Clinical trial NCT02432703
Conditions: Phobic Disorders
Keywords: Social Anxiety Disorder JNJ-42165279
Sponsor: Janssen Research & Development, LLC
Start date: 2015-06-11; Completion date: 2018-08-09
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the efficacy of JNJ-42165279 during 12 weeks of treatment in participants with Social Anxiety Disorder (SAD).

Detailed description:
This is a Phase 2a randomized (study drug assigned by chance), double-blind (neither the Investigator nor the participants know about the study intervention), placebo-controlled, parallel-group, multi-center study of JNJ-42165279 in participants with social anxiety disorder. Participants will receive 25 milligram (mg) JNJ-42165279 or matching placebo orally once-daily from Day 1 up to 12 weeks. Participants will primarily be assessed for the change from baseline in Liebowitz Social Anxiety Scale (LSAS) at Week 12. Safety will be monitored throughout the study.

Arms: arm 1: Participants will receive 25 milligram (mg) JNJ-42165279 orally once-daily from Day 1 up to 12 weeks. arm 2: Participants will receive a matching placebo orally once-daily from Day 1 up to 12 weeks.
Interventions: intervention 1: JNJ-42165279 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 25 milligram (mg) JNJ-42165279 orally once-daily from Day 1 up to 12 weeks. intervention 2: Participants will receive a matching placebo orally once-daily from Day 1 up to 12 weeks.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 25 August 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 
Social Anxiety Disorder.
Protocol 42165279SAX2001; Phase 2a
Amendment INT-3
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 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:    2014-004258-32
     
Status:
Approved
Date:
25 August 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica N.V.  
EDMS number: EDMS-ERI-92403433, 4.0
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.
NCT02432703


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 11
TIME AND EVENTS SCHEDULE .............................................................................................................. 17
ABBREVIATIONS ...................................................................................................................................... 20
1.
INTRODUCTION................................................................................................................................ 22
1.1.
Background .................................................................................................................................... 22
1.2.
Overall Rationale for the Study...................................................................................................... 27
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 28
2.1.
Objectives ...................................................................................................................................... 28
2.2.
Hypothesis ..................................................................................................................................... 28
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 29
3.1.
Overview of Study Design.............................................................................................................. 29
3.2.
Study Design Rationale.................................................................................................................. 30
3.3.
Stopping Criteria ............................................................................................................................ 35
3.3.1.
Individual Stopping Criteria......................................................................................................... 35
3.3.2.
Protocol Stopping Criteria........................................................................................................... 36
4.
SUBJECT POPULATION.................................................................................................................. 36
4.1.
Inclusion Criteria ............................................................................................................................ 37
4.2.
Exclusion Criteria ........................................................................................................................... 39
4.3.
Prohibitions and Restrictions ......................................................................................................... 42
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 43
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 44
7.
TREATMENT COMPLIANCE............................................................................................................ 44
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 45
9.
STUDY EVALUATIONS .................................................................................................................... 46
9.1.
Study Procedures........................................................................................................................... 46
9.1.1.
Overview..................................................................................................................................... 46
9.1.2.
Screening Phase ........................................................................................................................ 47
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 48
9.1.4.
Posttreatment Phase (Follow Up)............................................................................................... 54
9.2.
Safety Evaluations ......................................................................................................................... 55
9.2.1.
Adverse Events........................................................................................................................... 55
9.2.2.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 55
9.2.3.
Vital Signs................................................................................................................................... 56
9.2.4.
Electrocardiogram....................................................................................................................... 56
9.2.5.
Physical and Neurological Examinations.................................................................................... 56
9.2.6.
Clinical Laboratory Tests ........................................................................................................... 57
9.3.
Efficacy........................................................................................................................................... 59
9.3.1.
Evaluations ................................................................................................................................. 59
9.3.2.
Endpoints.................................................................................................................................... 60
9.4.
Biomarkers ..................................................................................................................................... 61


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9.5.
Pharmacokinetics........................................................................................................................... 61
9.5.1.
Evaluations ................................................................................................................................. 61
9.5.2.
Analytical Procedures................................................................................................................. 61
9.5.3.
Pharmacokinetic Parameters ..................................................................................................... 62
9.6.
Pharmacogenomic Evaluations ..................................................................................................... 62
9.7.
Sample Collection and Handling.................................................................................................... 63
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 63
10.1.
Completion ..................................................................................................................................... 63
10.2.
Discontinuation of Study Treatment............................................................................................... 63
10.3.
Withdrawal from the Study............................................................................................................. 64
11.
STATISTICAL METHODS................................................................................................................. 64
11.1.
Subject Information ........................................................................................................................ 64
11.2.
Sample Size Determination ........................................................................................................... 65
11.3.
Efficacy Analysis ............................................................................................................................ 65
11.4.
Safety Analysis............................................................................................................................... 66
11.5.
Interim Analysis.............................................................................................................................. 67
11.6.
Pharmacodynamic Analysis........................................................................................................... 67
11.7.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis ............................................ 68
11.8.
Data Review Committee (DRC)..................................................................................................... 68
12.
ADVERSE EVENT REPORTING ...................................................................................................... 68
12.1.
Definitions ...................................................................................................................................... 68
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 68
12.1.2.
Attribution Definitions.................................................................................................................. 70
12.1.3.
Severity Criteria .......................................................................................................................... 70
12.2.
Special Reporting Situations.......................................................................................................... 71
12.3.
Procedures..................................................................................................................................... 71
12.3.1.
All Adverse Events...................................................................................................................... 71
12.3.2.
Serious Adverse Events ............................................................................................................. 72
12.3.3.
Pregnancy................................................................................................................................... 73
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 73
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 73
13.1.
Procedures..................................................................................................................................... 74
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 74
14.
STUDY DRUG INFORMATION......................................................................................................... 74
14.1.
Physical Description of Study Drug(s) ........................................................................................... 74
14.2.
Packaging ...................................................................................................................................... 74
14.3.
Labeling.......................................................................................................................................... 74
14.4.
Preparation, Handling, and Storage............................................................................................... 74
14.5.
Drug Accountability ........................................................................................................................ 75
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 75
16.
ETHICAL ASPECTS ......................................................................................................................... 76
16.1.
Study-Specific Design Considerations........................................................................................... 76
16.2.
Regulatory Ethics Compliance....................................................................................................... 77
16.2.1.
Investigator Responsibilities ....................................................................................................... 77
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 77
16.2.3.
Informed Consent ....................................................................................................................... 78
16.2.4.
Privacy of Personal Data ............................................................................................................ 79
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 80
16.2.6.
Country Selection ....................................................................................................................... 80
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 80
17.1.
Protocol Amendments.................................................................................................................... 80


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17.2.
Regulatory Documentation ............................................................................................................ 81
17.2.1.
Regulatory Approval/Notification ................................................................................................ 81
17.2.2.
Required Prestudy Documentation............................................................................................. 81
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 82
17.4.
Source Documentation................................................................................................................... 82
17.5.
Case Report Form Completion ...................................................................................................... 82
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 83
17.7.
Record Retention ........................................................................................................................... 83
17.8.
Monitoring ...................................................................................................................................... 84
17.9.
Study Completion/Termination....................................................................................................... 84
17.9.1.
Study Completion ....................................................................................................................... 84
17.9.2.
Study Termination....................................................................................................................... 85
17.10.
On-Site Audits ................................................................................................................................ 85
17.11.
Use of Information and Publication................................................................................................ 85
REFERENCES............................................................................................................................................ 87
ATTACHMENTS......................................................................................................................................... 88
Attachment 1:
17-Item Hamilton Depression Rating Scale (HDRS17) ................................................. 88
Attachment 2:
Clinical Global Impression – Improvement (CGI-I)........................................................ 89
Attachment 3:
Sheehan Disability Scale (SDS) .................................................................................... 90
Attachment 4:
Generalized Anxiety Disorders (GAD-7)........................................................................ 91
Attachment 5:
Medical Outcomes Study (MOS) - 12-Item Sleep Scale Acute - Revised..................... 92
Attachment 6:
Liebowitz Social Anxiety Scale (LSAS).......................................................................... 94
Attachment 7:
Snaith-Hamilton Pleasure Scale (SHAPS) .................................................................... 95
Attachment 8:
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) .......................... 97
Attachment 9:
Self-Assessment of Treatment Experience ................................................................... 98
Attachment 10:
Columbia Suicide Severity Rating Scale – BASELINE................................................ 100
Attachment 11:
Columbia Suicide Severity Rating Scale – Since Last Visit......................................... 102
Attachment 12:
Anticipated Events ....................................................................................................... 104
Attachment 13:
Prohibited Cytochrome P450 Inhibitors and Inducers ................................................. 105
INVESTIGATOR AGREEMENT ............................................................................................................... 106
LAST PAGE.............................................................................................................................................. 106


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
16 Jan 2015
Amendment INT-1
14 Apr 2015
Amendment INT-2
Amendment INT-3
28 Sept 2016
25 August 2017
Amendments below are listed beginning with the most recent amendment.
Amendment INT-3 (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: 

To update the information on toxicology

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.

Adaptation of the number of subjects participating in the study. This will be changed from 122 to 137 to 
replace 15 subjects who had to stop early when the study was put on hold. 

Change in allowed medication and control of drug intake.

Add the optional use of a diary or electronic device to document the intake of study medication.
Applicable Section(s)
Description of Change(s)
Rationale: 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
Synopsis
Safety Evaluations
Added: 
In all women, serum and urine pregnancy test will be performed at Screening and Follow-
up and urine pregnancy test at study visits 2 and 9. 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 u: 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.
Section 1.1
Text on spermatogenesis and reproductive toxicology added to reflect recent non-clinical 
study results.
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, each study visit and at 
follow-up. 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.
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 


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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.
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 9.1.2, 9.1.3
and 9.1.4
Added: urine pregnancy test at visits 3 to 8 for WOCBP and serum and urine pregnancy 
test at screening and follow-up for all women (to be consistent with the Time and Events 
schedule).
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 Follow-up and urine pregnancy test at study visits 2 and 9. 

In WOCBP: urine pregnancy test will be performed at all other timepoints. 


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
If the urine pregnancy test is positive, a serum β-HCG test will be performed.
Applicable Section(s)
Description of Change(s)
Rationale: Adaptation of the number of subjects participating in the study. This will be changed from 122 to 137 to 
replace 15 subjects who had to stop early when the study was put on hold
Synopsis and Sections 
3.1, 4.0 and 11.2
Changed 122 subjects participating in this study into 137 subjects.
Synopsis and 
Section 11.2
Added sentence: To replace 15 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 122 
to 137.
Rationale:
•
Better clarify that administration of study medication at the site needs to be witnessed by study site personnel.
•
Remove ramelteon from the list of allowed nonbenzodiazepine sleep aids. Ramelteon is a melatonine agonist.
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
Replaced:
Note: Nonbenzodiazepines sleep aids (including: zolpidem, zaleplon, eszopiclone, and 
ramelteon) are allowed on a PRN (as needed) basis during the study. 
by 
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.
Rationale: Add the optional use of a diary or electronic device to document the intake of study medication.
Synopsis and 
Section 6,
T&E schedule
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.
Rationale:
Numbering of exclusion criterion 6 not correct after amendment 2.
Section 4.2
Replaced:
6. 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).


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Applicable Section(s)
Description of Change(s)
by:
6. Criterion modified by Amendment 2.
6.1. 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).
Amendment INT-2 (28 Sep 2016)
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 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      
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 “t” 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
11.4 Safety Analysis
Exclusion criteria 6 has been updated as follows:
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 4, Week 8 and Week 12 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.
Sub title updated as follows: Physical and Neurological Examinations


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Applicable Section(s)
Description of Change(s)
12.2 Special 
Reporting Situations
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 (14 Apr 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 address the comments raised 
by the Health Authorities of the United States of America and of Canada on safety issues.
Applicable Section(s)
Description of Change(s)
Rationale: Request to exclude women of child bearing potential until the risk for teratogenic effects is better 
understood.
4.1. Inclusion 
Criteria;
Inclusion criteria 6 has been updated as follows:
For this study only women who are not able to bear children will be enrolled. Before 
entry, female subjects must meet the following criteria depending on reproductive stage:

Postmenopausal, defined as

>45 years of age with amenorrhea for at least 18 months, or

>45 years of age with amenorrhea for at least 6 months and a serum follicle 
stimulating hormone (FSH) level >40 IU/mL, or

Menstrual

Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal 
ligation, or otherwise be incapable of pregnancy)

If heterosexually active, practicing a highly effective method of birth control, 
including hormonal prescription oral contraceptives, contraceptive injections, 
contraceptive patch, intrauterine device, double-barrier method (eg, condoms, 
diaphragm, or cervical cap, with spermicidal foam, cream, or gel), or male 
partner sterilization, consistent with local regulations regarding use of birth 
control methods for subjects participating in clinical trials, for the duration of 
their participation in the study, and for at least 3 months after intake of the last 
dose of study drug, or

Not heterosexually active

Note: Women who are not heterosexually active at screening must agree to 
utilize a highly effective method of birth control if they become heterosexually 
active during their participation in the study. Women must agree to continue 
using the same method(s) of contraception throughout the study and for at least 
3 months after receiving the last dose of study drug.
Inclusion criteria 7 of the original protocol has been deleted:
If a woman of childbearing potential, she must have a negative serum and urine -human 
chorionic gonadotropin (-hCG) pregnancy test at screening; and a negative urine 
pregnancy test on Day 1 (before receiving study drug).


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Applicable Section(s)
Description of Change(s)
Synopsis – Time & 
Events schedule.
-
Frequency of pregnancy tests updated (tests deleted on Weeks 1, 2, 4 and 8).
-
Footnote “k” updated : Performed for all women of childbearing potential.
4.3 Prohibitions and 
Restrictions
First paragraph of the original protocol related to women of child bearing potential has 
been deleted
Rationale: Request that the interval between adverse event assessments and routine clinical labs should not exceed 
2 weeks.
Synopsis – Time & 
Events schedule.
Safety visits added at Week 6 (Day 42) and Week 10 (Day 70)
9.1.3. Double-Blind 
Treatment Phase
Safety visits added at Week 6 (Day 42) and Week 10 (Day 70):
The following assessments will be performed as specified in the Time and Events 
schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Clinical safety laboratory assessments under fasted conditions, when feasible 
(including hematology, serum chemistry, coagulation and urinalysis)

C-SSRS

Record adverse events and concomitant medication
Rationale:
Clarification of stopping rules.
3.3.1. Individual 
Stopping crieria
QTcF replaced by QTcB in the third bullet.

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 Upper 
Limit of Normal (ULN) (confirmed by repeat),

AST and/or ALT >3 x ULN AND Total bilirubin >1.5  2 x ULN (confirmed by 
repeat).
16.1. Study-Specific
Design 
Considerations
….‘stopping rules’ have been developed for stopping treatment in the event that subjects 
have greater than 2 3 fold increase in transaminases or have an increase in total 
bilirubin to >2 x ULN …
Rationale: Abbreviation missing in the Time and Event Schedule section
Synopsis – Time & 
Events schedule
“Q-LES-Q: Quality of Life Enjoyment and Satisfaction Questionnaire” added below 
the footnotes
Rationale: Updated total blood volume  to be collected (2 additional safety visits at Weeks 6 and 10)
9.1.1. Individual 
Stopping crieria
For each subject, the maximum amount of blood drawn in this study will not exceed 150
200 mL
16.1. Study-Specific 
Design 
Considerations
The total blood volume to be collected will not exceed 150 200 mL


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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 Social Anxiety 
Disorder.
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 250 mg and a multiple dose regimen of 100 mg once-daily 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.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective of this study is to investigate the efficacy of JNJ-42165279 during 12 weeks of 
treatment in subjects with Social Anxiety Disorder (SAD).
Secondary Objectives
The secondary objectives of this study are:

To assess the safety and tolerability of JNJ-42165279 in subjects with SAD. 

