or month and/or year) then missing data will not be imputed, however, the following 
approaches will apply: 
 
• If the start year is the same as the year of first drug administration but the start day and 
month is missing, the medication will be considered as having started before the study.   
• If the start month and year is the same as the month and year of first drug administration 
but the start day is missing, the medication will be considered as having started before the 
study.   
• In case of a completely missing start date, the medication will be considered as having 
started before the study. 
• If the end year is the same as the year of last drug administration but the end day and month 
is missing, the medication will be considered as ongoing at the end of the study.   
• If the end month and year is the same as the month and year of first drug administration 
but the end day is missing, the medication will be considered as ongoing at the end of the 
study.   
• In case of a completely missing end date, the medication will be considered as ongoing at 
the end of the study. 
In addition, the following will also be listed: 
- preplanned surgery/procedures  
- antidepressant Treatment History Questionnaire (ATRQ) – any medication that is 
recorded on the ATRQ form  


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4. 
EFFICACY 
Efficacy data will be summarized for the ITT Analysis Sets (full and enriched) and listings will be 
created for the All Subjects Set.  
The efficacy variables in this study are listed in Table 2. 
Table 2: Efficacy Variables 
Endpoint 
Scale* 
Primary 
HDRS17 total score 
Secondary 
HDRS17 ≥30% improvement from double-blind treatment baseline on total 
score 
HDRS17 ≥50% improvement from double-blind treatment baseline on total 
score (clinical response) 
HDRS17 clinical remission 
HDRS17 anxiety/somatization factor score 
HAM-D6 score 
SIGH-A total score 
SIGH-A ≥30% improvement from double-blind treatment baseline on total 
score 
SIGH-A ≥50% improvement from double-blind treatment baseline on total 
score 
HAM-A6 score 
CGI-I 
Patient Reported 
Outcomes 
Clinically Useful Depression Outcome Scale (CUDOS-A) 
Cognitive and Physical Functioning Questionnaire (CPFQ) 
Snaith-Hamilton Pleasure Scale (SHAPS) 
Medical Outcomes Study Sleep-Revised (MOS Sleep-R) 
Perceived Stress Scale (PSS) 
Self-Assessment of Treatment Experience (SATE) 
* HDRS17  Hamilton Depression Rating Scale; HAM D6  Hamilton Depression Rating Scale; SIGH A  
Structured Interview Guide for the Hamilton Anxiety Scale; HAM A6  Hamilton Anxiety Rating Scale ; CGI I  
Clinical Global Impression – Improvement.  
4.1. 
Analysis Specifications 
4.1.1. 
Level of Significance 
The overall type I error rate for testing the JNJ-42165279 group versus the placebo group for the 
primary efficacy analysis will be controlled at the 1-sided significance level of 0.20. 
4.1.2. 
Imputation Methods for Missing Items 
Imputation of missing individual items will apply only to the HDRS17, as described in Section 
4.2.1. For all other scales where multiple items are summed to create a total score, if any item of 
the scale is missing on a visit, the total score for that scale at that visit will be left blank. 
4.2. 
Primary Efficacy Endpoint – HDRS17 Total Score 
The primary efficacy endpoint is the change from Baseline in HDRS17 total score at Week 6 of the 
double-blind treatment period.   


