Clinical trial NCT03227224
Conditions: Depressive Disorder, Major
Sponsor: Janssen Research & Development, LLC
Start date: 2017-08-16; Completion date: 2019-01-19
Enrollment: 287 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the dose-response relationship of 2 doses of JNJ-42847922 before interim analysis, and potentially 3 doses based on interim analysis results, compared to placebo as adjunctive therapy to an antidepressant drug in improving depressive symptoms in participants with Major Depressive Disorder (MDD) who have had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI); and to assess the safety and tolerability of JNJ-42847922 compared to placebo as adjunctive therapy to an antidepressant in participants with MDD.

Detailed description:
The study will investigate the antidepressant effects of a range of doses of JNJ-42847922 (seltorexant) (versus placebo), as adjunctive treatment to antidepressant drugs for treatment of MDD, and will assess the safety and tolerability of JNJ-42847922. The study will be conducted in 3 phases: a screening phase (up to 4 weeks), a double-blind treatment phase (6 weeks), and a post-treatment follow-up phase (2 weeks). Efficacy, safety, pharmacokinetic, and biomarker evaluations will be performed in the study at defined timepoints. The duration of the study will be up to approximately 12 weeks (84 days).

Arms: arm 1: Participants will receive 2 placebo capsules matching JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6). arm 2: Participants will receive 2 capsules of JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).
Interventions: intervention 1: Placebo intervention 2: JNJ-42847922
Intervention descriptions: intervention 1: Participants will receive 2 placebo capsules matching JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6). intervention 2: Participants will receive 2 capsules of JNJ-42847922 once daily orally from Day 1 to Day 41 (Week 6).

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 24 April 2018
Janssen Research & Development *
Clinical Protocol
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Adaptive 
Dose-Finding Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive 
Therapy to Antidepressants in Adult Subjects With Major Depressive Disorder Who Have 
Responded Inadequately to Antidepressant Therapy
Protocol 42847922MDD2001; Phase 2b
AMENDMENT 5
JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
*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 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 compound is being investigated in Phase 2 clinical studies. 
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2015-005282-22
Status:
Approved
Date:
24 April 2018
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-112972252, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03227224


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 26
TIME AND EVENTS SCHEDULE .............................................................................................................. 34
ABBREVIATIONS ...................................................................................................................................... 38
DEFINITIONS OF TERMS.......................................................................................................................... 39
1.
INTRODUCTION................................................................................................................................ 40
1.1.
Background .................................................................................................................................... 42
1.1.1.
Nonclinical Studies ..................................................................................................................... 42
1.1.2.
Clinical Studies ........................................................................................................................... 44
1.2.
Overall Rationale for the Study...................................................................................................... 50
1.3.
Overall Risk and Benefit Assessment............................................................................................ 51
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 52
2.1.
Objectives and Endpoints .............................................................................................................. 52
2.2.
Hypothesis ..................................................................................................................................... 55
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 55
3.1.
Overview of Study Design.............................................................................................................. 55
3.2.
Study Design Rationale.................................................................................................................. 58
4.
SUBJECT POPULATION.................................................................................................................. 64
4.1.
Inclusion Criteria ............................................................................................................................ 65
4.2.
Exclusion Criteria ........................................................................................................................... 67
4.3.
Prohibitions and Restrictions ......................................................................................................... 71
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 73
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 74
7.
TREATMENT COMPLIANCE............................................................................................................ 75
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 76
9.
STUDY EVALUATIONS .................................................................................................................... 77
9.1.
Study Procedures........................................................................................................................... 77
9.1.1.
Overview..................................................................................................................................... 77
9.1.2.
Screening Phase ........................................................................................................................ 78
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 80
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 81
9.2.
Efficacy Evaluations....................................................................................................................... 81
9.2.1.
Montgomery-Asberg Depression Rating Scale (MADRS).......................................................... 81
9.2.2.
Sheehan Disability Scale (SDS) ................................................................................................. 82
9.2.3.
Hamilton Anxiety Rating Scale (HAM-A) .................................................................................... 82
9.2.4.
Patient Reported Outcomes Measurement Information System-Sleep Disturbance 
(PROMIS-SD) and Fatigue (PROMIS-Fatigue) Short Form....................................................... 82
9.2.5.
Clinical Global Impression of Severity (CGI-S) .......................................................................... 83


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Status: Approved, Date: 24 April 2018
9.2.6.
Patient Global Impression of Severity (PGI-S) ........................................................................... 83
9.2.7.
Patient Health Questionnaire, 9-Item (PHQ-9)........................................................................... 83
9.2.8.
Snaith-Hamilton Pleasure Scale (SHAPS) ................................................................................. 83
9.2.9.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ-5D-5L) 
Questionnaire ............................................................................................................................. 83
9.2.10.
Work Limitations Questionnaire (WLQ) Short Form................................................................... 84
9.2.11.
Ruminative Response Scale (RRS) ........................................................................................... 84
9.3.
Pharmacokinetics........................................................................................................................... 84
9.3.1.
Evaluations ................................................................................................................................. 84
9.3.2.
Analytical Procedures................................................................................................................. 85
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 85
9.4.
Biomarkers Evaluations ................................................................................................................. 85
9.5.
Pharmacogenomic and Epigenetic (DNA) Evaluations ................................................................. 86
9.6.
Safety Evaluations ......................................................................................................................... 87
9.7.
Sample Collection and Handling.................................................................................................... 91
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 91
10.1.
Completion ..................................................................................................................................... 91
10.2.
Withdrawal From the Study............................................................................................................ 91
10.3.
Withdrawal From the Use of Research Samples........................................................................... 92
11.
STATISTICAL METHODS................................................................................................................. 93
11.1.
Subject Information ........................................................................................................................ 93
11.2.
Sample Size Determination ........................................................................................................... 93
11.3.
Efficacy Analyses ........................................................................................................................... 94
11.4.
Pharmacokinetic Analyses............................................................................................................. 95
11.5.
Biomarker Analysis ........................................................................................................................ 96
11.6.
Pharmacogenomic Analyses ......................................................................................................... 96
11.7.
Safety Analyses ............................................................................................................................. 97
11.8.
Interim Analysis.............................................................................................................................. 98
12.
ADVERSE EVENT REPORTING ...................................................................................................... 99
12.1.
Definitions ...................................................................................................................................... 99
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 99
12.1.2.
Attribution Definitions................................................................................................................ 100
12.1.3.
Severity Criteria ........................................................................................................................ 101
12.2.
Special Reporting Situations........................................................................................................ 101
12.3.
Procedures................................................................................................................................... 101
12.3.1.
All  Adverse Events................................................................................................................... 101
12.3.2.
Serious Adverse Events ........................................................................................................... 103
12.3.3.
Pregnancy................................................................................................................................. 103
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 104
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 104
13.1.
Procedures................................................................................................................................... 104
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 104
14.
STUDY DRUG INFORMATION....................................................................................................... 105
14.1.
Physical Description of Study Drug(s) ......................................................................................... 105
14.2.
Packaging .................................................................................................................................... 105
14.3.
Labeling........................................................................................................................................ 105
14.4.
Preparation, Handling, and Storage............................................................................................. 105
14.5.
Drug Accountability ...................................................................................................................... 105
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 106
16.
ETHICAL ASPECTS ....................................................................................................................... 106
16.1.
Study-Specific Design Considerations......................................................................................... 106


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
16.2.
Regulatory Ethics Compliance..................................................................................................... 108
16.2.1.
Investigator Responsibilities ..................................................................................................... 108
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 108
16.2.3.
Informed Consent ..................................................................................................................... 110
16.2.4.
Privacy of Personal Data .......................................................................................................... 111
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 111
16.2.6.
Country Selection ..................................................................................................................... 112
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 112
17.1.
Protocol Amendments.................................................................................................................. 112
17.2.
Regulatory Documentation .......................................................................................................... 112
17.2.1.
Regulatory Approval/Notification .............................................................................................. 112
17.2.2.
Required Prestudy Documentation........................................................................................... 112
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 113
17.4.
Source Documentation................................................................................................................. 114
17.5.
Case Report Form Completion .................................................................................................... 115
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 115
17.7.
Record Retention ......................................................................................................................... 116
17.8.
Monitoring .................................................................................................................................... 116
17.9.
Study Completion/Termination..................................................................................................... 117
17.9.1.
Study Completion/End of Study................................................................................................ 117
17.9.2.
Study Termination..................................................................................................................... 117
17.10.
On-Site Audits .............................................................................................................................. 117
17.11.
Use of Information and Publication.............................................................................................. 118
REFERENCES.......................................................................................................................................... 120
INVESTIGATOR AGREEMENT ............................................................................................................... 126