To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as once daily 
(qd) in subjects with SAD using a population PK approach, and explore the relationship between 
exposure to JNJ-42165279 and efficacy and safety parameters.
Exploratory Objectives
The exploratory objectives are:

To assess the efficacy of JNJ-42165279 on both anxiety and depression symptoms.

To evaluate the impact of treatment with JNJ-42165279 compared to placebo on patient-reported 
assessments of symptoms of anxiety, depression, impairment in daily living and quality of life.

To evaluate pharmacodynamic (PD) effects by the assessment of biomarkers of peripheral 
pharmacological activity after repeated doses of JNJ-42165279, including assessment of plasma 
concentrations 
of 
FAAs 
(anandamide 
AEA, 
palmitoylethanolamide 
[PEA], 
and 
oleoylethanolamide [OEA]) that are expected to rise as a consequence of the inhibition of their 
hydrolysis by FAAH.
                                                
a This section has been amended per Amendments INT-1, 2 and 3.


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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 SAD.

To explore any potential differences between healthy subjects and subjects with social anxiety 
disorder (SAD) using a population PK approach.
Hypothesis
JNJ-42165279 will be efficacious in reducing the symptom burden associated with SAD assessed on the 
Liebowitz Social Anxiety Scale (LSAS).
OVERVIEW OF STUDY DESIGN
This is a multi-center, double-blind, placebo-controlled, randomized, parallel-group study assessing the 
efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of treatment in subjects with SAD. 
Approximately 137 subjects will be enrolled in this 12 week treatment study randomly assigned in a 1:1 
ratio to either 25 mg of JNJ-42165279 or placebo (dosed once daily orally).
For all enrolled subjects, this study will consist of a 28-day eligibility screening period, a 12 week double-
blind treatment period and a follow-up examination between 7 and 28 days after last dose. The study 
duration for each subject will be maximally 20 weeks.
The study will be an outpatient study.
Screening
After giving written informed consent, subjects may be screened over a period of up to 28 days to assess 
their eligibility for the study according to the inclusion and exclusion criteria defined for this study. 
Double Blind Treatment Phase
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1. 
During the 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 effects will be explored at the time points 
listed in the Time and Events Schedule.
A pharmacogenomic blood sample will be collected from all eligible subjects on Day 1. Participation in 
the pharmacogenomic research component is required to assess whether the subject is carrier of the A-
allele variant for FAAH and to identify genetic 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 28 days following last dosing (Week 12), 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. 


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SUBJECT POPULATION
The target population for this study is male and female subjects with SAD who are between 18 and 
64 years of age inclusive, with symptom severity as measured by the LSAS score ≥ 70 for whom 
pharmacotherapy is indicated.   
Approximately 137 subjects with SAD will be enrolled in the proof-of-concept study to ensure 
53 subjects per treatment group completing the trial, assuming a dropout rate of approximately 15%. 
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
(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 Follow-up and urine 
pregnancy test at study visits 2 and 9. 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. 
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 SAD. 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
Liebowitz Social Anxiety Scale (LSAS)


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The LSAS3 is the primary clinical scale for evaluation of the efficacy of JNJ-42165279 in SAD. It is 
designed to record the severity of subjective anxiety and avoidance behavior across a range of social 
interaction and performance situations that may be feared by a subject. It has been commonly used to 
study treatment outcomes in clinical trials and, more recently, to evaluate the effectiveness of cognitive-
behavioral treatments.
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 that maybe co-morbid with SAD and determine both their influence on treatment and their 
responsiveness to treatment.  

17-item Hamilton Depression Rating Scale (HDRS17)
The HDRS is included as a means to determine the frequency and severity of signs and symptoms of 
depression that maybe co-morbid with SAD and determine both their influence on treatment and their 
responsiveness to treatment.  

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 SAD, the impact of treatment on sleep symptoms, and 
impairment in daily life. 

Sheehan Disability Scale (SDS)

Generalized Anxiety Disorders (GAD-7)

Snaith-Hamilton Pleasure Scale (SHAPS)

Medical Outcomes Study Sleep-Revised (MOS Sleep-R)

Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)

Self-Assessment of Treatment Experience 
BIOMARKER 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).
Venous blood samples may be stored and used for future analysis of JNJ-42165279 metabolites and 
exploratory proteomics and metabolomics or other markers related to neuropsychiatric disorders.
STATISTICAL METHODS
Sample Size Determination
The sample size for the study is based on the assumption of a treatment difference of at least 10 points in 
the mean change from baseline to the endpoint in LSAS total score between JNJ-42165279 treatment 
group and placebo. A standard deviation of 24 in the change in LSAS total score from baseline is used 


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based on published data.4,5,6  To detect the treatment difference of 10 points (which is judged to be 
clinically relevant4,5,6)  with a power of 90% at an overall 1-sided significance level of 0.20, 53 subjects in 
each group are required. When adjusted for a drop-out rate of approximately 15% of subjects, the required 
number of subjects is 61 per treatment group. To replace 15 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 
122 to137.
Efficacy Analysis
All efficacy analyses will be based on the intention-to-treat (ITT) analysis set. The JNJ-42165279 
treatment group will be compared with placebo using the primary efficacy endpoint, change from baseline 
in total LSAS score during the double-blind treatment phase.  
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 
baseline total LSAS score as a continuous covariate and a country and presence of comorbid major 
depressive disorder (MDD) 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 12-week 
endpoint.
The change from baseline for the secondary continuous efficacy endpoints will be analyzed in the same 
way as for the LSAS total score.
Sensitivity analyses of the primary endpoint will be performed using ANCOVA model; these will be 
detailed further in the Statistical Analysis Plan. 
Descriptive statistics for values and changes from baseline (where applicable) will be provided by 
treatment group for all efficacy measures, including subscale scores for selected scales at each time point 
of the double-blind treatment phase. 
Frequency tables for remission and response of social anxiety symptoms (derived from LSAS), as well as 
frequency tables for response of depressive and anxiety symptoms (derived from the HDRS17 and 
SIGH-A) will be provided by treatment group at each time point of the double-blind treatment phase.
Safety Analysis
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 one dose of study drug. 
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.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis
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.


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Population PK/PD analysis of biomarkers and/or efficacy markers may also be performed, and a suitable 
dose- and/or exposure-response model may be developed. If necessary or relevant for the analysis, 
Phase 1 data may be integrated to inform the model structure or key parameter values.


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TIME AND EVENTS SCHEDULEa
Phase
Screening
Double-Blind Treatmenta
Posttreatmentb
(Follow up)
EWb
Visit  
1
2
3
4
5
6
7
8
9
10
Week (end of)
-4 to 0
0
1
2
4
6
8
10
12
13 to 16
Day
-28 to -1
1
7
14
28
42
56
70
84
91 to 112
Clinic Visit (C) 
C
C
C
C
C
C
C
C
C
C
Study Procedures
Screening/Administrative
Informed consent (including pharmacogenomics)
X
Inclusion/exclusion criteria
X
X
Medical history and demographics
X
Prestudy therapy c
X
Preplanned surgery/procedure(s)
X
MINI interview
X
Study Drug Administration
Randomization
X
Dispense JNJ-42165279 or placebo
X
X
X
Optional: diary/tool to document drug intake
continuous
Drug accountability
X
X
X
X
X
Safety Assessments
Physical examination
X
X
X
Neurological examination t
X
X
X
X
C-SSRS
Xp
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
Body weight f
X
X
X
X
X
Height
X
Clinical laboratory assessmentsg
X
X
X
X
X
X
X
X
Xh
Serology
X
12-lead ECG i
X
Xd
X
X
Xh
                                                
a This section has been amended per Amendments INT-1, 2 and 3.


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Phase
Screening
Double-Blind Treatmenta
Posttreatmentb
(Follow up)
EWb
Visit  
1
2
3
4
5
6
7
8
9
10
Week (end of)
-4 to 0
0
1
2
4
6
8
10
12
13 to 16
Day
-28 to -1
1
7
14
28
42
56
70
84
91 to 112
Clinic Visit (C) 
C
C
C
C
C
C
C
C
C
C
Urine drug screen 
Xj
X
X
X
Alcohol screen
X
X
X
X
X
X
Xh
Pregnancy test 
Xk
Xk
Xu
Xu
Xu
Xu
Xu
Xu
Xk
Xk
Clinician-administered assessments
Liebowitz Social Anxiety Scale (LSAS)
X
X
X
X
X
X
X
HDRS17 using SIGH-D – performed by clinical site q
X
X
X
X
X
X
X
SIGH-A (includes HAM-A6) l - performed by clinical site 
X
X
X
X
X
X
CGI-I
X
X
X
X
X
Patient-reported assessments
Sheehan Disability Scale 
X
X
X
X
GAD-7
X
X
X
X
SHAPS
X
X
X
X
MOS Sleep-R
X
X
X
X
Q-LES-Q
X
X
X
X
Self-assessment of treatment experience
X
Pharmacokinetics
Blood sample collection for JNJ-42165279 m
X
X
Pharmacogenomics (DNA) 
Blood sample collection for pharmacogenomics n
X
Biomarkers
Blood sample collection for FAAs o
X
X
X
Ongoing Subject Review
Behavioral guidance r
Continuous
Concomitant therapy s
Continuous
Adverse events
Continuous


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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 28 days after last dose intake or early withdrawal. 
c.
Prestudy therapy will include all medications taken within the 30 days before screening.
d.
Triplicate ECG at Day 1
e.
Supine blood pressure, pulse, and oral temperature. Following the supine vital sign assessment, orthostatic vital signs (blood pressure, pulse) will be taken after 
standing for at least 3 minutes.
f.
Body weight will be measured with subjects lightly clothed.
g.
Serum chemistry, hematology, coagulation and urinalysis. 
h.
Only in case of any clinical significant abnormalities observed at Week 12.
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 performed at Screening and Follow-up. At all 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.
l.
The HAM-A6 is a subscale derived from the SIGH-A (structured interview guide version of the HAM-A).
m.
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 and 
28) and 2 hours postdose (only at Day 14). 
n.
A 10 mL blood sample will be collected for the pharmacogenomics component of this study.  A sample collected at a later time point does not constitute a protocol 
violation and would not require protocol amendment.
o.
A venous blood sample will be collected for the FAAs (AEA, PEA and OEA) and exploratory biomarkers. The Visit 2 sample must be taken before the first dose of 
JNJ-42165279 /placebo. 
p.
Baseline version completed at Screening.
q.
HDRS17 anxiety/somatization factor score determined from the assessment.
r.
Behavioral guidance from the investigator: at the beginning of the trial subjects will be advised to enter socially feared situations to help determine whether the 
treatment has beneficial or adverse effects on symptoms and behaviors and then at subsequent visits the investigator will query the subject about social situations 
that s/he has encountered since the last visit, and how s/he felt in those situations.
s.
Concomitant therapies must be recorded throughout the study beginning with signature of the ICF to the final follow up visit (Visit 8).
t.
A neurological examination will also be completed in case of adverse event of interest.
u.
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.
CGI-I=Clinical Global Impression – Improvement; C-SSRS = Columbia Suicide Severity Rating Scale; EW = Early Withdrawal; GAD-7 = 
Generalized Anxiety Disorders ;HAM-A6 = Hamilton Anxiety Rating scale; HDRS17 = Hamilton Depression Rating Scale; LSAS = Liebowitz 
Social Anxiety Scale; MINI = Mini International Neuropsychiatric Interview; MOS Sleep-R = Medical Outcomes Study Sleep-Revised;          
Q-LES-Q = Quality of Life Enjoyment and Satisfaction Questionnaire; 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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ABBREVIATIONS
Note: Pharmacokinetic Parameters are defined in Section 9.5.3
and 
questionnaires are defined after the Time and Events Schedule.
AEA
ALP
anandamide 
alkakine phosphatase
ALT
alanine aminotransferase 
ANOVA
analysis of variance 
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


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NOAEL
OEA
no-observed-adverse-effect-level 
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
Standard deviation 
TEAE
Treatment emergent adverse event
ULN
Upper Limit of Normal
Vss
Volume of distribution at steady state 
WBC
White blood cell
WOCBP
Women of child bearing potential


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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 250 mg and a multiple dose regimen of 100 mg once-daily 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.
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.
Background
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. 
Efficacy has 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 


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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 1 µM in the human ether-a-go-go related gene (hERG) 
patch clamp assay (IC50 = 27 µM) and at 10 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 25 mg/kg (Cmax = 6,628 ng/mL; 83-fold margin over the projected efficacious dose in 
humans of 80 ng/mL) did not induce relevant changes in cardiovascular, electrocardiographic, or 
respiratory parameters. At the highest dose of 150 mg/kg (mean plasma exposure of 
8,418 ng/mL), a 40% increase in heart rate was observed in one dog, and a 23% prolongation of 
the QTcF interval 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, dose-related decreased body 
temperature and decreases in motor function were noted from 25 to 500 mg/kg, with changes in 
sensory-motor and affective responses at 500 mg/kg. 
Pharmacokinetics and Product Metabolism in Animals
JNJ-42165279 has moderate to high oral bioavailability in rats (37 to 113%), dogs (57 to 109%), 
and monkeys (119%). After intravenous administration, clearance was low in the dog and 
monkey (6 and 11 mL/min/kg, respectively) and high in the rat (60 mL/min/kg); the volume of 
distribution at steady state (Vss) was moderate (1.1 L/kg to 2.5 L/kg); and the half-life ranged 
from 1.1 to 3.2 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 1.3 to 1.9 in the rat and 0.6 to 1.8 in the dog.
JNJ-42165279 is primarily metabolized by cytochrome P450 (CYP)3A4 in liver microsomes 
with multiple metabolites observed in vitro and in vivo. All metabolites formed in human 
hepatocytes or human liver microsomes were also detected in vitro or in vivo in the toxicology 
species investigated, with the exception of the di-oxidation metabolite M9, which was detected 
in human hepatocytes only. 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 coagulation parameters (increased prothrombin 
time [PT] and activated partial thromboplastin time [aPTT]) and the reproductive organs 
(decreased sperm motility and abnormal sperm morphology) were observed. In female rats, 