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4.2.1. 
Definition 
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in subjects diagnosed with depression (Hamilton M 1960). It is the most widely used symptom 
severity measure for depression. Each of the 17 items is rated by the clinician on either a 3- or a 
5-point scale. Higher scores indicate greater severity of depression. The HDRS17 total score will 
be calculated as the sum of the 17 item scores, and ranges from 0 to 52. 
If one HDRS17 Total Score item is missing, it will be imputed with the closest integer to the average 
of the remaining items at that time point. If more than 1 item is missing, no imputation will be 
performed and the HDRS17 Total Score will be missing. Imputation of item scores is performed 
prior to determining the endpoint for the HDRS17 Total Score. 
4.2.2. 
Estimand 
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 4 components: 
- Population: Subjects with a primary DSM-5 diagnosis of MDD with Anxious Distress 
- Variable: Change from baseline to Week 6 of the double-blind treatment period in HDRS17 
total score 
- Intercurrent event: No intercurrent events to be taken into account 
- Population-level summary: Difference in mean change from baseline to Week 6 of the 
double-blind treatment period in HDRS17 total score between treatment conditions. 
4.2.3. 
Analysis Methods 
4.2.3.1. 
Primary Analysis 
The primary efficacy analysis will be based on the eITT set. 
Descriptive statistics of actual values and mean changes from baseline for the HDRS17 total score 
at each scheduled time point will be provided by treatment group for the lead-in period, the double-
blind treatment period and the withdrawal period for the eITT set. A mean-SE plot over time will 
be presented for the HDRS17 total score observed values during the lead-in period, the double-
blind treatment period and the withdrawal period by treatment group. Listings will be created with 
HDRS17 item scores and the HDRS17 total score. 
The JNJ-42165279 treatment group will be compared with placebo using the change from double-
blind treatment baseline in the HDRS17 total score during the double-blind treatment period. The 
comparison will be performed with a mixed-effects model using repeated measures (MMRM), 
with time, treatment (placebo, JNJ-42165279) and time-by-treatment interaction as factors, 
double-blind treatment baseline total HDRS17 score as a continuous covariate, and country as 
categorical covariates. An unstructured variance-covariance matrix will be used. In case of 
convergence problems, simpler variance-covariance structures such as Toeplitz or AR(1) will be 
considered. The selection of any of these structures will be determined after exploration of the 


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observed correlation structure. The treatment-placebo differences will be obtained using the 
appropriate contrast in the MMRM models at the 6-week endpoint. A one-sided p-value with level 
of significance of 20% will be derived from the SAS results based on the above mixed-effects 
model (two-sided p-values at 40% significance level). The reduction in HDRS17 total score is 
expected to be larger after dosing with JNJ42165279, so the one-sided p-value will be calculated 
as described in the table below. 
Calculation of one-sided p-value 
Parameter 
Ha 
Estimated difference   
Mean JNJ – Mean Pla 
One-sided p-value 
Change in 
HDRS17 total 
score at Week 6 
Mean Chg JNJ- Mean Chg Pla< 0 
(larger reduction expected in JNJ 
vs pla) 
≤ 0 
p-value (2-sided test) / 2 
> 0 
1 – (p-value (2-sided test) / 2) 
 
Least-square mean changes from baseline (+/-SE) over time during the double-blind treatment 
period will be presented in a figure. 
4.2.3.2. 
Additional Analysis 
To assess the sensitivity of the results of the MMRM analysis of the primary endpoint, an analysis 
of covariance (ANCOVA) model for the change from baseline to the 6-week double-blind 
treatment endpoint in HDRS17 total score will be carried out. The ANCOVA model will include 
factors for treatment and (pooled) center and double-blind treatment baseline HDRS17 total sore 
as a covariate. In addition, the same ANCOVA model will also be performed on observed case 
data at week 6 of the double-blind treatment period. 
As a secondary analysis, the MMRM model described in Section 4.2.3.1 will be fitted with age, 
sex and duration of antidepressant treatment (in days) as additional covariates. 
The primary analysis specified in Section 4.2.3.1. will also be performed for the fITT set. 
Treatment effect for the fITT set will be estimated in 2 manners: using the same MMRM model 
as for the primary analysis and using the MMRM model with lead-in response status as additional 
categorical covariate.  
To explore the results for the subgroup of placebo responders, descriptive statistics of actual values 
and mean changes from baseline for the HDRS17 total score at each scheduled time point will be 
provided by treatment group for the lead-in period, the double-blind treatment period and the 
withdrawal period for the fITT subset of placebo responders. A mean-SE plot over time will also 
be presented for this subgroup. 
4.3. 
Secondary Efficacy Endpoints 
4.3.1. 
Definition 
The following secondary efficacy variables are used to measure depressive symptoms in subjects:  


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‐ 
HDRS17  ≥30% improvement from double-blind treatment baseline on total score: 
the percentage change from double-blind treatment baseline is calculated as 
 
100 ∗(𝐻𝐷𝑅𝑆17 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑎𝑛𝑦 𝑡𝑖𝑚𝑒 𝑝𝑜𝑖𝑛𝑡−𝐻𝐷𝑅𝑆17 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
𝐻𝐷𝑅𝑆17 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 
 