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
LIST OF ATTACHMENTS
Attachment 1:
Examples of Concomitant Drugs to be Avoided (Moderate or Strong 
Inhibitor/Inducer of CYP3A4 or CYP2C9 or Dual Inhibitor/Inducer of CYP3A4 
and CYP2C9) ........................................................................................................... 124
Attachment 2:
Anticipated Events.................................................................................................... 125
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
List of Completed Studies......................................................................................................... 45
Table 2:
Dose Description....................................................................................................................... 74
Table 3:
Description of Interventions ...................................................................................................... 75
FIGURES
Figure 1:
Schematic Overview of the Study Design................................................................................. 56


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
20 January 2016
Amendment 1
19 July 2016
Amendment 2
12 October 2016
Amendment 3
27 February 2017
Amendment 4
21 July 2017
Amendment 5
24 April 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 5 (24 April 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To add results of the male and female rat fertility studies. To exclude 
further enrollment of women of childbearing potential (WOCBP). In addition, other minor changes and 
clarifications related to study procedures were made. 
Applicable Section(s)
Description of Change(s)
Rationale: To update nonclinical data. 
Section 1.1.1. Nonclinical 
Studies (Toxicology); 
Section 16.1. Study-Specific 
Design Consideration

Updated nonclinical text to include findings from a 6-month toxicity study 
in rats and 9-month toxicology study in dogs.

Added results from the male and female rat fertility studies and relevant 
information from the literature.
References (68-74)

New literature references added.
Rationale: The female rat fertility study suggested that JNJ-42847922 reduced female fertility rates at all doses 
studied. Since it is not known what the relevance of these findings are to a woman’s ability to become pregnant 
after taking JNJ-42847922, no new WOCBP will be included in this study until more is learned about the effect 
of JNJ-42847922 on female reproduction. WOCBP who are currently enrolled in the study may continue study 
participation following discussion between the subject and the investigator of the new rat fertility study results, if 
they have a negative pregnancy test, and are using reliable contraception (as specified further in the protocol).
Synopsis (Subject Population); 
Section 3.2. Study Design 
Rationale; 
Section 4.1. Inclusion Criteria;
Section 16.1. Study-Specific 
Design Considerations

Inclusion Criterion #1: Revised text to indicate that the study population 
will include men and women “of non-childbearing potential 
(WONCBP)”. Added a definition of WONCBP.
Clarified in other relevant sections that the study population will include men 
and women “of non-childbearing potential (WONCBP)”.
Section 1.3. Overall Risk and 
Benefit Assessment; 
Section 3.2. Study Design 
Rationale; 
Section 16.1. Study-Specific 
Design Considerations
Added additional text to explain that WOCBP will be excluded based on the 
results of the female rat fertility study, and that “WOCBP who are currently 
enrolled in this study may continue study participation following discussion 
between the subject and the investigator of the new rat fertility study results, if 
they have a negative pregnancy test, and are using reliable contraception”
Deleted following sentence: “It is expected that this population will be 
representative for the targeted subject population for future clinical trials.” 
Updated the following sentence (addition shown in “italics”): “The “age of 
the” study population in this protocol is intentionally broad.”


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
Section 4.2. Exclusion Criteria

Exclusion Criterion #30: Made the following revisions:
Is pregnant, or breastfeeding, or planning to become pregnant while 
enrolled in this study or within 3 “1” months after the last dose of 
study drug.
Section 4.1. Inclusion Criteria

Inclusion Criteria #10 and #11 have been deleted (these criteria are no 
longer required now that the female population is restricted to WONCBP. 
The relevant information on WONCBP from Inclusion Criterion #11 was 
moved to Inclusion Criterion #1; the relevant information on 
contraceptive requirements for WOCBP from Inclusion Criterion #11 was 
moved to Section 4.3 [Criterion #2]).
Section 4.3 Prohibitions and 
Restrictions

Criterion #2: Added information regarding contraceptive requirements for 
WOCBP who continue in the study.
Synopsis (Safety Evaluations); 
Time and Events Schedule; 
Section 3.2. Study Design 
Rationale (Safety Evaluations); 
Section 9.1.1. Overview;
Section 9.1.2. Screening; 
Section 9.6. Safety Evaluations
(Clinical Laboratory Tests)
The scheduled serum and urine pregnancy tests were removed from the Time 
and Events schedule and footnote ‘t’ was updated as follows: 
t. 
Women of childbearing potential only. Additional sSerum or urine 
pregnancy tests may be performed “in WONCBP”, as determined 
necessary by the investigator or required by local regulation, to 
establish the absence of pregnancy at any time during the subject’s 
participation in the study. “A FSH test may also be performed at 
investigator judgment to assist in determining if a woman is of non-
childbearing potential. For WOCBP enrolled in the study before 
Amendment 5 and who continue in the trial, a serum pregnancy test 
must be performed at screening, and urine pregnancy tests must be 
performed at Day 1, Day 22, Day 42 (End-of Treatment/Early 
Withdrawal], and at the Follow-up Visit.”

Wording on pregnancy testing throughout the protocol was updated to 
clarify that pregnancy tests can be performed in WONCBP if determined 
necessary by the investigator, and to clarify that pregnancy tests are still 
required for WOCBP who continue in the study.
Rationale: The maximum age of the study population was increased from 64 years to 70 years to increase the 
patient population to help with recruitment and to learn about JNJ-42847922 in the elderly with MDD
Synopsis (Subject Population); 
Section 3.2. Study Design 
Rationale; 
Section 4.1. Inclusion Criteria 
(Criterion #1)

Changed the maximum age of the study population from 64 years to 
70 years, inclusive.
Rationale:  To make the evening dosing window less restrictive because no significant food effect has been 
observed up to now and to add further instructions on dosing. 
Synopsis (Overview of Study 
Design; Dosage and 
Administration; Description of 
Interventions); 
Time and Events Schedule 
(footnotes b & k); 
Section 3.1. Overview of Study 
Design; 
Section 6. Dosage and 
Administration; Table 3; 
Section 9.1.3. Double-blind 
Treatment Phase
Changed the dosing time from “at least” 3 hours after the last meal to 
“approximately” 3 hours after the last meal.
Added the following text in Section 6: “Subjects will administer the assigned 
study drug once daily at bedtime, approximately 3 hours after the last meal, 
from Day 1 to Day 41. Subjects are required to record the administration of 
study drug or any missed doses in subject diaries, which will be checked at 
each scheduled visit.”


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
8
Status: Approved, Date: 24 April 2018
Rationale: Adjustments were made to inclusion/exclusion criteria for clarity and to make less restrictive to assist 
with recruitment
Synopsis (Study Population); 
Section 3.1. Overview of Study 
Design; 
Section 4.1. Inclusion Criteria;
Section 9.1.2. Screening

Inclusion Criterion #2: Changed the required length of the current 
depressive episode from “≤1 year” to “≤18 months”. The corresponding 
change was made in Section 9.1.2., Screening. 

Inclusion Criterion #3: The text was updated as shown below: 
“Have had an inadequate response to at least 1 but no more than 2 “3”
antidepressants (see the inclusion criterion below), administered at an 
adequate dose and duration in the current episode of depression, as 
assessed by the MGH-ATRQ. An inadequate response is defined as <50% 
reduction in depressive symptom severity, as assessed by the 
MGH-ATRQ. An adequate trial is defined as an antidepressant treatment 
for at least 4 weeks at at least “or above” the minimum therapeutic dose, 
as specified in the MGH-ATRQ, for any particular antidepressant. The 
inadequate response must include the subject’s current antidepressant 
treatment.”
The corresponding change was also made in other relevant sections.

Inclusion Criterion #4: Clarified that current antidepressant treatment 
should be at “a stable dose (at or above the minimum therapeutic dose 
level)” for at least 4 weeks, and for no greater than 6 “12” months, at 
screening. 

Inclusion Criterion #12: Changed restriction on egg donation from 
3 months to “1 month” after receiving the last dose of study drug.

Inclusion Criterion #13: The text was updated as shown below:
“During the study and for a minimum of 1 spermatogenesis cycle 
(defined as approximately 3 months) after receiving the last dose of study 
drug, in addition to the highly effective method of contraception, a man”
Section 4.2. Exclusion Criteria

Exclusion Criterion #1: Added “(including narcolepsy)” after neurologic. 
Changed the HbA1c threshold for well-controlled diabetes mellitus from a 
HbA1c of “≤7%” to HbA1c of “≤7.5%” at screening.