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microscopic changes were observed in the kidney (mineralization and vacuolar degeneration) at 
25 mg/kg, while there were no findings at the low dose of 5 mg/kg. Based on these findings, the 
no observed adverse effect level (NOAEL) could not be established in male rats and was 5 
mg/kg in female rats. Relative to exposures at the anticipated clinically effective dose of 25 mg 
(Day 10 Cmax= 225 ng/mL and AUC = 2,204 ng.h/mL), Cmax and AUC exposures in the female 
rats provide 10-fold and 3.5-fold margins respectively. In dogs, doses of 5 and 15 mg/kg were 
well tolerated, while adverse effects at 10050 mg/kg were noted in the liver and gall bladder 
(vacuolation with cellular degeneration or necrosis that correlated with mild increases in 
aspartate transaminase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], and 
gamma-glutamyltransferase [GGT]), thymus (atrophy), bone (hypercellularity of the erythroid 
cell line in sternal bone marrow), and epididymis/testis (decreased sperm numbers and secondary 
spermatid degeneration/depletion). Based on these findings, the NOAEL in dogs was 15 mg/kg, 
providing Cmax and AUC margins of at least 26-fold and 35-fold over those at the anticipated 
human effective levels.
Reproductive and embryo-fetal safety was evaluated in rats and rabbits. Male rats treated with 
JNJ-42165279 for 4 weeks had significantly reduced sperm motility and increased number of 
abnormal sperm at doses of 100 and 200 mg/kg but not at 25 mg/kg; these changes were fully 
reversible following a 4-week recovery period. JNJ-42165279 at the high dose of 100 mg/kg, but 
not at ≤30 mg/kg, induced changes in female rat oestrus cycling (regularity and cycle length).
These changes as well as those on sperm motility are considered exaggerated effects of FAAH 
inhibition. The Cmax (3,280 ng/mL) and AUC (13,900 ng.h/mL) exposures in male rats at 25 
mg/kg (the NOAEL for fertility findings) provide margins of 14.6- and 6-fold over the 
anticipated human effective levels. In pregnant rats and rabbits, JNJ-42165279 induced minimal 
maternal toxicity (decreased food consumption and body weight gain). There were no fetal 
changes in rabbits. In rabbits, the NOAEL for fetal toxicity was the highest dose tested, offering 
Cmax and AUC margins of over 78-fold. Rat fetuses from pregnant rats treated with ≥30 mg/kg 
during the period of organogenesis (gestation Days 6-17) showed a dose-related increase in 
incidence of primary lens fiber degeneration which translated to an increased incidence of 
nuclear cataracts in young adult offspring from treated pregnant dams. Primary lens fiber 
degeneration and nuclear cataracts are common background findings in the Sprague Dawley rat 
strain used in these studies but their incidence was exacerbated by treatment with JNJ-42165279. 
A NOAEL was established at 10 mg/kg and associated exposures provide Cmax and AUC 
margins of 16- and 9-fold respectively. No lens changes were reported in adult rats and dogs 
treated with JNJ-42165279 daily for up to 3-months.  
JNJ-42165279 was not genotoxic in the in vitro bacterial/microsomal activation assay, the mouse 
lymphoma assay, or the in vivo chromosome aberration test in rats. 
Clinical Studies
This will be the seventh study involving the administration of JNJ-42165279 to humans.
A double-blind Phase 1 study (Study 42165279EDI1001) was completed with 29 healthy male 
subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic (PD) 


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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 multi-
exponential manner, with mean t1/2 values of 4.84 to 14.4 hours for doses of 2.5 to 250 mg.
The effect of concomitant food intake on the pharmacokinetics of JNJ-42165279 was 
investigated at the 30-mg dose level. The rate of absorption was delayed based on median tmax
values of 2.25 hours and 0.5 hours in the fed and fasted states, respectively. On average, the Cmax
values were 33% lower and AUC∞values were 16% higher when JNJ-42165279 was given with 
food, relative to administration in the fasted state. These apparent effects of food are not 
expected to be clinically significant.
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, 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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In the second multiple ascending dose (MAD) study 42165279EDI1002, four cohorts were 
studied: healthy males at 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. Concentrations of JNJ-42165279 in plasma, 
urine, and cerebrospinal fluid (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 AEA and OEA concentrations in 
CSF by approximately 41-times and 5.8-times (25 mg dose), respectively, and 77-times and 
7.4-times (75 mg dose), respectively, relative to predose. The concentrations of AA in CSF were 
unchanged. 
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 four 
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 transient 
elevations of liver transaminases relative to baseline (up to 2.5 times the upper limit of normal) 
that returned to normal after dosing stopped. No increases occurred in alkaline phosphatase 
(ALP) or bilirubin.  No such increases were observed in the 25 mg cohort. 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 


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findings in 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 200-mg itraconazole 
from Day 4 to Day 10 (inclusive). Subjects also received a dose of 30-mg JNJ-42165279 along 
with 200 mg itraconazole on Day 8.
Mean plasma JNJ-42165279 concentrations were greater over the entire PK sampling period 
after co-administration of JNJ-42165279 with itraconazole, compared with administration of 
JNJ-42165279 alone. Plasma JNJ-42165279 concentrations increased rapidly, with median tmax
values of 1.00 hour following administration of JNJ-42165279 with and without itraconazole.
Mean t1/2 was approximately 196% longer after JNJ-42165279 was co-administered with 
itraconazole, compared with JNJ-42165279 administered alone. The estimated geometric mean 
ratios (GMRs) of JNJ-42165279 Cmax, AUClast, and AUCfor the co-administered treatment 
relative to JNJ-42165279 administered alone were 136%, 373%, and 447%, respectively. These 
results indicate that CYP3A4 plays an important role in the metabolic elimination of 
JNJ-42165279 and that inhibition of this enzyme by potent inhibitors is expected to result in an 
increase in the concentrations of JNJ-42165279 in plasma.
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.
A fMRI study with a dose of 100 mg once-daily over 4 days in healthy young males 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
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, 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. Social anxiety disorder (SAD) 
is among the most common anxiety disorders and is associated with significant distress and 
dysfunction in affected individuals.  A number of treatments have been tested for SAD including 
SSRIs and other antidepressants, benzodiazepines, and pregabalin as well as cognitive and 


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behavioral treatments.  Each of these has strengths and limits, most notably poor tolerance to 
sexual adverse effects associated with SSRIs and other antidepressants, and sedation and risk for 
tolerance and abuse with benzodiazepines.  Moreover, many subjects with SAD do not respond 
or respond poorly to available treatments and remain symptomatic (Pollock et al 2014)4. There 
continues to be a need for effective, safe, and well tolerated treatments.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective of this study is to investigate the efficacy of JNJ-42165279 during 
12 weeks of treatment in subjects with SAD.
Secondary Objectives
The secondary objectives of this study are:

To assess the safety and tolerability of JNJ-42165279 in subjects with SAD. 

To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as once 
daily (qd) in subjects with SAD using a population PK approach, and explore the 
relationship between exposure to JNJ-42165279 and efficacy and safety parameters.
Exploratory Objectives
The exploratory objectives are:

To assess the efficacy of JNJ-42165279 on both anxiety and depression symptoms.

To evaluate the impact of treatment with JNJ-42165279 compared to placebo on patient-
reported assessments of symptoms of anxiety, depression, impairment in daily living and 
quality of life.

To evaluate pharmacodynamic (PD) effects by the assessment of biomarkers of peripheral 
pharmacological activity after repeated doses of JNJ-42165279, including assessment of 
plasma concentrations of FAAs (anandamide AEA, palmitoylethanolamide [PEA], and 
oleoylethanolamide [OEA]) that are expected to rise as a consequence of the inhibition of 
their hydrolysis by FAAH.

To explore the relationship between plasma PK and plasma concentrations of FAAs 
(anandamide AEA, palmitoylethanolamide [PEA] and oleoylethanolamide [OEA]) in 
subjects with SAD.

To explore any potential differences between healthy subjects and subjects with social 
anxiety disorder (SAD) using a population PK approach.
2.2.
Hypothesis
JNJ-42165279 will be efficacious in reducing the symptom burden associated with SAD assessed 
on the Liebowitz Social Anxiety Scale (LSAS).


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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Designa
This is a multi-center, double-blind, placebo-controlled, randomized, parallel-group study 
assessing the efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of treatment in 
subjects with SAD. 
Approximately one-hundred thirty-seven (137) subjects will be enrolled in this 12 week 
treatment study randomly assigned in a 1:1 ratio to either 25 mg of JNJ-42165279 or placebo 
(dosed once daily orally).
For all enrolled subjects, this study will consist of a 28-day eligibility screening period, a 
12 week double-blind treatment period and a follow-up examination between 7 and 28 days after 
last dose. The study duration for each subject will be maximally 20 weeks.
The study will be an outpatient study.
Screening
After giving written informed consent, subjects may be screened over a period of up to 28 days 
to assess their eligibility for the study according to the inclusion and exclusion criteria defined 
for this study. 
Double Blind Treatment Phase
Subjects who successfully complete the screening will visit the clinical site/unit on Day 1. 
During the Treatment Phase, primarily safety and tolerability will be monitored at regular 
intervals (e.g.  physical examination, suicidality risk assessment, vital signs, 12-lead ECG, safety 
labs, etc). Pharmacokinetics (plasma), and pharmacodynamic effects will be explored at the time 
points listed in the Time and Events Schedule.
A pharmacogenomic blood sample will be collected from all eligible subjects on Day 1. 
Participation in the pharmacogenomic research component is required to assess whether the 
subject is carrier of the A-allele variant for FAAH and to identify genetic 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.
                                                
a This section has been amended per Amendment INT-3.


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Follow Up
Minimally 7 and maximally 28 days following last dosing (Week 12), 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
Randomization, Blinding, Control, Study Phase/Periods, Treatment Groups
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. Blinded treatment will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints as well as adverse 
events. 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.
Population 
The target population for this study is male and female subjects with SAD who are between 
18 and 64 years of age inclusive, with symptom severity as measured by the Liebowitz Social 
Anxiety Scale score ≥ 70 for whom pharmacotherapy is indicated.   Subjects with SAD
frequently have additional comorbid anxiety disorders notably Generalize Anxiety Disorder 
(GAD), major depressive disorders (MDD), and substance use disorders.  To determine whether 
comorbid conditions influence the response to JNJ-42165279, and whether JNJ-42165279 has 
effects across anxiety and depression as a behavioral dimension, subjects with comorbid MDD 
and generalized anxiety disorder (GAD) will be allowed to participate provided that SAD is 
judged by the investigator to be the primary indication for treatment.  Subjects experiencing a 
current episode of MDD severe enough to warrant treatment of depression as the primary focus 
will be excluded. 
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, each study visit and at follow-up. 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.
                                                
a This section has been amended per Amendment INT-3.


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Trial Duration
12 weeks has been the duration of numerous randomized placebo controlled trials of the 
effectiveness of a monotherapy for SAD (Stein DJ et al 2009: Cochrane review article) and is 
supported by the observation from trials of paroxetine, that non-responders at 8 weeks of 
treatment could still demonstrate response after 12 weeks of treatment (Stein DJ, Stein MB, Pitts 
CD, Kumar R, Hunter B. Predictors of response to pharmacotherapy in social anxiety disorder: 
An analysis of 3 placebo-controlled paroxetine trials. Journal of Clinical Psychiatry 
2002:63(2):152–5)6.   Due to the chronic and recurrent nature of mood and anxiety disorders, 
treatment studies of longer duration will be required if this compound demonstrates acceptable 
safety and efficacy for at least 12 weeks.  
Rationale for Dose Selection
Modeling based on nonclinical pain models (with adjustment for differences in affinity of 
JNJ-42165279 for human FAAH) yielded an estimate of the exposure needed to provide 90% 
maximal effect of 80 ng/mL (see the Investigator’s Brochure), and is hypothesized to be a 
function of complete (>90%) inhibition of FAAH. Modeling of steady state concentrations based 
on the single ascending dose and multiple ascending dose studies predict that exposures above 
80 ng/ml will be reached by the majority of the subjects at steady state while taking 25 mg and 
sustained for at least 6 hours after dosing. The covalent binding of JNJ-42165279 to FAAH and 
slow hydrolysis from the enzyme catalytic site should result in inhibition to be sustained 
throughout the dosing interval resulting in a longer pharmacodynamic half-life.  Sustained 
occupancy of FAAH in the brain
was confirmed in the 
11C-MK3168
PET study 
42165279EDI1003. Occupancy following 10 mg was identical at Cmax and trough at steady 
state.  In the periphery, suppression of FAAH activity in WBC was also sustained throughout the 
dosing interval during chronic dosing at 25 mg in study 42165279EDI1002. In the same study, 
increases in FAA concentrations in cerebrospinal fluid (CSF) were observed after 7 days of 
dosing with 25 mg. The dose of 75 mg was observed to generate greater increases (77-times for 
AEA and 7.4-times for OEA) in median CSF FAA concentrations although the range of effect 
substantially overlapped with that occurring after 7 days dosing with 25 mg (41-times for AEA 
and 5.8 times for OEA). Substantial 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 (80 to 95% occupancy). The occupancy curve was asymptotic (>95%) with higher doses 
(25 and 50 mg) of JNJ-42165279. In study 42165279EDI1002, doses of 100 mg were associated 
with mild, reversible increases in liver transaminases in a few subjects while no such effects 
were observed in subjects taking 25 and 75 mg.  Based on these results, 25 mg JNJ-42165279 is 
predicted to consistently result in > 95% inhibition of FAAH activity without significant 
variability throughout the day and can provide robust pharmacodynamic effects. While slightly 
larger effects on CSF FAA turnover were seen with 75 mg, the dose of 25 mg offers a better 
safety margin given that exposures of JNJ-42165279 can increase (up to 4 fold in AUC) in the 
presence of strong CYP3A4 inhibitors. 


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Rationale for Clinical Endpoints
Primary
Liebowitz Social Anxiety Scale (LSAS)
The Liebowitz Social Anxiety Scale (LSAS) was developed in 1987 by Michael Liebowitz 
(Liebowitz MR. Social Phobia. Mod Probl Pharmacopsychiatry 1987;22:141-173)3. It is a short 
questionnaire with 24 items, 13 relating to performance anxiety and 11 concerning social 
situations. The LSAS is designed to record subjective anxiety across a range of social interaction 
and performance situations that may be feared by a subject. The responses to these situations and 
associated avoidance behavior reported by the subject can be used to assist in the diagnosis of 
social anxiety disorder, assess severity, and monitor change. It has been commonly used to study 
treatment outcomes in clinical trials and, more recently, to evaluate the effectiveness of 
cognitive-behavioral treatments. An example of the LSAS is provided in Attachment 6.
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, including subjects with comorbid GAD and MDD, and determine both their influence on 
treatment and their responsiveness to treatment.  
This original HAM-A scale assesses the severity of different anxiety-related symptoms 
(Hamilton 195913; Hamilton 196916). 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)20.  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)20. 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. 
Hamilton Depression Rating Scale (HDRS17)
Depression scales are included here as a means to determine the frequency and severity of signs 
and symptoms of depression that maybe co-morbid with SAD and determine both their influence 
on treatment and their responsiveness to treatment.  
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in subjects diagnosed with depression (Hamilton M 1960)14 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 


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the change in these ratings during treatment (r = 0.68) (Knesevich J 1977)18. Subscales, such as 
the HAM-D6 which focuses on psychic anxiety and may be more sensitive to certain treatments, 
can be derived from the HDRS17. 
The original HDRS17 scale lacks instructions for administration and clear anchor points for the 
assignment of severity ratings. For this reason, the structured interview guide version of the 
HDRS17 (the Structured Interview Guide for the Hamilton Depression Scale [SIGH-D]) will be 
used in the current study to facilitate and standardize gathering clinical information from the 
subject.
An example of the HDRS17 is provided in Attachment 1.
Clinical Global Impression Improvement (CGI-I)
The clinical global impression – improvement (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
Patient reported outcomes are included as a means of determining the frequency and severity of
signs and symptoms of anxiety, depression, impairment in everyday life, and quality of life that 
can occur with or as a consequence of SAD and determine both their influence on treatment and 
their responsiveness to treatment. The anxiety, depression, sleep, and disability scales parallel 
the clinician administered scales and will therefore allow comparison of effects from the 
investigator and subject perspective. 
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale (SDS) (Sheehan 1983)22 is a composite of three self-rated items 
designed to measure the extent to which three major sectors in the patient’s life are impaired by 
panic, anxiety, phobic, or depressive symptoms. This scale has been used widely in 
psychopharmacology randomized controlled trials and has been demonstrated to be sensitive to 
change, including a study of augmentation of treatment for refractory SAD (Pollack et al)4. This 
anchored visual analog scale uses visual-spatial, numeric, and verbal descriptive anchors 
simultaneously to assess disability across three domains: work, social life, and family life.
An example of the SDS is provided in Attachment 3.
Generalized Anxiety Disorders (GAD-7)


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Generalized Anxiety Disorder 7 (GAD-7) is a self-reported questionnaire for screening and 
severity measuring of generalized anxiety disorder (GAD) and is of particular interest because of 
the frequent comorbidity of GAD with SAD. GAD-7 has seven items, which measure severity of 
various signs of generalized anxiety disorder according to reported response categories of “not at 
all,” “several days,” “more than half the days,” and “nearly every day.” Assessment is indicated 
by the total score, which made up by adding together the scores for the scale all seven items. 
An example of the GAD-7 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) 23. 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.
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.
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) rates 16 aspects of 
quality of life, including physical health, mood, activities of daily living and overall life 
satisfaction.
An example of the Q-LES-Q is provided in Attachment 8.