A ≥30% improvement from double-blind treatment baseline on total score means that the 
percentage from baseline is ≤ -30 in this calculation. 
‐ 
HDRS17  ≥50% improvement from double-blind treatment baseline on total score 
(clinical response): the percentage change from double-blind treatment baseline is 
calculated in the same way as for the ≥30% definition. A ≥50% improvement from 
double-blind treatment baseline on total score means that the percentage from baseline is 
≤ -50 in this calculation. 
‐ 
HDRS17 clinical remission: Clinical remission is defined as having a HDRS17 total score 
≤ 7.  
‐ 
HDRS17 anxiety/somatization factor score: The HDRS17 anxiety/somatization factor 
derived from Cleary and Guy’s factor analysis of the HDRS17 scale, includes six items 
from the original 17-item version: the items for psychic anxiety, somatic anxiety, 
gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and 
insight. The HDRS17 anxiety/somatization factor score will be calculated as the sum of 
the 6 item scores, and ranges from 0 to 18, with higher scores indicating greater severity 
of symptoms. 
‐ 
HAM-D6 subscale score: A 6-item subscale from the HDRS17 (HAM-D6) will be 
analyzed as it has been shown to be a uni-dimensional scale that provides information to 
core depressive symptoms and is sensitive to treatment response (Bech 1975). The six 
items are: depressed mood, guilt feelings, work and interests, psychomotor retardation, 
psychic anxiety, and general somatics (tiredness and pains). The HAM-D6 score will be 
calculated by summing the 6 items scores, and ranges from 0 to 22. Higher scores indicate 
greater severity of core symptoms. 
‐ 
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A): The original 
HAM-A scale assesses the severity of different anxiety-related symptoms (Hamilton 1959; 
Hamilton 1969). It is the most widely used symptom severity measure for anxiety. As the 
original HAM-A scale lacks instructions for administration and clear anchor points for the 
assignment of severity ratings, the structured interview guide version (SIGH-A) is used in 
the current study. 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. The SIGH-A scale consists of 14 items with a score of 0 to 4. Higher 
scores indicate higher severity (0-absent, 1-mild, 2-moderate, 3-severe, 4-incapacitating). 
The SIGH-A total score will be calculated by summing the 14 item scores, and ranges from 
0 to 56. Higher scores indicate worse results. 


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‐ 
SIGH-A  ≥30% improvement from double-blind treatment baseline on total score: 
the percentage change from double-blind treatment baseline is calculated as 
 
100 ∗(𝑆𝐼𝐺𝐻−𝐴 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑎𝑛𝑦 𝑡𝑖𝑚𝑒 𝑝𝑜𝑖𝑛𝑡−𝑆𝐼𝐺𝐻−𝐴 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
𝑆𝐼𝐺𝐻−𝐴 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑎𝑡 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 
 
A ≥30% improvement from double-blind treatment baseline on total score means that the 
percentage from baseline is ≤ -30 in this calculation. 
‐ 
SIGH-A ≥50% improvement from double-blind treatment baseline on total score: the 
percentage change from double-blind treatment baseline is calculated in the same way as 
for the ≥30% definition. A ≥50% improvement from double-blind treatment baseline on 
total score means that the percentage from baseline is ≤ -50 in this calculation. 
‐ 
HAM-A6 subscale score: The HAM-A6 is a 6-item subscale derived from the original 
Hamilton Anxiety scale (HAM-A). It comprises 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. The HAM-A6 score will be 
calculated by summing the 6 item scores, and ranges from 0 to 24. Higher scores indicate 
greater severity of symptoms.  
‐ 
Clinical Global Impression Improvement (CGI-I): The CGI-I is a 7-point scale that 
requires the clinician to assess how much the subject’s illness has improved or worsened 
relative to a baseline state at the beginning of the intervention. The CGI-I is rated as: 1 very 
much improved; 2 much improved; 3 minimally improved; 4 no change; 5 minimally 
worse; 6 much worse; 7 very much worse. Responders on the CGI-I are defined as 
subjects with a score of 1 very much improved or 2 much improved. 
4.3.2. 
Analysis Methods 
The secondary efficacy endpoints will be analyzed for both the eITT and fITT analysis sets. 
For all continuous secondary efficacy endpoints, descriptive statistics of actual values and mean 
changes from baseline at each scheduled time point will be provided by treatment group for the 
lead-in period, the double-blind treatment period and the withdrawal period. A mean-SE plot over 
time will be presented for observed values during the lead-in period, the double-blind treatment 
period and the withdrawal period by treatment group. 
For each of the continuous secondary efficacy endpoints, the JNJ-42165279 treatment group will 
be compared to placebo using the same MMRM model as for the HDRS17 total score.  
To explore the results for the subgroup of placebo responders, descriptive statistics of actual values 
and mean changes from baseline for the continuous secondary endpoints at each scheduled time 
point will be provided by treatment group for the lead-in period, the double-blind treatment period 
and the withdrawal period for the fITT subset of placebo responders. Mean-SE plots over time will 
also be presented for this subgroup. 