Exclusion Criterion #5: Added the following text to define the criteria for 
lack of response: “as indicated by no or minimal (≤25% improvement in 
symptoms) when treated with an antidepressant of adequate dose (per 
MGH-ATRQ) and duration (at least 4 weeks).”   
Rationale: To clarify that concomitant therapies do not need to be recorded for subjects who fail screening unless 
there is an adverse event, and that modification of an effective preexisting therapy should not be made for the 
explicit purpose of entering a subject into the study. To add additional medications to the list of prohibited 
medications and timing of their discontinuation to add additional clarity for investigators. 
Section 8. Prestudy and 
Concomitant Therapy

Added the following text: “For subjects who fail screening, concomitant 
therapies do not need to be recorded unless there is an adverse event.”

Added: “Prior to study entry, modification of an effective preexisting 
therapy should not be made for the explicit purpose of entering a subject 
into the study.”

Added “tricyclic antidepressants” and “bupropion” to the list of 
prohibited medications.

Added: “When discontinuing a prohibited medication, the investigators 
should consider the time needed to sufficiently eliminate a drug from body 
system, eg, 5 half-lives of the drug.”


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
Rationale: Minor changes/clarifications were made to the timing and conduct of study procedures to allow 
flexibility to investigators and clarify timing of protocol procedures.
Time and Events Schedule 
(footnote r); 
Section 9.1.1. Overview; 
Section 9.6. Safety Evaluations 
(Electrocardiogram)
The wording pertaining to the order of study assessments was revised to 
indicate that the proposed order is a recommendation, not a requirement. 
Time and Events Schedule 
(footnotes h)
Revised footnote to allow for possible collection of nonfasted laboratory 
assessments at screening.
Time and Events Schedule 
(footnotes b&c); 
Section 9.3.1. Evaluations
Deleted the following sentence: The exact time of the last meal intake prior to 
dosing before PK sampling will also be recorded.
Section 9.6. Safety Evaluations 
(Vital signs)
Deleted the text stating that vital signs should be measured in non-fasting 
conditions whenever possible.
Added the following text: “In the places where oral or tympanic temperature 
are not standard practice, axillary temperature can be used. The same 
temperature measure should be used throughout the study.”
Section 9.6. Safety Evaluations 
(Clinical Laboratory Tests)
Made a correction to the following sentence: 

The following tests will be performed by the central laboratory “during 
the study”
Rationale: To clarify that only those subjects with acute suicidal ideation and with a clear plan should be 
discontinued from study treatment.
Section 10.2. Withdrawal from 
the Study
The following sentence was updated as shown below (new text indicated in 
“italics”):

The subject shows signals of acute suicidal ideation “with a clear plan”
at any time during the study; the subject should be referred to appropriate 
medical/psychiatric care.
Rationale: Wording regarding the reporting process for adverse events of special interest was updated.
Section 9.6. Safety Evaluations 
(Adverse events of Special 
Interest)
The following sentence was updated as shown below:

When reported, the investigator will be required to complete a detailed 
summary of the event and its clinical course utilizing the CRF page “AE 
of special interest narrative form” as soon as information on the outcome 
(recovered, resolving, or ongoing) is available. “In addition, the AE 
should be marked as an AE of special interest in the CRF.”  
Rationale: Wording regarding the transmission of serious adverse events to the sponsor was updated to remove 
reference to the Safety Report Form, as it is not relevant for this study.
Section 12.3.2. Serious Adverse 
Events
The following sentence was updated as shown below:

Information regarding serious adverse events will be transmitted to the 
sponsor using the Serious Adverse Event Form and Safety Report Form, 
which must be completed and reviewed “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” 
transmitted electronically or by facsimile (fax).
Rationale: To add the generic name for JNJ-42847922 (ie, seltorexant)
Title page; Running header; 
Synopsis; Section 1. 
Introduction

Added the generic name for JNJ-42847922, ie seltorexant, in several 
locations in addition to the previous descriptor of selective orexin-2 
receptor antagonist.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
Amendment 4 (21 July 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The key reasons for this amendment are to report preclinical safety data 
from a 9-month study in dogs, to add instructions to investigators to ensure awareness of preclinical data
regarding seizures/convulsions, to increase the sample size of this study, and to prohibit use of ketamine or 
esketamine for depression prior to or during the study.
Applicable Section(s)
Description of Change(s)
Rationale: Report preclinical safety data from a 9-month study in dogs and additional information from an 
earlier dog toleration study. Add exposure margins from the 3-month toxicology studies in rats and dogs.
Section 1.1.1 Nonclinical 
Studies, Section 3.2 Study 
Design Rationale, Section 9.1.2 
Screening Phase, Section 16.1 
Study-Specific Design 
Considerations

Addition of exposure margins from the 3-month toxicology studies in rats 
and dogs.

Addition of results from a 9-month toxicology study and earlier toleration 
study in dogs.
Rationale: Added instructions to investigators to ensure awareness of preclinical data regarding 
seizures/convulsions and the evaluation of related adverse events.
Section 9.1.2. Screening Phase

Added guidance for evaluation of subjects for seizures/convulsions 
during screening and treatment.
Section 9.6. Safety Evaluation

Added text regarding investigator monitoring and documentation of
CNS-related adverse event including tremor, ataxia, abnormal sensation, 
confusion, or possibility of seizure.
Rationale: Increased the planned sample size by 24 subjects to ensure higher confidence in evaluating each dose, 
especially in the case if JNJ-42847922 10 mg is added after the interim analysis.
Synopsis; Section 3.1. Overview 
of Study Design; Section 11.2. 
Sample Size Determination; 
Figure 1

The sample size was updated to increase the planned number of subjects 
randomized from 256 to approximately 280.

Due to the sample size increase, the data cutoff for the unblinded interim 
analysis corresponds to approximately 57% of the sample size of the 
study.
Rationale: Widened the time for the collection of PK sampling on Day 8
Time and Event Schedule 
footnote c; Section 9.3.1 
Evaluations

A single PK sample will be collected in the early morning on Day 8 
between 6 and 12 hours after dosing at night on Day 7.
Rationale: Prohibiting use of ketamine or esketamine for depression
Section 8 Prestudy and 
Concomitant Therapy

Subject use of ketamine or esketamine for depression is prohibited prior 
to screening and during the study
Rationale: Minor editorial changes were made throughout the protocol for clarity and/or consistency.
Throughout the protocol

Minor editorial, grammatical, formatting, or spelling changes were 
made.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
11
Status: Approved, Date: 24 April 2018
Amendment 3 (27 February 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: The key reasons for this amendment are to simplify the dose-finding 
strategy and reduce the sample size by: 1) removing Stage 2 from the original study design; 2) removing the 
active comparator (quetiapine) arm from the study; 3) reducing the number of JNJ-42847922 treatment arms.
Applicable Section(s)
Description of Change(s)
Rationale: The study was previously designed as a two-stage study with an active comparator arm (quetiapine) in 
Stage 2. To simplify the dose-finding strategy, Stage 2 and the active comparator arm have been removed. 
Study Title

The study title has been updated to reflect changes in study design; ie, 
references to ‘Two-Stage’ and ‘Active-Controlled’ have been removed.
Synopsis; Time and Events 
Schedule; Sections 1.2 (now 
deleted), Sections 2.1, 3.1, 3.2, 
5, 6, 9.1.1, 9.1.3, 9.3.1, 11.1, 
11.2, 11.3, 11.8, 12.1.1, 14.1, 
15, 16.1

References to ‘two-stage’, ‘Stage 1’, or ‘Stage 2’ have been removed.

References to the active comparator (quetiapine) have been removed. 
Section 4.2. Exclusion Criteria
The following exclusion criteria were removed as they are specific to quetiapine
use: 

Criterion #19: Has a history of previous nonresponse to an adequate trial of 
quetiapine as an adjunctive treatment for MDD (defined as ≥ 150 mg for 
6 weeks or more).