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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.
An example of the Self-Assessment of Treatment Experience is provided in Attachment 9.
Rationale for Biomarker Collection
Biomarkers for PD activity (FAAH inhibition, as measured in plasma concentrations of FAAs) 
have been selected based on data from previous studies
(42165279EDI1001
and 
42165279EDI1002) in which those biomarkers showed dose-related changes.
Rationale for DNA Collection
It is recognized that genetic variation can be an important contributory factor to inter-individual
differences in drug distribution and metabolism and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain inter-individual
variability in the distribution and metabolism of a drug and may help to identify population
subgroups that have different pharmacokinetic (PK) profiles of the drug.
A polymorphism in the FAAH gene (C385A) has been previously associated with reduced
activity of the FAAH enzyme and levels of FAAH protein, potentially leading to increased AEA
signaling in humans (Conzelman et al, 2012)8. Approximately one quarter of the population 
carries the associated A allele. Genotyping of this gene may help to explain variability in PD 
endpoints measured in this study. Additional pharmacogenomic analyses may be undertaken for 
the identification of other genetic factors that may influence PK, PD, safety, and/or tolerability of 
JNJ-42165279.
DNA 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 This section has been amended per Amendment INT-1.


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
A subject will be discontinued from the study when the QTc interval 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 Upper Limit of 
Normal (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). 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 POPULATIONa
Approximately 137 subjects with SAD will be enrolled in the proof-of-concept study to ensure 
53 subjects per treatment group completing the trial, assuming a dropout rate of approximately 
15%. 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 and subjects with co-morbid GAD and MDD will be allowed provided that SAD
is judged by the investigator to be the primary indication for treatment. Other anxiety disorders 
and MDD are common comorbid conditions in subjects with SAD Diagnostic and Statistical 
Manual of Mental Disorders (5th edition) (DSM-5).  In a recent treatment study of refractory 
SAD, roughly a third of subjects had current/lifetime GAD, roughly a third had a lifetime history 
of MDD, and 10-15% (depending on the site) had a current episode of MDD (Pollock et al 
2014)4.  Subjects who have a current episode of MDD of sufficient severity that it should be the 
primary focus of treatment should be excluded.  Any subject that is identified as having a current 
episode of MDD should be informed by the investigator and the potential risks and benefits of 
participating in the trial should be discussed with the subject before enrollment. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 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. 
                                                
a This section has been amended per Amendment INT-3.


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For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
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 SAD except those with performance 
only as a specifier. Subjects with a diagnosis of comorbid Generalized Anxiety Disorder 
(GAD) or Major Depressive Disorder (MDD) may be included if the investigator 
considers SAD to be the predominant diagnosis. Subjects with current or lifetime 
history of ADHD and specific phobia may be included as well.
3.
Subjects must have a Liebowitz Social Anxiety Scale score ≥ 70 at screening and 
baseline.
4.
Subjects with a current episode of MDD must have a HDRS17 total score ≤ 18
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 3.
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:
                                                
a This section has been amended per Amendments INT-1 and 3.


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
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 3.
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 and not a potential 
cause of cognitive impairment, 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 judges the 


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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. 
Subjects who have performance only SAD are excluded. Subjects with other current 
significant psychiatric condition(s) (Axis 1 under DSM-IV), including, but not limited 
to, MDD with psychotic features (lifetime), bipolar disorder (including lifetime 
diagnosis), obsessive-compulsive disorder, borderline personality disorder, eating 
disorder (e.g., bulimia, anorexia nervosa), autism spectrum disorders, post-traumatic 
stress disorder (PTSD) or schizophrenia are excluded. Subjects with a diagnosis of 
comorbid GAD or MDD may be included.  
2.
Subject is currently receiving specific psychotherapy for SAD.
3.
Has a history of more than two unsuccessful adequate pharmacological treatment trials 
for SAD, defined as lack of response to at least 10 weeks of treatment at adequate doses
(e.g., paroxetine ≥40 mg/day or its equivalent; or clonazepam ≥2.5 mg/day or its 
equivalent).
4.
Concurrent use of psychotropic medications.  Benzodiazepine must be discontinued at 
least 7 days before screening and antidepressant therapy must be discontinued at least 
2 weeks before screening (5 weeks for fluoxetine). Subjects who have had an adequate 
response to pharmacotherapy should not have this treatment discontinued solely for 
participation in the study.  Subjects who have elected, in consultation with their health 
care provider, to discontinue pharmacotherapy because of difficulty tolerating the 
                                                
a This section has been amended per Amendments INT-2 and 3.


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medication may be eligible provided those treatments are stopped according to the 
guidelines above. 
5.
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.
6.
Criterion modified by Amendment 2.
6.1.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).
7.
Subject has a clinically significant abnormal finding on 12-lead ECG such as QTc 
>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. 
8. 
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 baseline should be reviewed with the sponsor.  If the subject has any 
liver function tests >2 times the upper limit of normal, he/she should not be enrolled. 
9.
Subject has a history of malignancy within 5 years before screening (exceptions are 
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or 
malignancy that in the opinion of the investigator, with written concurrence with the 
sponsor's medical monitor, is considered cured with minimal risk of recurrence).
10.
If a subject is using a drug with moderate/strong CYP3A4 inhibiting properties at, or 
prior to, Screening it must be discontinued at least within 1 month prior to Day 1. Note: 
an existing medication should not be stopped solely for the purpose of the subject 
entering the study. Moderate and strong inducers of CYP3A4 are prohibited during the 
study (See Attachment 13).
11.
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.


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12.
Subject tests positive for human immunodeficiency virus (HIV) or antibodies at 
Screening and is not being treated.  Subjects with known HIV infection who are being 
treated, have shown a good response, are otherwise clinically stable, and can continue to 
comply with treatment may be enrolled. Subjects requiring treatment with medications 
that are moderate or strong CYP3A inhibitors (such as most protease inhibitors:  see 
Attachment 13) must be excluded.
13.
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) at screening. A positive screen for 
benzodiazepines is allowed if related to recent treatment.
14.
Subject has taken any disallowed therapies as noted in Section 8, Concomitant Therapy 
before the planned first dose of study drug.
15.
Subject has known allergies, hypersensitivity, or intolerance to JNJ-42165279 or its 
excipients (refer to Investigator's Brochure).
16.
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.
17.
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.
18.
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.
19.
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.
20.
Subject has a history of spontaneous, prolonged or severe bleeding.
21.
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.
22.
Subject 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 


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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.
23.
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.
24.
Subject is unable to comply with the study-specific requirements.
4.3.
Prohibitions and Restrictionsa
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.
If a man that is sexually active with a woman of childbearing potential, he must 
agree to use a double barrier method of birth control and to not donate sperm during 
the study and for 3 months after receiving the last dose of study drug.
2.
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.
3.
Subjects are prohibited from taking/consuming grapefruit, grapefruit juice, Seville 
oranges or poppy seeds from Screening through the end of the post-treatment phase.
4.
For a list of prohibited medications, please see Section 8 (Prestudy and Concomitant 
Therapy).
5.
The use of limited amounts of alcohol (up to 2 drinks daily) will be allowed.
6.
Subjects are not allowed to participate in cognitive behavioral therapy for SAD
during their participation in the trial.
                                                
a This section has been amended per Amendment INT-1.


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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization 
Central randomization will be implemented in this study. At the start of the double-blind phase, 
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. Presence of comorbid MDD and country will be used as stratification factors. 
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 analysis 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 analysis.


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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 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 (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. 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 as per Amendment INT-3.


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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. 
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 in cognitive behavioral therapy for SAD while 
participating in this study.  Investigators will inform subjects at their baseline visit and remind 
them at each subsequent visit of the need to enter socially feared situations in order to be able to 
determine how effective the medication is. At each visit (after the first visit), investigators will 
ask the subject about social situations that s/he has encountered since the last visit, and how s/he 
felt in those situations. 
Prohibited Medications
Refer to Section 4.2 (Exclusion Criteria) for prohibited medications evaluated at Screening.
Subjects must agree not to use any of the following medications with psychotropic properties 
during study participation, including but not limited to:

Psychiatric medications, including mood stabilizers, antipsychotics, antidepressants (e.g., 
MAOIs, SSRIs, SNRIs, or TCAs), or medications to treat anxiety (including 
benzodiazepines: see below)
                                                
a This section has been amended per Amendment INT-3.


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
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.

Other Prohibited Medications include:

Sedating antihistamines

S-adenosyl methionine (SAMe), St. John’s wort, ephedra or kava kava

Melatonin and ramelteon

Opiates, including morphine, codeine hydrocodone, oxycodone, and methadone

Anticonvulsants

Moderate and strong CYP3A4 inhibitors or inducers (Attachment 13)
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overviewa
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.
Information regarding collection, handling, shipment, and labeling of biological samples 
(including safety labs) will be provided in a separate lab manual. 
Any changes to the lab manual will not result in a protocol amendment.
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 
                                                
a This section has been amended per Amendment INT-1.


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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 maximal total blood volume 
collected per subject defined will not be exceeded. Such 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. Actual dates and times of 
assessments will be recorded in the source documentation and CRF or lab requisition form. 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 exact times for each blood draw will be recorded in the CRF or lab requisition form. 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.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
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 200 mL.
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:
                                                
a This section has been amended per Amendments INT-2 and 3.


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
Physical examination

Neurological examination

Body weight

12-lead ECG recording

Body temperature

Height

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

C-SSRS (baseline)

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
serology, hematology, serum chemistry, coagulation and urinalysis)

Urine drug screen

Alcohol screen (in blood)

All women: Serum and urine pregnancy test

Review of inclusion and exclusion criteria

Complete/Review Medical History and Demographics

Complete/Review Prestudy Therapy

Review preplanned surgery/procedures

Mini International Neuropsychiatric Interview (MINI)

LSAS

HDRS17 using the SIGH-D

Behavioral guidance from the investigator

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 recording (triplicate)
                                                
a This section has been amended per Amendments INT-1, 2 and 3.


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
Body temperature

Supine and standing 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)

Blood sample collection for pharmacogenomics

Blood sample collection for FAAs 

Urine drug screen

Alcohol screen (in blood)

All women: Urine pregnancy test

Review of inclusion and exclusion criteria

Randomization

Dispense JNJ-42165279/placebo

LSAS

HDRS17 using the SIGH-D

SIGH-A

SDS

GAD-7

SHAPS

MOS Sleep-R

Q-LES-Q

Behavioral guidance from the investigator

Record adverse events and concomitant medication
Study medication will be dispensed (incl. drug accountability) 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, which 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.   


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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 

Body temperature

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

WOCBP: urine pregnancy test.

Drug accountability/Treatment compliance will be assessed.

LSAS

HDRS17 using the SIGH-D

SIGH-A

CGI-I

Behavioral guidance from the investigator

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.

C-SSRS 

Body temperature

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)

WOCBP: urine pregnancy test.

Alcohol screen (in blood)

Blood sample collection for PK of JNJ-42165279

Drug accountability/Treatment compliance will be assessed.


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
LSAS

HDRS17 using the SIGH-D

SIGH-A

CGI-I

Behavioral guidance from the investigator

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.

Neurological examination

Body weight

12-lead ECG recording

Body temperature

Supine and standing 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 sample collection for PK of JNJ-42165279

Blood sample collection for FAAs 

Urine drug screen

Alcohol screen (in blood)

Dispense JNJ-42165279/placebo

Drug accountability/Treatment compliance will be assessed.

LSAS

HDRS17 using the SIGH-D

SIGH-A

CGI-I


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
SDS

GAD-7

SHAPS

MOS Sleep-R

Q-LES-Q

Behavioral guidance from the investigator

Record adverse events and concomitant medication
Week 6 (Day 42)
Subjects will visit the site at Day 42 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 42 as specified in the Time and Events 
schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)

C-SSRS

WOCBP: urine pregnancy test.

Record adverse events and concomitant medication
Week 8 (Day 56)
Subjects will visit the site at Day 56 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 56 as specified in the Time and Events 
schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Dispense JNJ-42165279/placebo

Neurological examination

C-SSRS 

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)

WOCBP: urine pregnancy test.

Alcohol screen (in blood)

Body temperature

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)


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
Drug accountability/Treatment compliance will be assessed.

LSAS

HDRS17 using the SIGH-D

SIGH-A

CGI-I

SDS

GAD-7

SHAPS

MOS Sleep-R

Q-LES-Q

Behavioral guidance from the investigator

Record adverse events and concomitant medication
Week 10 (Day 70)
Subjects will visit the site at Day 70 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 70 as specified in the Time and Events 
schedule. Assessments can be performed pre or post dose unless otherwise indicated.

Clinical safety laboratory assessments under fasted conditions, when feasible (including 
hematology, serum chemistry, coagulation and urinalysis)

C-SSRS

WOCBP: urine pregnancy test.

Record adverse events and concomitant medication
Week 12 (Day 84)
Subjects will visit the site at Day 84 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 84 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 pregnancy test

Urine drug screen

Alcohol screen (in blood)

Body temperature

Body weight

12-lead ECG recording

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

Blood sample collection for FAAs 

Drug accountability/Treatment compliance will be assessed.

LSAS

HDRS17 using the SIGH-D

SIGH-A

CGI-I

SDS

GAD-7

SHAPS

MOS Sleep-R

Q-LES-Q

Self-assessment of treatment experience

Behavioral guidance from the investigator

Record adverse events and concomitant medication
9.1.4.
Posttreatment Phase (Follow Up)a
Minimally 7 and maximally 28 days following last dosing (Week 12), 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:
                                                
a This section has been amended per Amendments INT-3.