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Frequency tables and figures for the categorical secondary efficacy endpoints will be provided at 
each scheduled time point by treatment group for the lead-in period, the double-blind treatment 
period and the withdrawal period. Chi square test will be used to test the overall differences 
between the treatment groups at week 6 of the double-blind treatment period. If deemed 
appropriate, Cochran–Mantel–Haenszel test with (pooled) center as stratification factor will be 
performed. 
A cumulative distribution plot of the percent reduction in HDRS17 total score from double-blind 
treatment baseline at Week 6 of the double-blind treatment period will be provided. A similar plot 
will be provided for the SIGH-A total score percent reduction. 
4.4. 
Patient Reported Outcomes 
4.4.1. 
Definitions 
‐ 
Clinically Useful Depression Outcome Scale (CUDOS-A): The CUDOS contains 18 
items assessing all of the Diagnostic and Statistical Manual of Mental Disorders (5th 
edition) (DSM-5) inclusion criteria for major depressive disorder and dysthymic disorder 
as well as psychosocial impairment and quality of life. The 16 symptom items are rated on 
a 5-point Likert scale in order to keep the scale brief. The CUDOS was designed to be brief 
(completed in less than 3 minutes), quickly scored (in less than 15 seconds), clinically 
useful (fully covering the DSM-5 symptoms of major depressive disorder and dysthymic 
disorder), reliable, valid and sensitive to change. The content of the CUDOS-A subscale 
was based on the DSM-5 criteria for the anxious distress specifier. A CUDOS-A total score 
will be calculated as the sum of the 5 item scores, and ranges from 0 to 20, with higher 
scores indicates higher levels of anxious distress. 
‐ 
Cognitive and Physical Functioning Questionnaire (CPFQ): The CPFQ is a brief self-
report scale that provides additional information regarding the impact of adjunctive 
treatment on aspects of cognitive function including attention, memory and mental acuity. 
Subjects with MDD are often reported to have difficulties with functioning in this area. A 
CPFQ total score will be calculated as the sum of the 7 item scores, and ranges from 7 to 
42, with higher scores indicating more difficulties with cognitive and physical functioning. 
‐ 
Snaith-Hamilton Pleasure Scale (SHAPS): The SHAPS is a 14-item, self-report 
instrument developed for the assessment of hedonic capacity.  The SHAPS was developed 
to minimize cultural, gender, and age biases in the evaluation of hedonic capacity. It not 
only measures hedonic tone, but also its absence, i.e. anhedonia. Anhedonia can be a core 
symptom of depression. Four major domains are covered in the scale, namely 
interest/pastimes, social interaction, sensory experience, and food/drink. Each of the 
SHAPS items has a set of four response categories: Strongly Disagree, Disagree, Agree 
and Strongly Agree, with either of the Agree responses receiving a score of 0 and either of 
the Disagree responses receiving a score of 1. A SHAPS total score will be calculated as 
the sum of the 14 item scores, and ranges from 0 to 14. A higher SHAPS total score 
indicates higher levels of present state of anhedonia. 