Criterion #21: Has a history of epilepsy, neuroleptic malignant syndrome 
(NMS) or Tardive Dyskinesia.
In addition, Criterion #23 was modified to remove mention of quetiapine.
Rationale: The JNJ-42847922 dose levels to be evaluated in this study have been revised (previous doses were 10, 
20, or 40 mg in Stage 1 with the option to add a 2.5 mg dose in Stage 2; the revised doses are starting doses of 20 or 
40 mg with the option to add a 10 mg dose after the interim analysis). Further review of clinical data from Phase 1 
studies suggests that the 20 mg dose is well tolerated and will likely be an effective dose. It is considered unlikely 
that doses lower than 10 mg will be effective and as such, the 2.5 mg dose has been removed.
Synopsis; Sections 2.1, 3.1, 3.2,
5, 6, 9.1.3, 11.2, 14.1

JNJ-42847922 dose levels were updated and references to the 2.5 mg dose 
level were removed.
Rationale: Updates were made to the sample size calculation and interim analysis based on changes in study design. 
A larger effect size was assumed (based on Phase 1b study results), resulting in a smaller number of subjects 
required.
Synopsis; Section 3.1.
Overview of Study Design; 
Section 3.2. Study Design 
Rationale; Section 11.2. Sample 
Size Determination; 
Section 11.8 Interim Analysis

The sample size calculation was updated, resulting in a decrease in the 
planned number of subjects (from 565 to 256).

The interim analysis will now be performed 6 weeks after 160 subjects have 
been randomized (previously after 175 subjects completed 6 weeks of 
treatment). 

The formal statistical criterion for declaring futility has been removed.

The statement regarding sample size re-estimation (SSR) has been removed, 
as SSR will no longer be performed at the interim analysis.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
12
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: A new section was added to the protocol (Section 1.3. Overall Risk and Benefit Assessment), in line 
with a new sponsor initiative to incorporate a discussion of benefit-risk within each protocol.
Section 1.3. Overall Risk and 
Benefit Assessment

New section added.
Rationale: Additional text was added regarding the rationale for the stratification of subjects by baseline insomnia 
severity index (ISI) and to ensure randomization of an approximately equal proportion of subjects with an ISI score 
<15 (subclinical or no clinically significant insomnia) and ≥15 (moderate to severe insomnia). 
Section 3.2. Study Design 
Rationale; References

An additional statement and 2 supporting references (Kenter [2016] and 
Mason [2014]) were added to provide further rationale regarding 
stratification of subjects by baseline ISI score. 
Section 5. Treatment Allocation 
and Blinding

The following sentence was added: “In order to randomize approximately 
equal proportions of subjects with and without significant insomnia 
symptoms at baseline, the number randomized in either stratum will be 
capped at 60% of the planned total sample size.”
Rationale: The Antidepressant Side Effect Checklist (ASEC) was removed from the study assessments, as at the 
time of enrollment subjects will have been on the same antidepressant for at least 4 weeks and will continue to take 
the same antidepressant at same dose during the entire study. Since adverse events will be monitored during the 
study and the safety profiles of SSRI/SNRIs have been well established, it is not considered necessary to measure 
adverse events specifically associated with underlying antidepressants.
Synopsis; Time and Events 
Schedule; Sections 2.1, 3.1, 3.2, 
9.1.2, 9.6, 11.7, and 17.4; 
References

References to ASEC were removed.
Rationale: The protocol previously defined an adequate trial of prior antidepressant treatment to be “an 
antidepressant treatment for at least 6 weeks at the minimum dose”. However, in clinical practice an adequate trial 
of an SSRI/SNRI can be assessed as early as 4 weeks after start of treatment. Therefore, an adequate trial of prior 
antidepressant treatment was revised to 4 weeks to align with standard of care clinical practice. Additional changes 
were made to clarify that the minimum dose should be at least the minimum therapeutic dose.
Section 4.1. Inclusion Criteria

Criterion #3 was updated as described in the rationale above.

Criterion #4 was updated to indicate that subjects should be receiving 
monotherapy treatment with one of the stated antidepressants for at least 
4 weeks (previously stated as 6 weeks).
Section 9.1.2. Screening Phase

Changes made to reflect revisions to the Inclusion Criteria described above.
Rationale: Updates were made to Exclusion Criterion #1 based on a request from the United States Food and Drug 
Administration to clarify the definition of “significant” renal or liver insufficiency. Additional updates were made to 
this criterion to further define exclusion criteria for subjects with other comorbidities.
Section 4.2. Exclusion Criteria
Criterion #1:

Further text added to define renal and liver insufficiency based on creatinine 
clearance and Child-Pugh classification, respectively.

Further text added to exclude subjects with significant or unstable 
immunologic disorders. 

Further text added to clarify that subjects with uncontrolled hypo- or 
hyperthyroidism or diabetes, or insulin-dependent diabetes mellitus will be 
excluded.

Further text added to define inclusion of subjects with “well-controlled” 
non-insulin dependent diabetes mellitus. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
13
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: Based on the results of recent PK simulations, a clinically meaningful interaction between 
JNJ-42847922 and the SSRI fluvoxamine (a moderate CYP2C9 inhibitor and mild CYP3A4 inhibitor) is considered 
unlikely. The protocol was therefore updated to allow subjects on fluvoxamine to participate in the study.
Section 4.1. Inclusion Criteria

Fluvoxamine was added to the list of SSRIs/SNRIs that may be used during 
the study.
Time and Events Schedule;
Section 9.1.2. Screening Phase

Fluvoxamine was added to the list of SSRIs/SNRIs that will be assayed by 
the central laboratory.
Section 4.2. Exclusion Criteria; 
Section 8. Prestudy and 
Concomitant Medications

Restrictions related to use of fluvoxamine were removed.
Attachment 1 (previously 
Attachment 2)

Fluvoxamine was removed from the list of concomitant drugs to be avoided.
Rationale: Subjects are scheduled to stay overnight at the study site on Day 1 for collection of pharmacokinetic 
(PK) and cortisol samples. However, in some circumstances, subjects may not be able to stay overnight at the study 
site on Day 1 for sample collection. Since the collection of PK and cortisol samples does not relate to the primary 
assessments of safety and efficacy, the protocol wording was revised to allow for exceptions to the overnight stay 
and the collection of samples (PK and cortisol). Such exceptions may only be made after discussion with the 
sponsor’s medical monitor. The reason for the exception must be documented in the subject’s source documents.  
Synopsis; Time and Events 
Schedule; Section 3.1. 
Overview of Study Design; 
Section 6. Dosage and 
Administration; Section 7. 
Treatment Compliance; Section 
9.1.3. Double-Blind Treatment 
Phase; Section 9.4. Biomarkers
Evaluations

Additional text added per rationale described above.

Additional text added to clarify that subjects who do not stay overnight will 
take their Day 1 dose at home.
Section 4.1. Inclusion Criteria

Criterion #9 was modified to remove reference to “peripheral biomarkers 
research (ie, blood, saliva)”, since salivary cortisol collection is no longer a 
required procedure for the study.
Rationale: Exclusion of immunodeficient subjects or subjects with hepatitis B or hepatitis C is considered to be 
adequately covered by Exclusion Criterion #1. Therefore, the exclusion criterion specific to subjects with HIV, 
hepatitis C and hepatitis B (Criterion #15) was deleted, and the serology sample that was previously planned for 
screening of these patients was removed.
Section 4.2. Exclusion Criteria

The following criterion (Criterion #15) was deleted: “Is known to be 
infected with human immunodeficiency virus (HIV), hepatitis B, or hepatitis 
C, or has positive results at screening.”
Synopsis; Time and Events 
Schedule; Section 9.1.2. 
Screening Phase; Section 9.6. 
Safety Evaluations

Removed the serology assessment at screening.
Rationale: In order to allow a broader group of the general MDD population to enroll, a small increase was 
implemented for the upper limit of body mass index (BMI) within Inclusion Criterion #6. 
Section 4.1. Inclusion Criteria

Criterion #6 was updated to encompass a BMI range of between 18 and 
35 kg/m2 inclusive (previously was 18 to 34 kg/m2 inclusive). 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
14
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: Other changes were made to the inclusion and exclusion criteria based on clinical review (see details 
below)
Section 4.1. Inclusion Criteria

Criterion #5 was modified to indicate that subjects must not demonstrate a 
clinically significant “improvement” (previously stated as “change”) from 
the screening to baseline visit. In addition, the following text was deleted for 
clarity: “ie, subjects must have a MADRS total score of at least 20 at the 
baseline visit”.

Criterion #8 was modified to delete the following text: “If there are 
abnormalities, they must be consistent with the underlying illness in the 
study population.”