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
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 12

All women: Blood and urine pregnancy test

Alcohol screen (in blood)

Body temperature

Body weight

12-lead ECG recording (only in case of any clinical significant abnormalities at Week 12)

Supine and standing vital signs (systolic and diastolic blood pressure and pulse)

Behavioral guidance from the investigator

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 guidances, 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 


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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 10 and Attachment 11 for examples of the C-SSRS (baseline) and C-SSRS 
(since last visit), respectively.
9.2.3.
Vital Signs
Vital signs (body temperature, pulse/heart rate, 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.
                                                
a This section has been amended per Amendment INT-2.


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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 Tests a
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:

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
-activated partial thromboplastin time (aPPT)
- mean corpuscular hemoglobin 
concentration
- International normalized ratio (INR)

Serum Chemistry Panel 
                                                
a This section has been amended per Amendment INT-3.
-sodium
-alkaline phosphatase
-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


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
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.

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 (blood) test
Pregnancy tests:

In all women: serum β-HCG and urine pregnancy test will be performed at Screening and 
Follow-up and urine pregnancy test at study visits 2 and 9. 

In 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.
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).


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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
Liebowitz Social Anxiety Scale (LSAS)
The LSAS was designed to assess the range of social interaction and performance situations that 
individuals with social phobia may fear and/or avoid (Liebowitz, 1987)3. The 24 items in the 
scale are divided into two subscales that address social interactional (11 items) and performance 
(13 items) situations. The clinician asks the patient to rate fear and avoidance during the past 
week on 0–3 Likert-type scales; however, the clinician is given latitude to question the patient’s 
responses and adjust the ratings accordingly. Thus, the LSAS provides six subscale scores: total 
fear, fear of social interaction, fear of performance, total avoidance, avoidance of social 
interaction and avoidance of performance. An overall total score is often calculated by summing 
the total fear and total avoidance scores, and this index is the one most commonly employed in 
studies of the pharmacotherapy of social phobia (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, 199–212)17.
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 195913; Hamilton 196915). 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, intellectual 
disturbances, and anxious behavior observed at the interview, as well as one somatic item, 
muscular tension (Bech 2007)10, 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. 


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
Hamilton Depression Rating Scale (HDRS17)
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)9. 
In addition the anxiety-somatization factor total score from the HDRS17 will be included 
(Cleary 1977)11. A cut-off of ≥ 7 on this factor has been used to define subjects with anxious 
depression in prior clinical trials (Fava 2008)12.

Clinical Global Impression Improvement (CGI-I)
Patient Reported Outcome Assessments

Sheehan Disability Scale (SDS)

Generalized Anxiety Disorders (GAD-7)

Snaith-Hamilton Pleasure Scale (SHAPS)

MOS Sleep-R

Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)

Self-Assessment of Treatment Experience
9.3.2.
Endpoints
Primary
The primary efficacy endpoint for this study will be the improvement in social anxiety 
symptoms, as measured by the change from baseline in the LSAS total score from baseline to the 
12-week endpoint in the double-blind treatment phase.
The primary comparison will be between the JNJ-42165279 and the placebo treatment groups.
Secondary
Secondary efficacy endpoints will include:

The change from baseline to the 12-week endpoint for LSAS Fear/Anxiety and Avoidance 
subscales.

The distribution (number and percentage) of subjects who are responders (≥50% 
improvement from baseline) and remitters (≥30% improvement from baseline) on the LSAS 
total score at the 12-week endpoint.

The change from baseline to the 12-week endpoint for: SIGH-A total score, HAM-A6 score, 
HDRS17 total score, HDRS17 anxiety/somatization factor total score, HAM-D6 score and the 
(CGI-I) value.

The distribution (number and percentage) of subjects who are responders (≥50% 
improvement from baseline) on SIGH-A total score assessed at the 12-week endpoint.


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Exploratory

The change from baseline to the 12-week endpoint for: SDS (Sheehan Disability Scale) 
GAD-7, Snaith-Hamilton Pleasure Scale (SHAPS) and MOS Sleep-R.

The change from baseline to the 12-week endpoint for Quality of Life Enjoyment and 
Satisfaction Questionnaire (Q-LES-Q)

Self-Assessment of Treatment Experience scale

The change from baseline to the 12-week endpoint for: HDRS17 total score, HDRS17 
anxiety/somatization factor total score and HAM-D6 score in subjects with comorbid MDD.

The change from baseline to the 12-week endpoint for: SIGH-A total score and HAM-A6
score in subjects with comorbid GAD.

The distribution (number and percentage) of subjects with comorbid MDD who are 
responders on depressive symptoms (based on two definitions: either ≥50% or ≥30% 
improvement on HDRS17 total score from baseline) at the 12-week endpoint. 

The distribution (number and percentage) of subjects with comorbid GAD who are 
responders on anxious symptoms (≥50% improvement on SIGH-A total score from baseline) 
at the 12-week endpoint.
9.4.
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). Venous 
blood samples may be stored and used for future analysis of JNJ-42165279 metabolites and 
exploratory proteomics and metabolomics or other markers related to neuropsychiatric disorders.
9.5.
Pharmacokinetics
9.5.1.
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.
9.5.2.
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. 
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 differences 


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between healthy subjects and subjects with SAD. 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.
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.
9.5.3.
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.
9.6.
Pharmacogenomic Evaluations
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic factors that may influence PK, PD, safety, and/or tolerability of 
JNJ-42165279 and to enable the development of safer, more effective and ultimately 
individualized therapies in the future. DNA samples will be analyzed for the FAAH gene.7
Additional analyses may be conducted if it is hypothesized that this may help resolve issues with 
the clinical data.


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DNA samples will be used for research related to JNJ-42165279. They may also be used to
develop tests/assays related to JNJ-42165279. Pharmacogenomic research may consist of the
analysis of one or more candidate genes or of the analysis of genetic markers throughout the
genome (as appropriate) in relation to JNJ-42165279 clinical endpoints. Analyses may be
performed across multiple clinical studies.
9.7.
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.
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. 
Venous blood samples may be stored and used for future analysis of JNJ-42165279 metabolites 
and exploratory proteomics and metabolomics or other markers related to neuropsychiatric 
disorders.  
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 12 (Day 84) 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


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
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 12 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.
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 12 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.
Subject Information
For all subjects who receive at least one dose of study drug descriptive statistics will be 
provided.


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11.2.
Sample Size Determinationa
The sample size for the study is based on the assumption of a treatment difference of at least 
10 points in the mean change from baseline to the endpoint in LSAS total score between 
JNJ-42165279 treatment group and placebo. A standard deviation of 24 in the change in LSAS 
total score from baseline is used based on published data. 4,5,6  To detect the treatment difference
of 10 points (which is judged to be clinically relevant 4,5,6)  with a power of 90% at an overall 
1-sided significance level of 0.20, 53 subjects in each group are required. When adjusted for a 
drop-out rate of approximately 15% of subjects, the required number of subjects is 61 per 
treatment group. To replace 15 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 122 to137.
The impact of this sample size (N=137) on the JNJ– 42165279 effect size to be detected for the 
other continuous secondary and exploratory endpoints for different values of significance level 
and power, assuming a drop-out rate of 15%, are presented in Table 1.
Table 1: JNJ–42165279 effect size to be detected for different values of significance level 
and power, assuming a drop-out rate of 15%
11.3.
Efficacy Analysis
All efficacy analyses will be based on the intention-to-treat (ITT) analysis set. The 
JNJ-42165279 treatment group will be compared with placebo using the primary efficacy 
endpoint- change from baseline in total LSAS score during the double-blind treatment phase.  
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 baseline total LSAS score as a continuous covariate and a country and presence of 
comorbid MDD 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 12-week 
endpoint.
The change from baseline for the secondary continuous efficacy endpoints will be analyzed in 
the same way as for the LSAS total score.
Sensitivity analyses of the primary endpoint will be performed using ANCOVA model; these 
will be detailed further in the Statistical Analysis Plan. 
                                                
a This section has been amended per Amendment INT-3.
1-sided significance level
Power
Effect size to be detected
0.10
80%
0.4
0.10
90%
0.5
0.20
80%
0.3
0.20
90%
0.4


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Descriptive statistics for values and changes from baseline (where applicable) will be provided 
by treatment group for all efficacy measures, including subscale scores for selected scales, at 
each time point of the double-blind treatment phase.
Frequency tables for remission and response of social anxiety symptoms (derived from LSAS), 
as well as frequency tables for response of depressive and anxiety symptoms (derived from the 
HDRS17 and SIGH-A) will be provided by treatment group at each time point of the double-blind 
treatment phase.
11.4.
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.
                                                
a This section has been amended per Amendment INT-2.


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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. 
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, blood pressure (systolic and diastolic) (supine and standing), 
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.
11.5.
Interim Analysis 
An interim analysis for purpose of sample size re-estimation may be performed after 50% of the 
subjects are recruited if observed SD substantially deviates from the hypothesized or if the drop-
out rate substantially deviates from the assumed. If one is required, details will be included in the 
statistical analysis plan.
11.6.
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.


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11.7.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analysis
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.
Population PK/PD analysis of biomarkers and/or efficacy markers may also be performed, and a 
suitable dose- and/or exposure-response model may be developed. If necessary or relevant for 
the analysis, Phase 1 data may be integrated to inform the model structure or key parameter 
values.
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. 
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 


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related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects 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.


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12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
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).


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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

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 12.
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.
                                                
a This section has been amended per Amendment INT-2.


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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

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 
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
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.
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 (eg, 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 


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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 25-mg tablets. 
The JNJ-42165279 placebo will be supplied as film-coated tablets, matching visually to the 
active tablets. JNJ-42165279/placebo will be manufactured and provided under the responsibility 
of the sponsor. 
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 31 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 must be stored at controlled room 
temperatures ranging from 15°C to 30°C, as indicated on the product specific labeling.


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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 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


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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerationsa
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 study treatment duration in this study of subjects with SAD is supported by the available 
toxicology and clinical data (see Investigator’s Brochure)1. A safety signal of reversible mild 
elevation of liver transaminases was identified in the Phase 1 multiple dose study, occurring in 
subjects exposed to more than 4 days dosing with 100 mg.  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, clinical safety labs will be collected every 
2 weeks and available for ongoing monitoring by the investigator and sponsor, ‘stopping rules’ 
have been developed for stopping treatment in the event that subjects have greater than 3 fold 
increase in transaminases 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 
exceeds 10% of subjects or increases 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. 
All medication treatment will occur within the context of carefully supervised and supportive 
care. Only investigators experienced in the treatment of SAD 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. MDD, both lifetime and current episode 
are known comorbidities in subjects with SAD. Subjects experiencing a current episode of MDD 
severe enough to warrant treatment of depression as the primary focus will be excluded and 
advised as to resources available for treatment.
Only experienced and qualified physicians are allowed to perform the applicable procedures.
The total blood volume to be collected will not exceed 200 mL, which is considered to be safe 
and acceptable in comparison to a Red Cross blood donation.
                                                
a This section has been amended per Amendment INT-1.


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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
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


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
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 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 


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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.
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 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 


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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 SAD, to understand differential drug responders, and to develop tests/assays related 
to JNJ-42165279 and SAD.  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 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.


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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:

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


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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. 
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 


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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.
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 
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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 conduct.
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.


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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 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 


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information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain 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.
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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Janssen Research & Development, L.L.C. Investigator's Brochure JNJ-42165279, Edition 3, February 2015.
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Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-370.
3.
Liebowitz MR. Social Phobia. Mod Probl Pharmacopsychiatry 1987;22:141-173.
4.
Pollack MH, Van Ameringen M, Simon NM, at al. A double-blind randomized controlled trial of augmentation 
and switch strategies for refractory social anxiety disorder. Am J Psychiatry. 2014;171(1):44-53.
5.
Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM.  Efficacy of low and higher dose extended-
release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. 
Psychopharmacology. 2005;177(3):280–288.
6.
Stein DJ, Stein MB, Pitts CD, Kumar R, Hunter B. Predictors of response to pharmacotherapy in social anxiety 
disorder: An analysis of 3 placebo-controlled paroxetine trials. Journal of Clinical Psychiatry 2002:63(2):152–
5
7.
Liebowitz MR, DeMartinis NA, Weihs K, at al. Efficacy of sertraline in severe generalized social anxiety 
disorder: results of a double-blind, placebo-controlled study. J clin psychiatry. 2003;64(7):785-792.
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.
Bech P, Gram LF, Dein E, Jacobsen O, Vitger J, Bolwig TG. Quantitative rating of depressive states. Acta 
Psychiatr Scand 1975 Mar; 51(3): 161-170.
10.
Bech P. Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled 
analysis of four placebo-controlled trials. Pharmacopsychiatry 2007 Jul; 40(4): 163-168.
11.
Cleary P, Guy W. Factor analysis of the Hamilton depression scale. Drugs Exp Clin Res 1977; 1: 115–120
12.
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 Mar; 165(3): 342–351.
13.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32(1): 50-55.
14.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960 Feb; 23: 56-62.
15.
Hamilton M. The diagnosis and rating of anxiety, In Studies of Anxiety , MM Lader, Ed., Meedley Bros., 
Kent, 1969. 
16.
Hamilton M. Standardised assessment and recording of depressive symptoms. Psychiatr Neurol Neurochir 
1969 Mar-Apr; 72(2): 201-205.  
17.
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, 199–212
18.
Knesevich JW, Biggs JT, Clayton PJ, Ziegler VE. Validity of Hamilton Rating-Scale for depression. Br J 
Psychiatry 1977 Jul; 131: 49-52. 
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;164:1035–1043.
20.
Shear MK, Vander Bilt J, Rucci P, et al. Reliability and validity of a structured interview guide for the 
Hamilton Axiety 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 Nov; 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;167:99–103.


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ATTACHMENTS
Attachment 1: 17-Item Hamilton Depression Rating Scale (HDRS17)


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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: Sheehan Disability Scale (SDS)


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Attachment 4: Generalized Anxiety Disorders (GAD-7)


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


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Attachment 6: Liebowitz Social Anxiety Scale (LSAS)


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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 .........................................................................   


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8.
I would enjoy looking smart when I have made an effort with my appearance
Strongly disagree .........................................................................   
Disagree......................................................................................   
Agree..........................................................................................   
Strongly agree .............................................................................   
9.
I would enjoy reading a book, magazine or newspaper
Definitely agree............................................................................   
Agree..........................................................................................   
Disagree......................................................................................   
Strongly disagree .........................................................................   
10.
I would enjoy a cup of tea or coffee or my  favourite drink
Strongly disagree .........................................................................   
Disagree......................................................................................   
Agree..........................................................................................   
Strongly agree .............................................................................   
11.
I would find pleasure in small things e.g. a bright sunny day, a telephone call from a 
friend
Strongly disagree .........................................................................   
Disagree......................................................................................   
Agree..........................................................................................   
Strongly agree .............................................................................   
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: Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)


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Attachment 9: 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.
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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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


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Attachment 10:
Columbia Suicide Severity Rating Scale – BASELINE


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Attachment 11:
Columbia Suicide Severity Rating Scale – Since Last Visit


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Attachment 12:
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 based 
on reports by healthy subjects in Phase 1 studies:

headache

dizziness

fatigue

increase of hepatic enzymes  
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.