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‐ 
Medical Outcomes Study Sleep-Revised (MOS Sleep-R): Symptoms of poor sleep 
commonly occur in anxiety and mood disorders. The MOS Sleep-R is a subject-completed 
scale containing 12 items that addresses various dimensions of sleep. Ten items are 
answered on a 6-point scale, where 1=“all of the time” and 6=“none of the time”. One item 
on sleep latency is answered on a 5 point Likert scale from 1=“0-15 minutes” to 5=“more 
than 60 minutes”. One item on the duration of sleep allows the subject to write in the 
number of hours slept per night. The instrument yields six subscales: sleep disturbance, 
snoring, shortness of breath or headache, sleep adequacy, sleep somnolence, and sleep 
quantity. The version to be used in this study has a recall period of the 4 past weeks. 
Quantity of sleep is scored as the average number of hours slept per night. Other subscales 
scores are converted to a T-score with a mean of 50, standard deviation (SD) of 10 and 
range of 0 to 100, where higher scores indicate fewer sleep-related problems. 
‐ 
Perceived Stress Scale (PSS): The PSS is the most widely used psychological instrument 
for measuring the perception of stress. It is a measure of the degree to which situations in 
one’s life are appraised as stressful. The questions in the PSS ask about feelings and 
thoughts during the last month. In each case, respondents are asked how often they felt a 
certain way (0 never, 1 almost never, 2 sometimes, 3 fairly often, 4 very often). A PSS 
total score is obtained by reversing responses (e.g. 0 4, 1 3, 2 2) to the 4 positively stated 
items (items 4, 5, 7 and 8) and then summing across all items. The PSS total score ranges 
from 0 to 40 with higher scores indicating higher severity of symptoms.   
‐ 
Self-Assessment of Treatment Experience (SATE): The SATE questionnaire is a 4-item 
self-report scale designed to provide additional information regarding the subject’s 
subjective experience while taking the treatment. 
4.4.2. 
Analysis Methods 
The patient reported outcome efficacy endpoints will be analyzed for both the eITT and fITT 
analysis sets. 
For all continuous patient reported outcome efficacy endpoints, descriptive statistics of actual 
values and mean changes from baseline at each scheduled time point will be provided by treatment 
group for the lead-in period, the double-blind treatment period and the withdrawal period. A mean-
SE plot over time will be presented for observed values during the lead-in period, the double-blind 
treatment period and the withdrawal period by treatment group. 
Frequency tables and figures for the categorical patient reported outcome efficacy endpoints will 
be provided at each scheduled time point by treatment group for the lead-in period, the double-
blind treatment period and the withdrawal period. 
5. 
SAFETY 
All safety analyses will be based on the Safety analysis set, except for the analysis of adverse 
events, that will also be performed for the enriched Safety analysis set.                                                                   
All safety data will be listed for the All Subjects Set. 


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5.1. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution 
A conservative approach will be used to handle the missing dates for adverse events. The rules for 
estimating incomplete AE onset dates will be as follows: 
(1) The missing day of the month will be estimated as follows: If the month and year are known 
and double-blind study medication started during that month then the estimated date is the 
start date of double-blind study medication.  If the month and year are known and double-
blind study medication started prior to that month then the estimated date is the 1st day of 
the month.  If the month and year are known and double-blind study medication started after 
the month, then no estimation will be done, and the AE will not be considered as treatment 
emergent for the double-blind phase. 
(2) If both the day and the month are missing: No estimation will be performed.  However, these 
AEs will be considered treatment emergent for the double-blind phase and will be included 
in the double-blind treatment summaries, except for the calculation of duration of the AE.  
Attempts will be made to get at least the month for the adverse events.  
The rules for estimating incomplete AE onset times will be as follows: 
The missing times will be estimated as follows: use time 00:00:00 of the given/imputed date for 
the start date/time of an AE and use 23:59:59 for the end date/time of an AE. 
For incomplete AE resolution dates, the rules are: 
(1) The missing day of the month will be estimated as follows:  If the month and year are known 
and the study medication was stopped before, or during that month, the estimated date is the 
last day of the month or the end of the double-blind phase, whichever is earlier.  If the study 
medication stopped after that month then the estimated date is the last day of the month. 
(2) If both the day and the month are missing:  the estimated resolution date is the end of the 
double-blind phase. 
5.2. 
Adverse Events 
The verbatim terms used in the CRFs by the investigator to identify adverse events (AEs) will be 
coded using the current Medical Dictionary for Regulatory Activities (MedDRA) maintained by 
the sponsor. 
Therapeutic reach is the number of days after the last dose intake that a subject is still considered 
to be potentially affected by study drug. For JNJ-42165279, therapeutic reach is defined as 4 days. 
AEs during the double-blind treatment period will be summarized using the therapeutic reach. 
Therapeutic reach will only be applied to the end of double-blind treatment period or to subjects 
who discontinue during the double-blind treatment period. 