Criterion #11 was modified to indicate that subjects must agree to remain on 
a highly effective method of birth control throughout the study and for at 
least 1 month after the last dose of study drug (previously 3 months after the 
last dose of study drug).
Section 4.2. Exclusion Criteria

Criterion #5 previously excluded subjects with a “history of treatment 
resistance to antidepressant medication (≥3 lifetime treatment failures)”. The 
wording has been revised to exclude those subjects with a “history of lack of 
response to 3 or more adequate antidepressant treatments.”

Criterion #9 was modified to add “autism spectrum disorder” as one of the 
diagnoses that will be exclusionary.

Criterion #11 updated to indicate that only those subjects with hypersomnia 
“that is not related to insomnia disorder” will be excluded.

Criterion #17 updated for further clarity regarding exclusion of subjects with 
ECG abnormalities.

Criterion #20 was modified to indicate that subjects with prior transcranial 
magnetic stimulation should be excluded.
Rationale: The requirement for subjects to refrain from strenuous exercise during the study was revised, as this 
criterion would be difficult to define and standardize, and there is currently no evidence to suggest that strenuous 
exercise would impact study assessments listed in the protocol.
Section 4.3. Prohibitions and 
Restrictions

Criterion #5 was revised to indicate that “Subjects are advised not to change 
the frequency or level of exercise during the study.”
Rationale: The protocol previously stated that subjects were allowed to have a low-fat meal prior to blood 
biomarker sampling; however, since biomarker samples are taken on the same day as clinical laboratory samples 
(which should be taken under fasted conditions) it was decided that subjects should be fasted on Day 1, 8, 22 and 
42 visits. Therefore, details regarding the low-fat diet/meals in relation to biomarker assessments were removed. 
Time and Events Schedule; 
Section 9.1.3. Double-Blind 
Treatment Phase; Section 9.4. 
Biomarkers Evaluations; 
Attachment 1 (now deleted)

Text regarding low-fat diet/meal was removed

Text added to indicate that subjects should attend visits under fasted 
conditions.

The attachment that provided examples of low-fat meals (previously 
Attachment 1) was removed and subsequent attachment numbers were 
updated.
Rationale: Revisions were made to Section 8, Prestudy and Concomitant Therapy, based on further clinical review 
and to improve readability and consistency.
Section 8. Prestudy and 
Concomitant Therapy

Medications were summarized according to pharmaceutical class.

Restrictions regarding use of certain medications (eg, benzodiazepines, 
hypnotics, sedating antidepressants, melatonin) were revised.

The restriction regarding consumption of quinine, grapefruit, Seville 
oranges, and poppy seed was removed. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
15
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Attachment 1 (previously 
Attachment 2)

Grapefruit and grapefruit juice were removed from the list of concomitant 
drugs to be avoided.
Rationale: For consistency with other sections of the protocol, the text in Section 9.5 was updated to clarify that 
samples for pharmacogenomic research will be collected where local regulations permit, and that subject 
participation in pharmacogenomic research is optional. 
Section 9.5. Pharmacogenomic 
and Epigenetic (DNA) 
Evaluations

The following text added to the start of the first paragraph: 
“A pharmacogenomic blood sample will be collected to allow for 
pharmacogenomic research where local regulations permit.”

The following text was added to the start of the second paragraph: 
“Subject participation in the pharmacogenomic research is optional.”
Rationale: Further guidance was added regarding the methodology for collection of body weight and waist 
circumference measurements, in order to standardize these assessments.
Section 9.6. Safety Evaluations

Physical Examination subsection was updated with additional information 
regarding collection of body weight and waist circumference.
Rationale: The protocol previously stated that subjects should take their baseline SSRI/SNRIs in the morning 
throughout the study. As not all subjects with MDD take their antidepressant medication in the morning, this was 
revised.
Synopsis; Section 3.1. 
Overview of Study Design;
Section 6. Dosage and 
Administration

The text was changed to indicate that baseline SSRIs/SNRIs should be taken 
“at approximately the same time as prior to entering the study”.
Rationale: Pharmacokinetic sections were revised to reflect updates related to the interim analysis and to indicate 
that some of the PK analyses stated in the protocol will only be performed if considered necessary. Full details of 
the PK analyses will be described in a separate analysis plan.
Synopsis; Section 3.2. Study 
Design Rationale; Section 
9.3.3. Pharmacokinetic 
Parameters; Section 11.4. 
Pharmacokinetic Analyses; 
Section 11.8. Interim Analysis

Removed the word “pooled” when referring to PK population analysis.

Text added to indicate that a snapshot date for PK samples may be defined 
prior to the interim analysis.

Revised text in Section 11.8, Interim Analysis, to indicate that exposure 
analyses will be performed based on data available at the time of the interim 
analysis (not, as previously stated, “on an ongoing basis prior to the interim 
analysis”).
Rationale: The list of anticipated events in Attachment 2 (previously Attachment 3) was updated to remove events 
not considered specifically relevant to MDD.
Attachment 2. Anticipated 
Events
The following events were removed from the list of Anticipated Events: 

Activation or hypomania/mania 

Excessive happiness.
Rationale: There is no plan to include TruCulture collection in this study, so related text was deleted. 
Section 9.4. Biomarkers
Evaluations

Text regarding collection of samples for TruCulture was removed.
Rationale: Detailed information regarding blood sample volumes was removed, as this level of detail was not 
considered necessary for the protocol. Full details on blood volumes will be provided in the Laboratory Manual.
Section 9.1. Study Procedures

The table detailing blood volumes was removed and replaced with a simple 
statement that: “The total blood volume to be collected from each subject 
will be approximately 190 mL.”


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
16
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: Made corrections to the order of assessments (to bring in line with the Time and Events Schedule)
Section 9.1.1. Overview

Updated the order of assessments.
Rationale: It is not considered appropriate to hospitalize subjects for the duration of this study, so this option was 
removed from Section 12.3.2, Serious Adverse Events.
Section 12.3.2. Serious Adverse 
Events

The following text was removed: “For convenience the investigator may 
choose to hospitalize the subject for the duration of the treatment period.”
Rationale: To add clarification regarding the source documentation for the subject- and investigator-completed 
scales and the assessments completed by the central rater.
Section 17.4. Source 
Documentation

Text was added to indicate that investigator-completed scales will be 
completed on worksheets, and these worksheets will be considered as the 
source data.

Text was added to indicate that patient-reported outcomes (PROs) will be 
completed by the subject using the questionnaires provided, and the patient-
completed documents will be considered source documents. 

Details were added to note that MADRS (SIGMA version), CGI-S and SSQ 
will be completed electronically by the central rater.
Rationale: Minor changes made to the schedule of study assessments in the Time and Events Schedule based on 
clinical review.
Time and Events Schedule

An additional urine or blood sample for antidepressant compliance was 
added at Day 1 and Day 22.

An additional assessment of ISI was added at screening.

Physical examination was removed at follow-up visit.

C-SSRS was removed from Day 43 telephone contact.

Additional text added to footnote ‘k’ to clarify that subjects should record 
administration of study drug or any missed doses in subject diaries, which 
will be checked at each scheduled visit.
Rationale: Minor changes were made to the Background section (Section 1.1) for consistency with the current 
Investigator’s Brochure.
Section 1.1.1. Nonclinical 
Studies

Edits made to Nonclinical Pharmacokinetics Section to reflect most recent 
data in the Investigator’s Brochure.
Section 1.1.2. Clinical Studies

Added details regarding total number of subjects dosed in completed clinical 
studies.

The description of adverse events in the 42847922MDD1001 study was 
updated to describe TEAEs by treatment group.
Rationale: Other minor editorial changes were made throughout the protocol for clarity and/or consistency.
Throughout the protocol

Minor editorial, grammatical, formatting, or spelling changes were made.