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Attachment 13:
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


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INVESTIGATOR AGREEMENT
LAST PAGE
PPD

SAP_001.pdf: 
1
Approved, Date: 17 September 2018
Janssen Research & Development *
Statistical Analysis Plan
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 
Social Anxiety Disorder
Protocol 42165279SAX2001; Phase 2a
JNJ-42165279  
Status:
Approved
Date:
17 September 2018
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS -ERI-99935209
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.
NCT02432703


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 6
1.4.
Sample Size Justification ................................................................................................................. 6
1.5.
Randomization and Blinding ............................................................................................................ 6
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Treatment Groups............................................................................................................................ 8
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 8
2.3.
Other General Definitions................................................................................................................. 8
2.3.1.
Study Day 1 or Day 1.................................................................................................................... 8
2.3.2.
Study Day or Relative Day for a Visit ........................................................................................... 8
2.3.3.
Baseline ........................................................................................................................................ 8
2.3.4.
End Point ...................................................................................................................................... 8
2.3.5.
Analysis Phases ........................................................................................................................... 8
2.4.
Visit Windows................................................................................................................................... 8
2.5.
Analysis Sets.................................................................................................................................. 11
2.5.1.
All Subjects Analysis Set ............................................................................................................ 11
2.5.2.
All Randomized Analysis Set...................................................................................................... 11
2.5.3.
Intent-to-Treat (ITT) Analysis Set ............................................................................................... 12
2.5.4.
Safety Analysis Set..................................................................................................................... 12
2.5.5.
Per Protocol Analysis Set ........................................................................................................... 12
2.6.
Definition of Subgroups.................................................................................................................. 12
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 12
4.
SUBJECT INFORMATION................................................................................................................ 13
4.1.
Demographics and Baseline Characteristics ................................................................................. 13
4.2.
Disposition Information................................................................................................................... 13
4.3.
Treatment Compliance................................................................................................................... 14
4.4.
Extent of Exposure......................................................................................................................... 14
4.5.
Protocol Deviations ........................................................................................................................ 14
4.6.
Prior and Concomitant Medications ............................................................................................... 14
5.
EFFICACY ......................................................................................................................................... 15
5.1.
Analysis Specifications................................................................................................................... 15
5.1.1.
Level of Significance................................................................................................................... 15
5.1.2.
Imputation Methods for Missing Items........................................................................................ 16
5.2.
Primary Efficacy Endpoint – LSAS Total Score ............................................................................. 16
5.2.1.
Definition..................................................................................................................................... 16
5.2.2.
Analysis Methods........................................................................................................................ 16
5.2.2.1.
Primary Analysis...................................................................................................................... 16
5.2.2.2.
Additional Analysis .................................................................................................................. 17
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 17
5.3.1.
Definitions ................................................................................................................................... 17
5.3.1.1.
LSAS fear/anxiety subscale..................................................................................................... 17
5.3.1.2.
LSAS avoidance subscale....................................................................................................... 17
5.3.1.3.
LSAS >50% improvement from baseline on total score.......................................................... 17
5.3.1.4.
LSAS ≥30% improvement from baseline on total score.......................................................... 18
5.3.1.5.
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A) total score ................... 18
5.3.1.6.
HAM-A6 score .......................................................................................................................... 18
5.3.1.7.
HDRS17 total score .................................................................................................................. 18
5.3.1.8.
HDRS17 anxiety/somatization factor score .............................................................................. 19


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5.3.1.9.
HAM-D6 score.......................................................................................................................... 19
5.3.1.10.
CGI-I ........................................................................................................................................ 19
5.3.1.11.
SIGH-A >50% improvement from baseline on total score....................................................... 19
5.3.2.
Analysis Methods........................................................................................................................ 20
5.4.
Exploratory Efficacy Endpoints ...................................................................................................... 20
5.4.1.
Definition..................................................................................................................................... 20
5.4.1.1.
SDS ......................................................................................................................................... 20
5.4.1.2.
GAD-7...................................................................................................................................... 20
5.4.1.3.
SHAPS..................................................................................................................................... 21
5.4.1.4.
MOS Sleep – R........................................................................................................................ 21
5.4.1.5.
Q-LES-Q.................................................................................................................................. 21
5.4.1.6.
Self-Assessment of Treatment Experience............................................................................. 22
5.4.1.7.
HDRS17 total score in subjects with comorbid MDD................................................................ 22
5.4.1.8.
HDRS17 anxiety/somatization factor score in subjects with comorbid MDD ........................... 22
5.4.1.9.
HAM-D6 score in subjects with comorbid MDD ....................................................................... 22
5.4.1.10.
SIGH-A total score in subjects with comorbid GAD ................................................................ 22
5.4.1.11.
HAM-A6 score in subjects with comorbid GAD........................................................................ 22
5.4.1.12.
HDRS17 ≥50% improvement from baseline on total score in subjects with 
comorbid MDD......................................................................................................................... 22
5.4.1.13.
HDRS17 ≥30% improvement from baseline on total score in subjects with 
comorbid MDD......................................................................................................................... 22
5.4.1.14.
SIGH-A >50% improvement from baseline on total score in subjects with 
comorbid GAD ......................................................................................................................... 22
5.4.2.
Analysis Methods........................................................................................................................ 23
6.
PHARMACOGENOMIC ANALYSES................................................................................................ 23
7.
BIOMARKERS................................................................................................................................... 23
8.
SAFETY............................................................................................................................................. 24
8.1.
Incomplete/Missing Dates for Adverse Events .............................................................................. 24
8.2.
Adverse Events .............................................................................................................................. 25
8.3.
Clinical Laboratory Tests................................................................................................................ 26
8.4.
Vital Signs and Physical/Neurological Examination Findings........................................................ 27
8.5.
Electrocardiogram.......................................................................................................................... 29
8.6.
Other Safety Parameters ............................................................................................................... 30
8.6.1.
C-SSRS ...................................................................................................................................... 30
REFERENCES............................................................................................................................................ 32
ATTACHMENT: LIEBOWITZ SOCIAL ANXIETY SCALE (LSAS) ........................................................... 33


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ABBREVIATIONS
AE
adverse event
AEA
anandamide
ANCOVA
analysis of covariance
BMI
body mass index
CGI-I
Clinical Global Impression – Improvement
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating scale
ECG
electrocardiogram
eCRF
electronic case report form
FAAH
fatty acid amide hydrolase
FAAs
fatty acid amides
GAD
generalized anxiety disorder
GAD-7
Generalized Anxiety Disorder 7
HAM-A6
6-item subscale of the Hamilton Anxiety Rating scale
HAM-D6
6-item subscale derived from the HDRS17
HDRS17
17-item Hamilton Depression Rating Scale
HR
heart rate
ICH
International Conference on Harmonization
ITT
Intent-to-Treat
IVRS
interactive voice response system
IWRS
interactive web response system
LSAS
Liebowitz Social Anxiety Scale
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MOS Sleep-R
Medical Outcomes Study- 12-item Sleep Scale Acute - Revised
OEA
oleoylethanolamide
PD
pharmacodynamic
PEA
palmitoylethanolamide
PK
pharmacokinetic(s)
Q-LES-Q
Quality of Life, Enjoyment, and Satisfaction Questionnaire
SAD
social anxiety disorder
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDS
Sheehan Disability Scale
SHAPS
Snaith-Hamilton Pleasure Scale
SI
standard international
SIGH-A
Structured Interview Guide for the Hamilton Anxiety Scale
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent abnormality


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1.
INTRODUCTION
In January 2016, Janssen had decided to suspend the 42165279SAX2001 study (see the press 
release on 18 January 2016 on Janssen.com). The study was unblinded and the randomization 
codes were provided to the investigators so that the patients could be informed about their 
treatment. Safety information was analyzed, and a separate Statistical Analysis Plan (SAP)
was written and approved for the interim safety analysis. No efficacy data was analyzed, and 
datasets containing efficacy information of the subjects who were unblinded at trial 
suspension will remain in a secure location at the data management department until final DB 
lock (see Partial Database Lock Notification form dated 24 March 2016 and Note to File 
dated 15 December 2016).
This SAP contains definitions of analysis sets, derived variables, and statistical methods for 
the final analysis of efficacy, biomarker and safety data. The final analysis will include 
subjects who were enrolled prior to study suspension and subjects who were enrolled after the 
study had resumed. See Section 2.5 for a definition of the analysis sets.
1.1.
Trial Objectives
The primary objective of this study is to investigate the efficacy of JNJ-42165279 during 
12 weeks of treatment in subjects with social anxiety disorder (SAD).
The secondary objectives of this study are:

To assess the safety and tolerability of JNJ-42165279 in subjects with SAD. 

To assess the plasma pharmacokinetic (PK) profile of JNJ-42165279 administered as 
once daily (qd) in subjects with SAD using a population PK approach, and explore the 
relationship between exposure to JNJ-42165279 and efficacy and safety parameters.
The exploratory objectives are:

To assess the efficacy of JNJ-42165279 on both anxiety and depression symptoms.

To evaluate the impact of treatment with JNJ-42165279 compared to placebo on patient-
reported assessments of symptoms of anxiety, depression, impairment in daily living and 
quality of life.

To evaluate pharmacodynamic (PD) effects by the assessment of biomarkers of 
peripheral pharmacological activity after repeated doses of JNJ-42165279, including 
assessment of plasma concentrations of fatty acid amides (FAAs) (anandamide [AEA], 
palmitoylethanolamide [PEA], and oleoylethanolamide [OEA]) that are expected to rise 
as a consequence of the inhibition of their hydrolysis by fatty acid amide hydrolase 
(FAAH).

To explore the relationship between plasma PK and plasma concentrations of FAAs 
(AEA, PEA and OEA) in subjects with SAD.

To explore any potential differences between healthy subjects and subjects with SAD 
using a population PK approach.


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1.2.
Trial Design
This is a multi-center, double-blind, placebo-controlled, randomized, parallel-group study 
assessing the efficacy, safety, and tolerability of JNJ-42165279 during 12 weeks of treatment 
in subjects with SAD. 
Approximately one-hundred twenty-two (122) subjects will be enrolled in this 12 week 
treatment study randomly assigned in a 1:1 ratio to either 25 mg of JNJ-42165279 or placebo 
(dosed once daily orally).
For all enrolled subjects, this study will consist of a 28-day eligibility screening period, a 
12 week double-blind treatment period and a follow-up examination between 7 and 28 days 
after last dose. The study duration for each subject will be maximally 20 weeks.
The study will be an outpatient study.
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint for this study is the reduction of symptom burden associated 
with social anxiety disorder (SAD), as measured by the change from baseline to the 12-week 
endpoint in the Liebowitz Social Anxiety Scale (LSAS) total score. The null hypothesis to be 
tested to address the primary objective is that there is no difference between JNJ42165279 
and placebo based on the primary efficacy endpoint.
1.4.
Sample Size Justification
The sample size for the study is based on the assumption of a treatment difference of at least 
10 points in the mean change from baseline to the endpoint in LSAS total score between 
JNJ-42165279 treatment group and placebo. A standard deviation of 24 in the change in 
LSAS total score from baseline is used based on published data.7,10,11  To detect the treatment 
difference of 10 points (which is judged to be clinically relevant 7,10,11)  with a power of 90% 
at an overall 1-sided significance level of 0.20, 53 subjects in each group are required. When 
adjusted for a drop-out rate of approximately 15% of subjects, the required number of 
subjects is 61 per treatment group.
The impact of this sample size (N=122) on the JNJ– 42165279 effect size to be detected for 
the other continuous secondary and exploratory endpoints for different values of significance 
level and power, assuming a drop-out rate of 15%, are presented in Table 1. 
Table 1: JNJ–42165279 effect size to be detected for different values of significance level 
and power, assuming a drop-out rate of 15%
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. At the start of the double-blind 
phase, subjects will be randomly assigned to one of two treatment groups based on the first of 
1-sided significance level
Power
Effect size to be detected
0.10
80%
0.4
0.10
90%
0.5
0.20
80%
0.3
0.20
90%
0.4


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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. Presence of comorbid major depressive disorder (MDD) and country will be used as 
stratification factors.
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 analysis 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 analysis.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Treatment Groups
Tables summarizing data in the double-blind treatment phase will have columns for ‘Placebo’ 
and ‘JNJ-42165279 25 mg’.
Subjects who received an incorrect treatment will be analyzed under the treatment they were 
randomized to.
2.2.
Pooling Algorithm for Analysis Centers
No pooling of centers will be carried out.
2.3.
Other General Definitions
2.3.1.
Study Day 1 or Day 1
Study Day 1 or Day 1 refers to the first day of double-blind study drug administration.  All 
efficacy and safety assessments at all visits will be assigned a day relative to this date.
2.3.2.
Study Day or Relative Day for a Visit
Study day or relative day for a visit is defined as: 
–
Visit date - Date of first dose of study medication (date of Day 1) +1, if visit date is 
date of Day 1
–
Visit date - Date of Day 1,  if visit date is < date of Day 1
By definition there is no ‘Day 0’.
2.3.3.
Baseline
Baseline is defined as the last non-missing observation prior to first dose of study drug. 
2.3.4.
End Point
End point is defined as the last non-missing post-baseline observation during the Double-
Blind treatment phase (defined in Section 2.3.5).
2.3.5.
Analysis Phases
All data collected from the Baseline visit to the End Point/Early Withdrawal visit (inclusive) 
will be assigned to the Double-Blind Treatment analysis phase. Data collected prior to the 
Baseline visit will be assigned to the Screening analysis phase, and data collected after the 
End Point/Early Withdrawal visit will be assigned to the Post Treatment analysis phase.
2.4.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are 
applied to assign actual visits to protocol visits. Listed in Table 2 are the visit windows and 
the target days for each visit. The reference day is Study Day 1 (which is the first day the 
study drug was taken in the double-blind phase).     


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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 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 is assigned to a visit 
window, it will no longer be used for a later time point except for the end point. Listed below 
(Table 2) are the visit windows and the target days (if applicable) for each visit defined in the 
protocol.