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A treatment-emergent AE (TEAE) is an event that is new in onset or increased in severity 
following treatment initiation. Any event with a start date and time after the first dose intake will 
be considered treatment-emergent. An event that starts prior to and ends after the initiation of study 
medication will be considered treatment-emergent only if the severity increases after the start of 
medication. An event that starts in the withdrawal or follow up period but within the therapeutic 
reach of 4 days of the double-blind treatment period will be considered treatment-emergent during 
the double-blind treatment period. Adverse events with onset date during the withdrawal/follow-
up period outside the therapeutic reach of 4 days will be summarized separately. 
• The number (%) of subjects with TEAEs will be summarized by system organ class and 
preferred term for each treatment group and study period. A summary will be created for 
the most common TEAEs (≥5% incidence in either treatment group). Both of these 
summaries will also be provided for the enriched Safety analysis set. 
• In addition, TEAEs will be summarized by severity and relationship to study drug for each 
treatment group and study period by system organ class and preferred term. For the 
summaries of AEs by severity/relationship to study drug, the observation with the most 
severe occurrence/closest relationship to study drug will be chosen if there is more than 
one incident of an adverse event reported during the treatment phase by the subject.  
• The following TEAEs are considered to be of special interest in this study: severe 
headache, change in mental states, change in sensory function, change in motor function 
or coordination. The number (%) of subjects with TEAEs of special interest will be 
summarized by system organ class and preferred term for each treatment group and study 
period. Listings will be created with the results of neurological examinations following the 
incidence of these AEs. 
• Data listings will be generated for all AEs, deaths, serious adverse events (SAEs), severe 
AEs and discontinuations due to AEs and AEs of special interest. These listings will not 
be limited to TEAEs but will also include any adverse events with onset before the start of 
study treatment or after the end of study treatment. If there is no data to present then the 
listing should be created and should state "No data to present". 
5.3. 
Clinical Laboratory Tests 
For each study period, descriptive statistics on actual values and changes from respective period 
baseline at each scheduled time point for hematology, chemistry, urinalysis and coagulation will 
be provided for the Safety analysis set. Laboratory summaries will be provided in Standard 
International (SI) units. All laboratory data will be listed for the All Subjects set. 
Cross-tabulations (with classes for below, within, and above the central laboratory range) showing 
the shift of laboratory values from baseline to each scheduled time point and endpoint will be 
presented by treatment group and study period. 


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Clinical laboratory test values will be considered “treatment emergent markedly abnormal” 
(TEMA) using the criteria defined by the Sponsor (Johnson & Johnson Research & Development, 
LLC) listed in Table 3. The identification of TEMA laboratory values is based on baseline value 
(in any period) being missing or within the normal range and the corresponding post baseline value 
being markedly high/low as per the values in Table 3. If post baseline laboratory results are above 
the upper limit and the baseline value is below the lower limit, then the post baseline abnormality 
will also be considered TEMA. The same applies to the post baseline value being below the lower 
limit with the baseline value being above the upper limit.  
The incidence of TEMA will be presented by treatment group and study period at each scheduled 
time point and endpoint. 
 
Table 3: Laboratory Parameters: Criteria for Markedly Abnormal Values 
Laboratory Parameter 
Markedly Low 
Markedly High 
Albumin (g/L) 
<20 
> 2 x ULN 
Alkaline phosphatase (U/L) 
N/A 
> 1.5 x ULN 
Alanine aminotransferase (ALT) (U/L)  
N/A 
> 3 x ULN 
Aspartate aminotransferase (AST) (U/L) 
N/A 
> 3 x ULN 
Bicarbonate [mmol/L] 
15.1 
34.9 
Bilirubin (umol/L)  
N/A 
> 1.5 x ULN 
Urea Nitrogen (mmol/L)  
N/A 
> 3 x ULN 
Calcium (mmol/L) 
<1.75 
>3 
Chloride (mmol/L) 
<90 
>120 
Creatine kinase (U/L)  
N/A 
> 3 x ULN 
Creatinine (umol/L) 
N/A 
> 1.5 x ULN 
Gamma glutamyl transferase (U/L) 
N/A 
> 3 x ULN 
Glucose (mmol/L) 
<3.33 
> 3 x ULN 
Lactate dehydrogenase (U/L) 
N/A 
> 1.5 x ULN 
Phosphate (mmol/L) 
<0.484 
> 1.5 x ULN 
Potassium (mmol/L) 
<2.8 
>5.8  
Protein (g/L) 
N/A 
> 2 x ULN 
Prothrombin International Normalized Ratio 
N/A 
≥1.3 
Sodium (mmol/L) 
<125.0 
>155.0 
Hemoglobin (g/L) 
<75 
> 1.1 x ULN 
Platelets (x10e9/L) 
<100 
> 3 x ULN 
Erythrocytes (x10e12/L)  
<3 
> 2 x ULN 
Leukocytes (x10e9/L)  
<2.5 
> 2.5 x ULN 
Hematocrit [fraction] 
 