References/citation numbers were updated.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
17
Status: Approved, Date: 24 April 2018
Amendment 2 (12 October 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 key reasons for this amendment are: 1) to clarify timing of evening 
dosing to occur at bedtime and at least 3 hours after the last meal; 2) to clarify that pharmacogenomic sampling is 
optional and to include a separate informed consent form (ICF) for pharmacogenomic sampling; 3) to update and/or 
clarify eligibility criteria; 4) to update and/or clarify the description of the placebo capsule; 5) to clarify that 
anticipated events will not be designated in Japan; and 6) to provide the latest clinical information regarding 
JNJ-42847922.
Applicable Section(s)
Description of Change(s)
Rationale: Currently, only limited pharmacokinetic (PK) exposure data are available after nighttime dosing under 
fed conditions. Additional studies are ongoing to evaluate the potential food effect on absorption. Pending results 
from these studies, a conservative measure for patient safety has been implemented in the current protocol to require 
bedtime dosing at least 3 hours after the last meal. 
Synopsis Dosage and 
Administration; 
Time and Events Schedule; 
3.1. Overview of Study Design;
6. Dosage and Administration;
9.1.3. Double-Blind Treatment 
Phase

Text added to indicate that study drug should be administered "at least 3 
hours after the last meal".
Rationale: To clarify participation in genetic research is optional and to include a separate ICF for this sampling, in 
order to account for differences in local regulations regarding genetic research.
Synopsis Pharmacogenomic 
and Epigenetic (DNA) 
Evaluations;
3.1. Overview of Study Design

Added clarification that blood samples for genetic research will be collected 
only from subjects who consent separately to this component of the study, 
and that subject participation in genetic research is optional.
Time and Events Schedule 

Added "ICF for optional genetic research samples" to the list of 
Screening/Administrative Procedures.
4.1. Inclusion Criteria

Text related to pharmacogenomics has been removed from Inclusion 
Criterion #9 and a new Inclusion Criterion has been added (#15) to indicate 
that subjects "must sign a separate informed consent form (or their legally-
acceptable representative must sign) if he or she agrees to provide optional 
DNA samples for research (where local regulations permit). Refusal to give 
consent for the optional DNA research samples does not exclude a subject 
from participation in the study."
9.1. Study Procedures

Footnote added to Table 4 to indicate that pharmacogenomics/epigenetic 
blood samples will be collected only from subjects who have consented to 
provide optional DNA samples for research.
9.3.1. Evaluations

Added clarification that genetic analyses will not be performed on PK plasma 
samples.
10.3. Withdrawal From the Use 
of Research Samples 

Instructions have been added regarding the handling of optional research 
samples following withdrawal of the subject from the study or withdrawal of 
consent from the use of research samples.

Text was also added to clarify that destruction of genetic samples may not be 
possible if the subject withdraws consent after the study is over.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
18
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
16.2.2. Independent Ethics 
Committee or Institutional 
Review Board

Instructions have been added regarding approval of optional research samples 
and corresponding ICF by the IEC/IRB.
16.2.3. Informed Consent

Added details regarding the ICF for optional genetic research.
Rationale: Updated Inclusion Criterion # 4 to be consistent with Inclusion Criterion # 3.
4.1. Inclusion Criteria

Updated the text of Inclusion Criterion # 4 to clarify the length of 
monotherapy treatment with SSRI/SNRI antidepressants for depressive 
symptoms is required to be "at least the minimum therapeutic dose for at 
least 6 weeks". 
Rationale: To define inclusion criteria more precisely and to avoid enrolling a treatment resistant population.
4.1. Inclusion Criteria

Updated the text of Inclusion Criterion # 2 to add "the length of the current 
depressive episode must be ≤1 year".
9.1.2. Screening Phase

Added "the length of the current depressive episode must be ≤1 year" to the 
screening requirements.
Rationale: To clarify the description of the placebo as a powder-filled capsule.
Synopsis Description of 
Interventions;
6. Dosage and Administration;
14.1. Physical Description of 
Study Drug(s)

The description of the placebo formulation was corrected from "tablet" to 
"powder-filled capsule" or "capsule" (where required).

Additonal text was added in Section 6 and Section 14.1 to clarify that the 
active tablet formulations are "over-encapsulated".
Rationale: To clarify that no adverse events will be designated as "Anticipated Events" in Japan. As such, no 
serious events will be exempt from expedited reporting to the Japanese Health Authority.
Attachment 3 Reporting of 
Anticipated Events

Added clarification that anticipated events are exempt from expedited 
reporting to Health Authorities, "except for Japan (no events will be 
designated as anticipated events in Japan)."
Rationale: It is impractical to assess disallowed medications prior to screening because subjects will not have been 
seen by investigators prior to the screening visit. Disallowed medications should be reviewed after the subject has 
signed the ICF at screening and discontinued before Baseline (Day 1). 
8. Prestudy and Concomitant 
Therapy

Updated timing of discontinuation of disallowed medications from 
"screening" to "Baseline (Day 1)".

Added timing of discontinuation of over-the-counter hypnotics "from Day 1 
until the follow-up visit".
Rationale: To broaden the definition of the Full Analysis Set (FAS).
Synopsis Statistical Methods; 
11.1. Subject Information

The definition of the FAS was broadened to include all subjects who were 
randomly assigned to study drug and received at least 1 dose of study drug. 

A statement was added to clarify that the FAS is the same as the safety 
analysis set.
Rationale: To update the protocol to include the primary estimand.
11.3. Efficacy Analyses

The definition of the primary estimand (population, endpoint, and measure of 
intervention) was added.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
19
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: To add insulin to the serum chemistry panel collected for safety assessment, and to add an additional 
serum chemistry sample at the Baseline visit.
Time and Events Schedule

Removed footnote “s” (which indicates that only hematology samples will be 
collected) from the clinical laboratory test requirements at the Baseline visit.
9.1. Study Procedures

Updates made to the text and to Table 4 to reflect the new blood collection 
volume based on the additional serum chemistry sample at baseline.
9.6. Safety Evaluations

Added insulin to the list of laboratory tests included in the serum chemistry 
panel.
Rationale: To add collection of psychiatric history to the procedures at baseline.
Time and Events Schedule;
9.1.2. Screening Phase

Added collection of psychiatric history at the screening visit (Visit 1).
Rationale: To update the protocol based on recent availability of final Clinical Study Reports for studies 
42847922EDI1009, 42847922EDI1010, 42847922EDI1011, 42847922MDD1001, and 42847922ISM2002, and 
updated Investigator's Brochure. Updates were also made to clarify safety and tolerability in Japanese subjects (as
Japanese subjects will be enrolled in the current study).
1.1.2. Clinical Studies;
3.2. Study Design Rationale

The status of studies 42847922EDI1009, 42847922EDI1010, 
42847922EDI1011, 42847922MDD1001, and 42847922ISM2002 was 
updated from "ongoing" to "completed" in Table 1 and in text.
1.1.2. Clinical Studies

New text has been added to describe PK findings from Study 
42847922EDI1010.

New text has been added to describe safety and tolerability results from 
Study 42847922ISM1002.
1. Introduction;
1.1.1. Nonclinical Studies;
1.1.2. Clinical Studies;
15. Study Specific Materials;
References

References to Addendum to the Investigator's Brochure have been removed,
as the information from the Addendum is now captured within the latest 
edition of the Investigator's Brochure (Edition 5, Oct 2016).
Rationale: Minor changes for consistency with the above listed changes and corrected minor errors.
Throughout the protocol

Minor editorial, grammatical, formatting, or spelling changes were made.

References/citation numbers were updated.
Amendment 1 (19 July 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 key reasons for this amendment are: 1) to add a 3rd dosage arm of 
JNJ-42847922 to Stage 1; 2) to include population pharmacokinetic (PK) and exposure-response analyses at interim 
analysis; 3) to add the Insomnia Severity Index (ISI) as a continuous variable to be a specific endpoint; 4) to include 
diagnostic measures of major depressive disorder (MDD) capable of evaluating associated specifiers, such as
anxious distress; 5) to update and/or clarify eligibility criteria; and 6) to provide the latest clinical information 
regarding JNJ-42847922.
Applicable Section(s)
Description of Change(s)
Rationale: Included 20-mg JNJ-42847922 treatment group in Stage 1 to confirm the positive exploratory efficacy 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
20
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
and tolerability results observed in subjects with moderate to severe MDD in the 42847922MDD1001 study.
Allocation ratios of Stage 1 were updated accordingly.
Synopsis, 2.1. Objectives and Endpoints, 
3.1. Overview of Study Design, Figure 1, 
3.2. Study Design Rationale, 5. Treatment 
Allocation and Blinding, 9.1.3. Double-
blind Treatment Phase, 11.2. Sample Size 
Determination

Included an additional treatment group of 20-mg JNJ-42847922 in 
Stage 1.