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Table 2: Visit Windows
Parameter
Scheduled 
Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)1
Target Time 
Point 
(Day)
Analysis 
Phase5
MINI Interview, 
Height, Serology
1
Screening
<1
-28 to -1
Screening
LSAS,
HDRS17
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
3
Week 1
2 to 10
7
DB Treatment
4
Week 2
11 to 21
14
DB Treatment
5
Week 4
22 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
SIGH-A
2
Baseline
≤1
1
DB Treatment
3
Week 1
2 to 10
7
DB Treatment
4
Week 2
11 to 21
14
DB Treatment
5
Week 4
22 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
CGI - I
3
Week 1
2 to 10
7
DB Treatment
4
Week 2
11 to 21
14
DB Treatment
5
Week 4
22 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
SDS, GAD-7, 
SHAPS, MOS Sleep 
– R, Q-LES-Q
2
Baseline
≤1
1
DB Treatment
5
Week 4
2 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
Self-assessment of 
treatment experience
9
Week 12
2 to End of DB4
84
DB Treatment
End Point2
DB Treatment
12-Lead ECG, Body 
Weight
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
5
Week 4
2 to 56
28
DB Treatment
9
Week 12
57 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up3
> End of DB4
91 to 112
Post Treatment
Vital Signs, Body 
temperature
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
3
Week 1
2 to 10
7
DB Treatment
4
Week 2
11 to 21
14
DB Treatment
5
Week 4
22 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up
> End of DB4
91 to 112
Post Treatment
CSSR-S
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
3
Week 1
2 to 10
7
DB Treatment
4
Week 2 
11 to 21
14
DB Treatment
5
Week 4
22 to 35
28
DB Treatment
6
Week 6
36 to 49
42
DB Treatment
7
Week 8
50 to 63
56
DB Treatment
8
Week 10
64 to 77
70
DB Treatment


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Table 2: Visit Windows
Parameter
Scheduled 
Visit 
Number
Time Interval
(label on output)
Time Interval
(Day)1
Target Time 
Point 
(Day)
Analysis 
Phase5
9
Week 12
78 to End of DB4
84
DB Treatment
End Point2
DB Treatment
Clinical Laboratory 
Assessments
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
4
Week 2 
2 to 21
14
DB Treatment
5
Week 4
22 to 35
28
DB Treatment
6
Week 6
36 to 49 
42
DB Treatment
7
Week 8
50 to 63
56
DB Treatment
8
Week 10
64 to 77
70
DB Treatment
9
Week 12
78 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up3
> End of DB4
91 to 112
Post Treatment
Urine Drug Screen
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
5
Week 4
2 to 56
28
DB Treatment
9
Week 12
57 to End of DB4
84
DB Treatment
End Point2
DB Treatment
Alcohol Screen
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
4
Week 2 
2 to 21
14
DB Treatment
5
Week 4
22 to 42
28
DB Treatment
7
Week 8
43 to 70
56
DB Treatment
9
Week 12
71 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up3
> End of DB4
91 to 112
Post Treatment
Pregnancy test
1
Screening
<1
-28 to -1
Screening
2
Baseline
≤1
1
DB Treatment
9
Week 12
2 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up
91 to 112
Post Treatment
Physical 
Examination
1
Screening
<1
-28 to -1
Screening
9
Week 12
2 to End of DB4
84
DB Treatment
End Point2
DB Treatment
10
Follow Up
> End of DB4
91 to 112
Post Treatment
1 Relative to first day of study medication
2 End Point is defined as the last non-missing post-baseline measurement during the double-blind treatment phase. 
3 Only in case of any clinical significant abnormality observed at Week 12 (except for weight)
4 End of DB = the end of the double-blind treatment phase
5 On output tables, DB Treatment will be presented as “Double-Blind Treatment”.
2.5.
Analysis Sets
2.5.1.
All Subjects Analysis Set
The All Subjects analysis set includes all subjects with information entered into the clinical 
database. This set will be used for the listings unless specified otherwise.
2.5.2.
All Randomized Analysis Set
The All Randomized analysis set includes all subjects who were randomized (i.e., subjects 
who reported a randomization date, or were assigned a randomization number) regardless of 
whether or not the treatment was received. 


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This analysis set will be used for summarizing the overall study completion/withdrawal 
information.
2.5.3.
Intent-to-Treat (ITT) Analysis Set
The ITT analysis set is defined as all randomized subjects who received at least one dose of 
study medication (either placebo or JNJ-42165279), and have at least one assessment in the 
double-blind treatment phase on any of the efficacy parameters. Subjects who withdrew early 
from the study at the time of study suspension will not be included in the ITT analysis set (7 
placebo subjects, 8 JNJ-42165279 subjects). Subjects who had already completed the study at 
the time it was suspended, however, will be included in the ITT set (9 placebo subjects, 9 
JNJ-42165279 subjects).
The ITT analysis set is the analysis set for the efficacy analyses.
2.5.4.
Safety Analysis Set
The Safety analysis set is defined as all randomized subjects who received at least one dose 
of study medication (either placebo or JNJ-42165279). Screen failures and randomized 
subjects who received no double-blind study medication will be excluded from the Safety 
analysis set. 
The Safety analysis set is the analysis set for the safety analyses.
2.5.5.
Per Protocol Analysis Set
The Per Protocol analysis set includes all ITT subjects who did not have a major protocol 
deviation during the study. In case there is a substantial amount of subjects with a major 
protocol deviation, a sensitivity analysis of the primary efficacy parameter will be performed 
for the per protocol analysis set.
2.6.
Definition of Subgroups
Some of the secondary efficacy endpoints will be analyzed for the subgroup of subjects with 
comorbid MDD/GAD. See Section 5.4 for a definition of these exploratory endpoints.
Exploratory analyses of selected parameters will be performed for the subgroup of subjects 
who enrolled prior to study suspension versus those who enrolled after the study had 
resumed. 
Exploratory sensitivity analyses of the primary efficacy parameter will be performed for the 
subgroup of subjects who did not meet criteria for sufficient compliance based on 
pharmacokinetic results. These criteria are defined by the clinical pharmacology department.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
A blinded interim analysis for the purpose of sample size re-estimation may be performed 
after 50% of the subjects are recruited if the observed standard deviation substantially 
deviates from the hypothesized standard deviation, or if the drop-out rate substantially 
deviates from the assumed drop-out rate. 


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No interim analysis for efficacy is planned.
4.
SUBJECT INFORMATION
Subject information will be summarized for the Safety Analysis Set and listings will be 
created for the All Randomized analysis set.
4.1.
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be listed and summarized by 
treatment group and overall:
Age (years), sex, race, ethnicity, weight (kg), height (cm), body mass index (BMI, 
calculated as weight (kg)/[height(m)]2), country, presence of comorbid major 
depressive disorder (MDD), presence of comorbid generalized anxiety disorder 
(GAD).
Continuous variables (age, weight, height and BMI) will be summarized using descriptive 
statistics (N, mean, standard deviation [SD], median and range [minimum and maximum]). 
Categorical variables (race, ethnicity, country, presence of comorbid MDD, presence of 
comorbid GAD) will be summarized using a frequency distribution with the number and 
percentage of subjects in each category.
Psychiatric history at baseline will be summarized by treatment group and overall using 
descriptive statistics for the following assessments: LSAS total score, SIGH-A total score, 
HAM-A6 score, HDRS17 total score, HDRS17 anxiety/somatization factor score, HAM-D6
score.
The summary of demographics and baseline characteristics and psychiatric history at baseline 
will be created for both the Safety Analysis Set and the ITT Analysis Set. The summary will 
also be presented by country and by enrollment prior to/after study suspension.
Listings will be created for the following assessments:
Randomization information, inclusion/exclusion criteria, childbearing potential, date 
of last menses, date of signature on informed consent, issue date of the protocol the 
subject consented to at study enrollment, preplanned surgery/procedures, psychiatric 
evaluation (M.I.N.I.), medical history, comments, study execution period. 
4.2.
Disposition Information
The number and percentage of subjects in the All Randomized Subjects, ITT, Per Protocol 
and Safety analysis sets will be presented overall, and by country and center. In addition, 
summaries of the reasons for exclusion from each analysis set (i.e., Per Protocol set and ITT 
set) will be provided. The number of screen failures together with the withdrawal reason will 
be presented. 
The distribution of the number of subjects who complete the entire course of treatment and 
who discontinue will be presented by treatment group and overall. The distribution of study 


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termination reasons will also be presented. In addition, the number and percentage of subjects 
who discontinue on or prior to each study visit will be summarized by treatment group and 
overall. The distribution of time to discontinuation will be presented graphically using 
Kaplan-Meier estimates. The time to treatment discontinuation will be calculated as the 
duration (in days) from Study Day 1 (defined in Section 2.3.1) to treatment discontinuation. 
Subjects who complete the double-blind treatment period will be censored at the end of 
treatment date.
Study completion and withdrawal information for each subject will also be presented in a 
listing.
4.3.
Treatment Compliance
The number of tablets dispensed and returned at each visit will be listed.
4.4.
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 the last day of 
study drug in the double-blind treatment phase: last day of study drug administration – first 
day of study drug administration + 1.
Treatment duration will be listed and summarized by treatment group using descriptive 
statistics (N, mean, SD, median, and range). A frequency distribution will also be provided 
using the following categories: <1 week (<7 days), 1-<2 weeks (7-<14 days), 2-<4 weeks
(14-<28 days), 4–<6 weeks (28-< 42 days), 6-<8 weeks (42-<56 days), 8-<10 weeks (56-< 70 
days), 10-<12 weeks (70-<84 days) and ≥12 weeks (≥84 days).
4.5.
Protocol Deviations
Deviations that occurred during the study will be listed by treatment group. Major deviations 
will be presented as grouped by the Data Management Group prior to the unblinding.
4.6.
Prior and Concomitant Medications
The following groups of medication will be tabulated by treatment group, by medication class 
and generic term of the medication:
-
Prior medications: medications with start date/time and end date/time prior to first 
dose intake 
-
Prior and ongoing medications: medications with start date/time prior to first dose 
intake and end date/time after first dose intake
-
Concomitant medications: medications with start date/time after first dose intake 


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Data listings will be provided for all medications received from the signing of informed 
consent prior to study start and concomitantly during the study. 
5.
EFFICACY
All efficacy analyses will be based on the ITT analysis set. The efficacy variables in this 
study are listed in Table 3.
All efficacy data will be listed for the subjects in the ITT analysis set.
Table 3: Efficacy Variables
Endpoint
Scale*
Primary
LSAS total score
Secondary
LSAS fear/anxiety subscale
LSAS avoidance subscale
LSAS >50% improvement from baseline on total score
LSAS >30% improvement from baseline on total score
SIGH-A total score
HAM-A6 score
HDRS17 total score
HDRS17 anxiety/somatization factor score
HAM-D6 score
CGI-I
SIGH-A >50% improvement from baseline on total score 
Exploratory
SDS
GAD-7
SHAPS
MOS Sleep - R
Q-LES-Q
Self-Assessment of Treatment Experience
HDRS17 total score in subjects with comorbid MDD
HDRS17 anxiety/somatization factor score in subjects with comorbid MDD
HAM-D6 score in subjects with comorbid MDD
SIGH-A total score in subjects with comorbid GAD
HAM-A6 score in subjects with comorbid GAD
HDRS17 ≥50% improvement from baseline on total score in subjects with 
comorbid MDD          
HDRS17 ≥30% improvement from baseline on total score in subjects with 
comorbid MDD
SIGH-A >50% improvement from baseline on total score in subjects with 
comorbid GAD
* CGI-I = Clinical Global Impression – Improvement; GAD-7 = Generalized Anxiety Disorders; 
HAM-A6 = Hamilton Anxiety Rating Scale; HAM-D6 = Hamilton Depression Rating Scale; HDRS17 = 
Hamilton Depression Rating Scale; LSAS = Liebowitz Social Anxiety Scale; MOS Sleep – R: Medical 
Outcomes Study Sleep-Revised; SDS = Sheehan Disability Scale; Q-LES-Q = Quality of Life 
Enjoyment and Satisfaction Questionnaire; SHAPS = Snaith-Hamilton Pleasure Scale; SIGH-A = 
Structured Interview Guide for the Hamilton Anxiety Scale
5.1.
Analysis Specifications
5.1.1.
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.


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5.1.2.
Imputation Methods for Missing Items
Imputation of missing individual items will apply only to the LSAS, as described in Section 
5.2.1. 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. 
5.2.
Primary Efficacy Endpoint – LSAS Total Score
5.2.1.
Definition
The primary efficacy endpoint will be the improvement in social anxiety symptoms, as 
measured by the change from baseline in the LSAS total score from baseline to the 12-week 
endpoint in the double-blind treatment phase.
The LSAS was designed to assess the range of social interaction and performance situations 
that individuals with social phobia may fear and/or avoid (Liebowitz, 1987)6. The 24 items in 
the scale are divided into two subscales that address social interactional (11 items) and 
performance (13 items) situations. The clinician asks the patient to rate fear and avoidance 
during the past week on 0–3 Likert-type scales; however, the clinician is given latitude to 
question the patient’s responses and adjust the ratings accordingly. An example of the LSAS 
is provided in the Attachment.
An overall total score is calculated by summing the 24 fear and 24 avoidance scores. The 
LSAS total score has a maximum of 144, with higher scores indicating higher probability of 
social anxiety disorder.
If an LSAS item is missing, it will be imputed with the closest integer to the average of the 
remaining items within the LSAS subscale (fear/anxiety, avoidance) at that time point and 
then the total will be summed. If more than 1 item is missing, no imputation will be 
performed and the total LSAS score will be left missing. Imputation of item scores is 
performed prior to determining the endpoint for the LSAS.
5.2.2.
Analysis Methods
5.2.2.1.
Primary Analysis
Descriptive statistics of actual values and changes from baseline for the LSAS total score at 
each scheduled time point and endpoint will be provided by treatment group (mean, SD, 
median and range). A mean-SE plot over time will be presented for the LSAS total score 
observed values by treatment group. Listings will be created with LSAS item scores and the 
LSAS total score.
The JNJ-42165279 treatment group will be compared to placebo by means of a mixed-effects 
model using repeated measures (MMRM) with time, treatment (placebo, JNJ-42165279) and 
time-by-treatment interaction as factors, baseline LSAS total score and age as a continuous 
covariate and country and presence of comorbid MDD 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 observed 


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correlation structure. The treatment-placebo differences will be obtained using the 
appropriate contrast in the MMRM model at the 12-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 LSAS total score is expected to be larger after dosing with JNJ, so the one-sided 
p-value will be calculated as described in Table 4.
Table 4: Calculation of one-sided p-value
Parameter
Ha
Estimated difference  
Mean JNJ – Mean Pla
One-sided p-value
Change in LSAS 
total score at 
Week 12
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)
5.2.2.2.
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 12-week
endpoint in LSAS total score will be carried out. The ANCOVA model will include factors 
for treatment, country and presence of comorbid MDD and baseline LSAS total score and age
as a covariate. In addition, the same ANCOVA model will also be performed on observed 
case data at Week 12. 
As a secondary analysis, the MMRM model described in Section 5.2.2.1 will be fitted with 
race, history of MDD and baseline SDS total score as additional covariates.
As a sensitivity analysis, the MMRM model described in Section 5.2.2.1 will be fitted on the 
set of ITT subjects excluding the subjects who had completed the study at the time it was 
suspended (9 subjects in each treatment group).
5.3.
Secondary Efficacy Endpoints
5.3.1.
Definitions
5.3.1.1.
LSAS fear/anxiety subscale
The LSAS fear/anxiety subscale will be calculated by summing the 24 fear/anxiety item 
scores of the LSAS, and ranges from 0 to 72. 
5.3.1.2.
LSAS avoidance subscale
The LSAS avoidance subscale will be calculated by summing the 24 avoidance item scores of 
the LSAS, and ranges from 0 to 72. 
5.3.1.3.
LSAS >50% improvement from baseline on total score
The percentage change from baseline is calculated as 


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100 ∗(	
	       −	
	    )
	
	    
A ≥50% improvement on LSAS total score means that the percentage change from baseline is 
≤-50 in this calculation. 
5.3.1.4.
LSAS ≥30% improvement from baseline on total score
The percentage change from baseline is calculated as 
100 ∗(	
	       −	
	    )
	
	    
A ≥30% improvement on LSAS total score means that the percentage change from baseline is 
≤-30 in this calculation. 
5.3.1.5.
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-
A) total score
The SIGH-A is included as a means to determine the frequency and severity of signs and 
symptoms of anxiety, including subjects with comorbid GAD and MDD, and determine both 
their influence on treatment and their responsiveness to treatment.  
The original HAM-A scale assesses the severity of different anxiety-related symptoms 
(Hamilton 19594; Hamilton 19693). 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)9. 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)9. 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. 
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.
5.3.1.6.
HAM-A6 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.
5.3.1.7.
HDRS17 total score
The HDRS17 is a clinician-administered rating scale designed to assess the severity of 
symptoms in subjects diagnosed with depression (Hamilton M 1960)2. It is the most widely 


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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 HDRS17 total score will be calculated by summing the 17 item scores, and ranges from 0 
to 52. Higher scores indicate greater severity of depression.
The original HDRS17 scale lacks instructions for administration and clear anchor points for 
the assignment of severity ratings. For this reason, the structured interview guide version of 
the HDRS17 (the Structured Interview Guide for the Hamilton Depression Scale [SIGH-D]) 
will be used in the current study to facilitate and standardize gathering clinical information 
from the subject.
5.3.1.8.
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 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.
5.3.1.9.
HAM-D6 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)1. 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.
5.3.1.10.
CGI-I
The clinical global impression – improvement (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.
5.3.1.11.
SIGH-A >50% improvement from baseline on total score
The percentage change from baseline is calculated as 
100 ∗(	 
       −	 
    )
	 
    
A ≥50% improvement on SIGH-A total score means that the percentage change from 
baseline is ≤ -50 in this calculation.