 
         male 
0.24 
0.55 
         female 
0.28 
0.5 
 
Graphical presentations will be created for the following liver function tests: alanine 
aminotransferase, aspartate aminotransferase, albumin, bilirubin, alkaline phosphatase, gamma 
glutamyl transferase. Liver function test results standardized to the upper limit of normal (based 
on central laboratory ranges) will be graphically presented over time for each subject. The 
incidence of liver function tests above the central laboratory normal limit will be presented by 
treatment group at each scheduled time point and endpoint. 
Graphical presentations will also be created for prothrombin international normalized ratio results. 


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Clinical laboratory tests that meet the criteria for abnormal and markedly abnormal will be listed 
by subject. Results on urine drug screen, alcohol screen and pregnancy test will be presented in 
separate listings. 
Rule for BQL/UQL (if applicable) 
For the measurement that is BQL/UQL, the value will be imputed based on the lowest/highest 
limit of quantifiable value for the summary table, e.g. if the original result of measurement is 
marked as ‘<0.1’, the value will be imputed as 0.1 correspondingly. For the listing, however, the 
original values as stated in the database will be presented. 
5.4. 
Vital Signs and Physical Examination Findings 
Descriptive statistics for absolute values and changes from baseline will be presented at each 
scheduled time point and endpoint by treatment group and study period for body weight, supine 
systolic blood pressure (mmHg), supine diastolic blood pressure (mmHg), pulse rate (beats per 
minute) and oral temperature (oC).  
Mean-SE plots over time will be presented for vital sign values by treatment group.  In addition, 
scatter plots of post-baseline versus baseline values will be presented by treatment group. All 
individual vital signs data will be listed. 
Abnormal values are defined in Table 4 and will be summarized using frequency distribution tables 
over time by treatment group and study period. A listing of subjects meeting any of the abnormality 
criteria will be provided. 
Table 4: Vital Signs Abnormality Ranges (Supine and Standing) 
 
Low 
Normal 
High 
SBP (mmJHg) 
<90 
90-140 
>140 
DBP (mmHg) 
<50 
50-90 
>90 
Pulse (bpm) 
<45 
45-90 
>90 
Temperature (C) 
<35.5 
35.5-37.5 
>37.5 
 
The incidence of subjects who have a treatment-emergent abnormality (as defined in Table 5 
below) at each scheduled time point and endpoint will be presented by treatment group and study 
period.  


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Table 5: Treatment-Emergent Abnormality Categories for Vital Signs 
Vital Parameter 
Post-baseline value outside of normal limit if: 
Abnormally low 
Abnormally high 
Pulse (bpm) 
A decrease from baseline of 
 15 to a value < 45 
An increase from baseline of 
 15 to a value > 90 
Systolic BP 
(mmHg) 
A decrease from baseline of 
 20 to a value < 90 
An increase from baseline of 
 20 to a value > 140 
Diastolic BP 
(mmHg) 
A decrease from baseline of 
 15 to a value < 50 
An increase from baseline of 
 15 to a value > 90 
 
Physical and neurological examination abnormalities will be listed. If a subject has an abnormality 
noted at any time, all the observations will be listed. 
5.5. 
Electrocardiogram 
Triplicate 12-lead ECG will be obtained at Day 1 (predose), otherwise a single, 12-lead ECG will 
be obtained at each scheduled time point. The ECG variables that will be analyzed are heart rate 
(HR), ECG intervals (RR, PR, QRS, and QT) as well as corrected QT intervals according to 
Bazett’s formula (QTcB) and Fridericia’s formula (QTcF).  
Summary tables for actual values and changes from baseline will be presented by treatment group 
and period at each scheduled time point and at endpoint. Mean-SE plots over time will be presented 
for ECG values by treatment group. Scatter plots of post-baseline versus baseline values will be 
presented by treatment group. 
The frequency of subjects who have abnormal values will be summarized by treatment group and 
study period.  All data for subjects that have abnormal values will be presented in a separate listing.  
The following abnormality ranges will be used for ECG parameters (Table 6): 
 
Table 6: ECG Abnormality Ranges  
 
Low 
Normal 
High 
HR (bpm) 
<45 
45-90 
> 90 
PR Interval (msec) 
<120 
120-220 
>220 
QRS Interval (msec) 
- 
<120 
≥120 
QT Interval (msec) 
- 
<500 
≥500 
 
Criteria for abnormal corrected QTc interval values and changes from baseline are presented in 
Table 7. Abnormal values and changes will be summarized using frequency distribution tables 
over time by treatment group and period. A listing of subjects meeting any of the abnormality 
criteria will be provided. 
 