Updated the allocation ratios in Stage 1 (2:1:1:1 ratio to receive 1 
of 4 treatments: placebo: JNJ-42847922 10 mg: JNJ-42847922 
20 mg: JNJ-42847922 40 mg).
Rationale: Population PK and exposure-response analyses were included at interim analysis to guide dose selection 
for Stage 2; procedures for these analyses are described. Constitution of the Interim Analysis Committee (IAC) will 
include a clinical pharmacologist to interpret the output from population PK and exposure-response analyses.
Synopsis, 3.2. Study Design Rationale, 
9.3.3. Pharmacokinetic Parameters, 11.4 
Pharmacokinetic Analysis
Added population PK and exposure-response analysis at interim 
analysis.
Synopsis, 11.8. Interim Analysis
Added procedure for exposure-response analyses.
11.8. Interim Analysis
Added “clinical pharmacologist” function to the composition of the 
IAC.
Rationale: To evaluate the relationship between improvement in depressive symptoms and baseline insomnia 
severity and to capture the subject’s assessment of JNJ-42847922 compared to placebo as adjunctive therapy to an 
antidepressant in improving insomnia severity.
Synopsis, 2.1. Objectives and Endpoints
Added the following endpoints:

Correlation between baseline ISI score as a continuous variable 
and change from baseline to the end of Week 6 in the 
Montgomery-Asberg Depression Rating Scale (MADRS) total 
score.

Shift in ISI score category from baseline to the end of Week 6.
Time and Events Schedule
Added ISI at end-of-study/early withdrawal visit.
11.3. Efficacy Analysis
Updated the text for analysis of correlation between baseline ISI score 
and MADRS.
Rationale: To explore the response to JNJ-42847922 in the subgroup of subjects with MDD with anxious distress.
Synopsis, 2.1. Objectives and Endpoints
Added an objective and endpoint to assess the efficacy of 
JNJ-42847922 in improving depressive symptoms in the 
subpopulation of subjects with MDD with anxious distress.
11.3. Efficacy Analysis
Added text for subgroup analysis (MDD with anxious distress or 
MDD without anxious distress).
Rationale: Certain SSRIs/SNRIs (eg, fluvoxamine) can affect CYP3A4 and CYP2C9; hence, all permitted 
SSRIs/SNRIs are specified. In addition to the strong inhibitors/inducers or dual inhibitors/inducers of CYP3A4 and 
CYP2C9, the list of concomitant medications to be avoided was updated to include moderate inhibitors/inducers of 
CYP3A4 and CYP2C9.
4.1. Inclusion Criteria, 12.1.1. Adverse 
Event Definitions and Classifications
Added desvenlafaxine, vilazodone, vortioxetine, milnacipran, or 
levomilnacipran as permitted SSRIs/SNRIs.
4.2. Exclusion Criteria, 8. Prestudy and 
Concomitant Medications
Updated the text of Exclusion Criterion # 7 and the second-to-last 
bullet in Section 8 to clarify that the use of moderate
inhibitors/inducers of CYP3A4 and CYP2C9 is exclusionary. Added a 
note that the SSRI, fluvoxamine, is a moderate CYP2C9 inhibitor and 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
21
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
mild CYP3A4 inhibitor, and is therefore excluded from the protocol.
Attachment 2
Modified the table to include examples of moderate 
inhibitors/inducers of CYP3A4 and CYP2C9. Added "fluvoxamine" 
under Dual Inhibitors/Inducers of CYP3A4 and CYP2C9.
Rationale: To limit the study enrollment to non-geriatric population.
Synopsis, 3.2. Study Design Rationale,
4.1. Inclusion Criteria
In Inclusion Criterion # 1, the upper age limit was clarified to be less 
than 65 years (ie, “18 to 64 years” instead of “18 to 65 years”).
Rationale: The Structured Clinical Interview for DSM-5 Axis I Disorders – Clinical Trials Version (SCID-CT) will 
be implemented at screening as this scale, unlike Mini International Neuropsychiatric Interview (MINI 7.0), covers 
the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) specifiers for MDD (ie, anxious 
distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood 
incongruent psychotic features, catatonia, peripartum onset, seasonal pattern). The SCID Screening Questionnaire 
(SSQ) interview offers advantages over the SAFER (the acronym SAFER stands for interview’s attention to the 
following criteria: State versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps 
[pervasive, persistent, and pathological]) interview; it can be tailored to the protocol, flag potential exclusionary 
diagnoses and flag other clinical concerns that may interfere with study participation.
Synopsis, Time and Events Schedule, 3.1. 
Overview of Study Design, 3.2. Study 
Design Rationale, 4.1. Inclusion Criteria, 
9.1.2. Screening Phase
Inclusion Criterion # 2 was modified to replace MINI (Version# 7.0) 
and the SAFER with SCID-CT and SSQ, respectively.
Rationale: To clarify that the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ) scale will be administered by investigators.
4.1. Inclusion Criteria
Updated the text of Inclusion Criterion # 4 to clarify the inclusion of 
subjects receiving monotherapy treatment with SSRI/SNRI 
antidepressants for depressive symptoms.
Modified the note in Inclusion Criterion # 4 to “Dose and duration of 
treatment should be verified by the investigator using the medical or 
pharmacy records. The investigator will use this information to 
complete the MGH-ATRQ, which will then be corroborated by the 
independent rater”.
Rationale: Updated the inclusion criterion for the screening and baseline MADRS total scores to be consistent with 
those reported in the adjunctive treatment MDD trials with currently approved treatments.
Synopsis, 3.1. Overview of Study Design, 
4.1. Inclusion Criteria, 9.1.2 Screening 
Phase
Inclusion Criterion # 5 was modified to revise the required MADRS 
total score at screening and baseline visits (ie, ≥25 at screening and 
≥20 at baseline).
Rationale: To clarify eligibility of subjects with hypothyroidism. 
4.2. Exclusion Criteria
Exclusion Criterion # 2 was modified to clarify that subjects with 
known hypothyroidism who have been on stable treatment for at least 
3 months prior to screening are required to have thyroid-stimulating 
hormone [TSH] and free thyroxine (FT4) obtained. Any subject with 
an elevated TSH should also have FT4 measured. In any case where 
the TSH value is out of range, but FT4 is normal, the findings should 
be discussed directly with the medical monitor before the subject is 
enrolled. If the FT4 value is out of range, the subject is not eligible.
Synopsis, Time and Events Schedule, 
Table 4, 9.1.2 Screening Phase, 9.6. Safety 
Evaluations
Added description to perform FT4 analysis for subjects with known 
hypothyroidism who have been on stable treatment for at least 
3 months prior to screening or for any subject with an elevated TSH.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
22
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify eligibility of subjects with suicidal ideation, intention and planning.
4.2. Exclusion Criteria
Exclusion Criterion # 4 was modified to clarify that only subjects with 
non-serious items (1-3 of the suicidal ideation section of the Columbia 
Suicide Severity Rating Scale [C-SSRS]) may be included at the 
discretion of the investigator.
Rationale: Provide clarification regarding concurrent or history of other psychiatric disorders.
4.2. Exclusion Criteria
Exclusion Criterion # 8 was modified to indicate that a primary 
DSM-5 diagnosis of panic disorder, generalized anxiety disorder, 
social anxiety disorder, or specific phobia that has been the primary 
focus of psychiatric treatment within the past 2 years is exclusionary. 
Also, current or lifetime history of obsessive-compulsive disorder, 
posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa is 
exclusionary.
Rationale: To clarify definition of clinically significant electrocardiogram (ECG) abnormalities.
4.2. Exclusion Criteria
Exclusion Criterion # 17 was modified to clarify definition of 
clinically significant abnormalities.
Rationale: To remove restrictions on caffeine use.
4.2. Exclusion Criteria
Deleted Exclusion Criterion # 24 “Drinks, on average, more than 
500 mg of caffeine per day. Refer to Attachment 2 for average 
caffeine content of various beverages”.
4.3. Prohibitions and Restrictions
Deleted Prohibitions and Restriction # 3 “Use of 
caffeine/methylxanthine-containing products (eg, beverages, coffee, 
teas, colas, or energy drinks) after 3 PM is prohibited throughout the 
study. Limited use of these products (up to 500 mg of caffeine daily) 
is permitted before 3 PM. Refer to Attachment 2 for average caffeine 
content of various beverages”.
Attachments
Deleted Attachment # 2 and updated attachment numbers accordingly.
Rationale: To provide the latest clinical and nonclinical information regarding JNJ-42847922.
Synopsis, 
1. Introduction
Added the exploratory efficacy results from a multiple dose study 
(42847922MDD1001) of JNJ-42847922 in subjects with MDD.
1.1.1 Nonclinical Studies
Added a sentence for neurobehavioral findings in the Safety 
Pharmacology subsection. Deleted information about safety margins 
from the Toxicology subsection, as detailed information is presented 
in the latest version of the Investigator’s Brochure and Addendum to 
the Investigator's Brochure.
1.1.2. Clinical Studies 
Updated the section with latest information about ongoing and 
completed studies, pharmacokinetics, pharmacodynamics, and safety 
(including newly identified adverse drug reactions [ADRs]).
Note: the information about ongoing and completed studies was added 
in the form of a table (ie, Table 1); the table numbers of other existing 
tables were updated accordingly.
Rationale: The number of subjects to be randomized in the quetiapine XR arm was increased to increase the power 
in the active comparator group to better demonstrate that differences between active drug and placebo can be 
detected. Consequently, the total sample size and the maximum sample size for sample size re-estimation were 
increased.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
23
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Synopsis, 
3.1. Overview of Study Design, 5. 
Treatment Allocation and Blinding, 9.1.3. 
Double-blind 
Treatment 
Phase, 
11.2. 
Sample Size Determination
The number of subjects to be randomized to quetiapine XR was 
increased to 65.
Synopsis, 3.1. Overview of Study Design, 
11.2. Sample Size Determination
Total sample size for the study was increased to 565; the text for 
sample size calculation in the synopsis and Section 11.2 was updated 
accordingly.
Synopsis, 
11.2. 
Sample 
Size 
Determination, 11.8. Interim Analysis
The maximum sample size for sample size re-estimation was 
increased to 665.
Rationale: To further characterize the safety and tolerability profile of JNJ-42847922.
Synopsis, Time and Events Schedule,
2.1. 
Objectives 
and 
Endpoints, 
3.1. 
Overview of Study Design, 3.2. Study 
Design Rationale, 9.1.2. Screening Phase, 
9.6. Safety Evaluations, 11.7. Safety 
Analysis, 17.4 Source Documentation
Included the Antidepressant Side Effect Checklist (ASEC) to the 
safety evaluations and endpoints.
Rationale: To mitigate potential driving risk for subjects treated with JNJ-42847922 or quetiapine.
4.3. Prohibitions and Restrictions, 16.1 
Study-Specific Design Considerations
Modified the restriction related to driving, operating machinery, or 
engaging in hazardous activity on the day after first dosing to 
“subjects should be cautioned not to drive a car or operate machinery 
or engage in any potentially hazardous activities if they have had less 
than a full night’s sleep (6-8 hours) following administration of the 
study drug or at any time during the study if the subject feels that his 
or her baseline competency is impaired”.
Deleted "Such subjects may be discontinued or advised not to drive or 
operate machinery".
Rationale: To clarify the rationale for selection of doses in MDD population.
3.2. Study Design Rationale
Modified the text under Dose and Dose Administration Interval 
subheading to add findings from studies in subjects with MDD.
Rationale: Blood for biomarkers represents combined volume of multiple tubes; specific mention of TruCulture 
samples is not required in the Time and Events Schedule and blood volume table.
Time and Events Schedule
Deleted “These samples include blood collection for TruCulture” 
from the footnote (current footnote # m) of the Time and Events 
Schedule.
9.1.1. Overview
Deleted “including 3 mL sample for TruCulture tube” from footnote d 
of the blood volume table (current Table # 4).
Rationale: Subjects will now complete all self-assessments on paper, as it was decided that electronic patient-
reported outcome (ePRO) devices will not be used in the study.
9.1.1. Overview
Deleted “using a tablet device supplied by the study site. Details of 
data storage and transmission of subject self-assessments are provided 
in a separate document” and added “(PRO) at study site" in the first 
sentence of second paragraph.
Rationale: To add an option for blood sample collection and to clarify location (central or local laboratory) for the 
assay of the background antidepressants.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
24
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Time and Events Schedule, 9.1.2. 
Screening Phase
Modified footnote j in the Time and Events Schedule and the last 
bullet in Section 9.1.2. to “A urine sample will be collected and sent 
to the central laboratory to assess compliance with the following 
background antidepressant medications: citalopram, escitalopram,
fluoxetine, paroxetine, sertraline, and venlafaxine. All other 
SSRI/SNRI background antidepressants qualifying the subject for 
enrollment will be assayed (urine or blood sample) locally at the study 
site, if possible”.
Rationale: Instead of investigators or designee, the Clinical Global Impression of Severity (CGI-S) will now be 
administered by independent centralized remote raters.
9.2. Efficacy Evaluations, 9.2.5. Clinical 
Global Impression of Severity (CGI-S)
Modified the text to clarify that CGI-S will be administered by 
independent, centralized remote raters.
Rationale: To remove restriction on consumption of food and drinks before an ECG measurement.
9.6. Safety Evaluations
Deleted "Hot and cold drinks and food should be avoided 30 minutes 
before an ECG measurement whenever possible".
Rationale: To add additional details about the pharmacogenomic analysis.
11.6. Pharmacogenomic Analysis
Added “Pharmacogenomic data obtained from this study may also be 
included in an ongoing cross-study analysis to investigate the 
relationship between depression severity, phenotypes, and 
biomarkers”.
Rationale: 