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5.3.2.
Analysis Methods
For all continuous secondary endpoints, descriptive statistics of actual values and changes 
from baseline at each scheduled time point and endpoint will be provided by treatment group 
(mean, SD, median and range). This includes LSAS fear/anxiety subscale, LSAS avoidance 
subscale,
SIGH-A 
total 
score,
HAM-A6
score, 
HDRS17
total 
score, 
HDRS17 
anxiety/somatization factor score and HAM-D6 score. A mean-SE plot over time will be 
presented for these continuous endpoint observed values by treatment group. 
For each of the continuous secondary endpoints, the JNJ-42165279 treatment group will be 
compared to placebo by means of a mixed-effects model using repeated measures (MMRM) 
with time, treatment (placebo, JNJ-42165279) and time-by-treatment interaction as factors, 
baseline score of the continuous endpoint and age as a continuous covariate and country and
presence of comorbid MDD 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 observed correlation structure. The treatment-placebo 
differences will be obtained using the appropriate contrast in the MMRM model at the 12-
week endpoint. One-sided p-values with level of significance of 20% will derived as 
described in Section 5.2.2.1.
Frequency counts and percentages will be provided at each scheduled time point and 
endpoint by treatment group for the following variables: LSAS ≥50% improvement, LSAS 
≥30% improvement, CGI-I, CGI-I response and SIGH-A ≥50% improvement.
5.4.
Exploratory Efficacy Endpoints
5.4.1.
Definition
5.4.1.1.
SDS
The Sheehan Disability Scale (SDS) is a composite of three self-rated items designed to 
measure the extent to which three major sectors in the patient’s life are impaired by panic,
anxiety, phobic, or depressive symptoms. This anchored visual analog scale uses visual-
spatial, numeric, and verbal descriptive anchors simultaneously to assess disability across 
three domains: work, social life, and family life. An SDS total score will be calculated as the 
sum of the three self-rates item scores, and ranges from 0 to 30. Higher scores indicates 
higher impairment of the patient’s life.
5.4.1.2.
GAD-7
Generalized Anxiety Disorder 7 (GAD-7) is a self-reported questionnaire for screening and 
severity measuring of generalized anxiety disorder (GAD) and is of particular interest 
because of the frequent comorbidity of GAD with SAD. GAD-7 has seven items, which 
measure severity of various signs of generalized anxiety disorder according to reported 
response categories of “not at all,” “several days,” “more than half the days,” and “nearly 
every day.” A GAD-7 total score is calculated as the sum of the 7 item scores, and ranges 
from 0 to 21, with higher scores indicating higher severity of symptoms. 


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5.4.1.3.
SHAPS
The Snaith-Hamilton Pleasure Scale (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.
5.4.1.4.
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. 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.
5.4.1.5.
Q-LES-Q
The Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q) is a 16-item self-
administered questionnaire designed to measure degree of enjoyment and satisfaction in 
general activities. The Q-LES-Q measures each of the items using a 5-point Likert-type scale
as: 1=very poor; 2=poor; 3=fair; 4=good; 5=very good. The scoring of the Q-LES-Q involves 
summing only the first 14 items to yield a raw total score. The last 2 items are not included in 
the total score but are stand-alone items. The raw total score ranges from 14 to 70. The raw 
total score is transformed into a percentage maximum possible score using the following 
formula:
100 ∗
(   −   )
(     −   )
The minimum possible raw score on the Q-LES-Q is 14, and the maximum possible raw 
score is 70. Higher Q-LES-Q scores reflect greater enjoyment and satisfaction with general 
activities.  


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5.4.1.6.
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.
5.4.1.7.
HDRS17 total score in subjects with comorbid MDD
The HDRS17 total score will be calculated as described in Section 5.3.1.7, for subjects with 
comorbid MDD.
5.4.1.8.
HDRS17 anxiety/somatization factor score in subjects with 
comorbid MDD
The HDRS17 anxiety/somatization factor score will be calculated as described in Section 
5.3.1.8, for subjects with comorbid MDD. 
5.4.1.9.
HAM-D6 score in subjects with comorbid MDD
The HAM-D6 score will be calculated as described in Section 5.3.1.9, for subjects with 
comorbid MDD. 
5.4.1.10.
SIGH-A total score in subjects with comorbid GAD
The SIGH-A total score will be calculated as described in Section 5.3.1.5, for subjects with 
comorbid GAD.
5.4.1.11.
HAM-A6 score in subjects with comorbid GAD
The HAM-A6 score will be calculated as described in Section 5.3.1.6, for subjects with 
comorbid GAD. 
5.4.1.12.
HDRS17 ≥50% improvement from baseline on total score in 
subjects with comorbid MDD
The percentage change from baseline is calculated as 
100 ∗(!"	17       −!"	17    )
!"	17    
A ≥50% improvement on HDRS17 total score means that the percentage change from baseline 
is  ≤-50 in this calculation. The HDRS17 ≥50% improvement will be calculated for subjects 
with comorbid MDD.
5.4.1.13.
HDRS17 ≥30% improvement from baseline on total score in 
subjects with comorbid MDD
The HDRS17 ≥30% improvement on total score will be calculated for subjects with comorbid 
MDD in a similar manner as described in Section 5.4.1.12
5.4.1.14.
SIGH-A >50% improvement from baseline on total score in 
subjects with comorbid GAD
The SIGH-A ≥50% improvement will be calculated as described in Section 5.3.1.11, for 
subjects with comorbid GAD.


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5.4.2.
Analysis Methods
For all continuous exploratory endpoints, descriptive statistics of actual values and changes 
from baseline at each scheduled time point and endpoint will be provided by treatment group 
(mean, SD, median and range). A mean-SE plot over time will be presented for the observed 
values by treatment group. This includes SDS total score, GAD total score, SHAPS total 
score, MOS Sleep-R, Q-LES-Q percentage maximum possible score, HDRS17 total score, 
HDRS17 anxiety/somatization factor score, HAM-D6 score, SIGH-A total score and HAM-A6
score.
Frequency counts and percentages will be provided at each scheduled time point and 
endpoint by treatment group for the following variables: Q-LES-Q last 2 items, Self-
Assessment of Treatment Experience scale, HDRS17 ≥50% improvement, HDRS17 ≥30% 
improvement and SIGH-A ≥50% improvement.
6.
PHARMACOGENOMIC ANALYSES
It is recognized that genetic variation can be an important contributory factor to 
interindividual differences in drug distribution and response and can also serve as a marker 
for disease susceptibility and prognosis. Pharmacogenomic research may help to explain 
interindividual variability in clinical outcomes and may help to identify population subgroups 
that respond differently to a drug. The goal of the pharmacogenomic component is to collect 
DNA to allow the identification of genetic factors that may influence PK, PD, safety, and/or 
tolerability of JNJ-42165279 and to enable the development of safer, more effective and 
ultimately individualized therapies in the future. DNA samples will be analyzed for the 
FAAH gene. Additional analyses may be conducted if it is hypothesized that this may help 
resolve issues with the clinical data.
DNA samples will be used for research related to JNJ-42165279. They may also be used to 
develop tests/assays related to JNJ-42165279. Pharmacogenomic research may consist of the 
analysis of one or more candidate genes or of the analysis of genetic markers throughout the 
genome (as appropriate) in relation to JNJ-42165279 clinical endpoints. Analyses may be 
performed across multiple clinical studies.
The relationship between genetic subgroups for the FAAH gene (C/C or A/C) and JNJ-
42165279 biomarker endpoints (AEA, PEAE and OEA) will be examined through descriptive 
statistics and graphical presentations. A similar analysis will be performed to explore the 
relationship between genetic subgroups and the LSAS total score.
7.
BIOMARKERS
Biomarker analyses will be based on the safety analysis set, which will include all 
randomized subjects who receive at least one dose of study medication (either placebo or 
JNJ-42165279).
During the study, the following biomarker evaluations will be performed at Day 1, Day 28 
and Day 84/ end of withdrawal visit: plasma concentrations of FAAs (AEA, PEA and OEA). 


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Descriptive statistics of actual values and changes and percent changes from baseline for 
concentrations of AEA, PEA and OEA at each scheduled time point and endpoint will be 
provided by treatment group (mean, SD, median and range). A mean-SE plot over time will 
be presented by treatment group, and results will be listed.
8.
SAFETY
All safety analyses will be based on the safety analysis set, which will include all randomized 
subjects who receive at least one dose of study medication (either placebo or JNJ-42165279).
All safety data will be listed for the subjects in the safety analysis set.
8.1.
Incomplete/Missing Dates for Adverse Events
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:
(3) 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.
If both the day and the month are missing:  the estimated resolution date is the end of the 
double-blind phase.


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8.2.
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 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 JNJ42165279, therapeutic reach is 
defined as 4 days. AEs will be summarised using the therapeutic reach. Therapeutic reach 
will only be applied to the end of double-blind treatment period or to subjects who 
discontinue.
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 follow up period but within 
the therapeutic reach of 4 days will be considered treatment-emergent. Adverse events with 
onset date during the follow-up phase 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. A summary will be created for the most common 
TEAEs (≥5% incidence in either treatment group). In addition, TEAEs will be summarized 
by severity and relationship to study drug for each treatment group 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.
TEAEs will also be summarized by sex, by country, and by enrollment prior to/after study 
suspension. 
Serious AEs (SAEs) and TEAEs that lead to study discontinuation will be summarized 
separately by treatment group, system organ class and preferred term. 
Treatment-emergent headaches, TEAEs related to liver function test abnormalities and 
TEAEs of special interest (diplopia, vision impairment, gait disturbance, severe headache)
will be presented graphically over time for each individual subject.
Data listings will be generated for all AEs, deaths, other serious SAEs, severe AEs and 
discontinuations due to AEs. 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.


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8.3.
Clinical Laboratory Tests
Descriptive statistics (N, mean, SD, median and range) for absolute values and changes from 
baseline will be provided by treatment group at each scheduled time point and endpoint for 
the clinical laboratory tests (hematology, chemistry and urinalysis). Laboratory summaries 
will be provided in Standard International (SI) units.
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.
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 5. The identification of TEMA laboratory values is based 
on the post-baseline (after the start of double-blind study medication) value being out of 
range while the baseline value is either missing or within the range given in Table 5. 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 at each scheduled time point, at 
endpoint, and at any time during the double-blind treatment phase.


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Table 5: 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
Blood 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, at endpoint, and at any time 
during the double-blind treatment phase.
Graphical presentations will also be created for prothrombin international normalized ratio 
results.
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 a listing.
8.4.
Vital Signs and Physical/Neurological Examination Findings
Descriptive statistics (N, mean, SD, median and range) for absolute values and changes from 
baseline will be presented at each scheduled time point and endpoint by treatment group for 
height, body weight and BMI. Similar summary tables will be presented for systolic blood 


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pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (beats per minute) and 
temperature (oC). 
Mean-SE plots over time will be presented for vital sign values by treatment group, and a
subject data listing will be provided. In addition, scatter plots of post-baseline versus baseline 
values will be presented by treatment group.
Abnormal values are defined in Table 6, and will be summarized using frequency distribution 
tables over time by treatment group. A listing of subjects meeting any of the abnormality 
criteria will be provided.
Table 6: 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 7
below) at each scheduled time point and endpoint and at any time during the double-blind 
treatment phase will be presented by treatment group. Shift from baseline tables at each 
scheduled time point and endpoint will be generated for the vital signs values using the 
classes (below, within, and above normal ranges) for each treatment group.
Table 7: 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
BP = blood pressure
A listing of subjects meeting any of the abnormality criteria will also be provided. 
The orthostatic hypotension measurements will be calculated as the standing measurement 
minus the supine measurement. Orthostatic hypotension is defined as a decrease in systolic 
(>20 mmHg), or diastolic (>10 mmHg) blood pressure after standing for at least 2 minutes 
with an increase in pulse rate of >15 beats per minute (Table 8).  


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Table 8: Abnormal limits for orthostatic parameters 
Vital Signs Parameter
Outside of normal limit if difference 
(Standing minus supine)
(1)    Pulse (bpm)
> 15 bpm
(2a)  Systolic blood pressure (mmHg) (SBP)
< - 20 mmHg
(2b)  Diastolic blood pressure (mmHg) (DBP)
< -10 mmHg
Orthostatic hypotension requires that conditions (1) and [(2a) or (2b)] are met.
For subjects who are unable to stand and have the vital signs measured in a sitting or supine 
position instead of the standing position, the difference between standing and supine value 
will remain missing. 
Frequency table of the occurrence of orthostatic hypotension at each scheduled time point 
and endpoint and at any time during the double-blind treatment phase will be presented by 
treatment group. Listings will be provided for subjects who have orthostatic hypertension.  
Physical examination abnormalities and neurological examination results will be listed.
8.5.
Electrocardiogram
A triplicate 12-lead ECG will be obtained at Day 1, 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). 
The corrected QTcF and QTcB intervals will be calculated according to the following 
formula:

Fridericia: QTcF (msec) = QT(msec) * (HR(bpm)/60)1/3

Bazett: QTcB (msec) = QT(msec) * (HR(bpm)/60)1/2
Summary tables for actual values and changes from baseline will be presented by treatment 
group at each scheduled time point and at endpoint. Mean of triplicate ECG values obtained 
on Day 1 (pre-dose) will be used as a baseline value. 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 are flagged with abnormal values will be summarized by 
treatment group.  The values will be listed for all the subjects with abnormal flags if the ECG 
values are out of normal range.  The following abnormality ranges will be used for ECG 
parameters (Table 9):
Table 9: ECG Abnormality Ranges
Low
Normal
High
HR (bpm)
<45
45-90
> 90
PR Interval (msec)
<120
120-220
>220


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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 10. Abnormal values and changes will be summarized using frequency distribution 
tables over time by treatment group. A listing of subjects meeting any of the criteria will be 
provided.
Table 10: 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
8.6.
Other Safety Parameters
8.6.1.
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


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7: Aborted attempt
8: Interrupted attempt
9: Non-fatal suicide attempt
10: Completed suicide
A frequency distribution at each scheduled time point and endpoint will be provided by 
treatment group. A listing will be provided of C-SSRS items throughout the study for 
subjects with suicidal ideation or behavior at any time point.


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ATTACHMENT: LIEBOWITZ SOCIAL ANXIETY SCALE (LSAS)