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Table 7: Criteria for Abnormal QTc Values and Changes From Baseline 
Parameter 
Classification 
Criteria 
QTc value 
Normal 
450 
> 450 – 480 
>450 - 480  
> 480 – 500 
>480 – 500 
> 500 
> 500 
QTc change from baseline 
No concern 
30 
Concern 
>30 – 60 
Clear concern 
> 60 
These criteria are based on ICH E14 Guideline 
5.6. 
C-SSRS 
The Columbia Suicide Severity Rating scale (C-SSRS) is a low-burden measure of the spectrum 
of suicidal ideation and behavior. It is a semi structured clinician-administered questionnaire 
designed to solicit the occurrence, severity, and frequency of suicide-related ideation and 
behaviors during the assessment period.  
Using the C-SSRS, potentially suicide-related events will be categorized using the following 
scores:  
Suicidal Ideation (1-5) 
1: Wish to be dead 
2: Non-specific active suicidal thoughts 
3: Active suicidal ideation with any methods (not plan) without intent to act 
4: Active suicidal ideation with some intent to act, without specific plan 
5: Active suicidal ideation with specific plan and intent 
Suicidal Behavior (6-10) 
6: Preparatory acts or behavior 
7: Aborted attempt 
8: Interrupted attempt 
9: Non-fatal suicide attempt 
10: Completed suicide 


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A frequency distribution at each scheduled time point and endpoint will be provided by treatment 
group and study period. A listing will be provided of C-SSRS items throughout the study for 
subjects with suicidal ideation or behavior at any time point. 
6. 
PHARMACOGENOMIC ANALYSES 
DNA samples will be analyzed for the FAAH gene. The relationship between genetic subgroups 
for the FAAH gene (C/C or A/C) and JNJ-42165279 
 
) will be examined through descriptive statistics and graphical presentations. A similar 
analysis will be performed to explore the relationship between genetic subgroups and the 
 
 
7. 
BIOMARKERS 
Biomarker analyses will be based on the biomarker analysis set. 
During the study, the following biomarker evaluations will be performed at the start of the lead-in 
period, at Week 2 and at Week 6 of the double-blind treatment period and at Week 2 of the 
withdrawal period/end of withdrawal visit: plasma concentrations of FAAs (AEA, PEA and OEA) 
and blood and saliva collection for exploratory biomarkers. The analysis of FAAs is included in 
this SAP, a separate biomarker SAP will be written for the analysis of the exploratory biomarkers. 
7.1. 
Summary of FAA Biomarker Values 
The FAA biomarker analytes will be summarized 
 using descriptive statistics 
of actual values, changes and percent 
 
Mean-SE plots 
, and results will be listed.  
Associations between 
 will be explored for 
each of the analytes using scatterplots and Pearson and Spearman correlation coefficients. 
7.2. 
Relationship Between FAA Biomarker Analytes and 
 
To investigate the 
 biomarkers, associations between FAA levels at the 
 
 will be explored using scatterplots and Pearson and Spearman 
correlation coefficients. 
Associations between FAA levels at the 
 
 will be explored using 
scatterplots and Pearson and Spearman correlation coefficients. 
 
7.3. 
Relationship Between FAA Biomarker Analytes and 
 
 
Descriptive statistics of actual values, changes and percent 
 will be 
provided 
 for all FAA biomarker analytes 
 for 
 
  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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states. Acta Psychiatr Scand 1975; 51(3): 161-170. 
2. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32(1): 50-55. 
3. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62. 
4. Lee S. et al: Does elimination of placebo responders in a placebo run-in increase the treatment 
effect in randomized clinical trials? A meta-analytic evaluation; Depression and Anxiety 
2004;19(1)10-19 
5. 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