To correct the reference for SIGH-A.

To include references for the newly added measures (ASEC, SCID-CT).

To include reference for recently issued addendum (Addendum 1 to Investigator's Brochure Edition 4).

As the SAFER interview has been removed, reference for SAFER is not required. 
References

Deleted the reference for SIGH-A (original Reference # 54, 
Shear MK 2001) and added a new reference (current Reference # 
65, Williams JBW 2008)

Added the following references for ASEC:

Bet PM 2013 (current Reference # 4)

Uher R 2009 (current Reference # 60)

Added the following reference for SCID-CT

First MB 2015 (current Reference # 16)

Added reference for Addendum 1 to Investigator's Brochure 
Edition 4. (current Reference # 24)

Deleted the following reference for SAFER

Desseilles M 2013 (original Reference # 9)
Rationale: Attachments containing all investigator- and patient-administered scales and questionnaires were deleted 
because these will now be provided in a binder sent to each study site. This will also avoid the need for an 
amendment to update the version number of a scale, should a new version become available.
15. Study-specific Materials 
Replaced “PRO questionnaires and PRO completion guidelines” with 
“A binder containing all patient- and investigator-administered 
questionnaires and scales, along with completion guidelines”.
Attachments
Removed all sample scales and corresponding citations from the text. 
Updated all attachment numbers accordingly.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
25
Status: Approved, Date: 24 April 2018
Applicable Section(s)
Description of Change(s)
Rationale: Updates based on the latest protocol template (Version 21.0, dated 6 June 2016)
Abbreviations and Definitions of Terms
Removed "eSource" and "Electronic source system" since the terms 
are no longer used in the text.
4.1 Inclusion Criteria
Inclusion Criterion # 11: Added a leading phrase indicating that 
contraceptive use by men or women should be consistent with local 
regulations.
Inclusion Criterion # 13: Deleted the phrase "user independent".
4.3 Prohibitions and Restrictions
Revised Criterion # 2 to indicate that "all requirements must be met 
during the study as noted in the Inclusion and Exclusion Criteria".
12.3.1 All Adverse Events
In the paragraph listing the sponsor's responsibility, added additional 
text related to handling serious anticipated events.
12.3.2 Serious Adverse Events
Updated the text for reporting SAEs electronically as well as by 
facsimile.
17.4 Source Documentation
In the last paragraph, changed all instances of "eSource" to "electronic 
source" for clarity, as it was not intended to refer to a specific software 
product. Added the sentence: "Data in this system may be considered 
source documentation".
Attachment 3: Anticipated Events
Revised the paragraph under the "Reporting of Anticipated Events" 
subheading.
Investigator Agreement Page
Removed the LAST PAGE designation.
Rationale: Minor changes for consistency with the above listed changes and corrected minor errors.
Throughout the protocol

Minor editorial, grammatical, formatting, or spelling changes 
were made.

Abbreviations were updated.

Reference/citation numbers were updated.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
26
Status: Approved, Date: 24 April 2018
SYNOPSIS
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Adaptive 
Dose-Finding Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive Therapy to 
Antidepressants in Adult Subjects With Major Depressive Disorder Who Have Responded 
Inadequately to Antidepressant Therapy
JNJ-42847922 (seltorexant) is a potent and selective antagonist of the human orexin-2 receptor (OX2R, 
negative log of inhibition constant [pKi]=8) that is being developed for the treatment of insomnia and 
major depressive disorder (MDD). Preclinical evidence supports a role for the orexin system in 
modulating the hypothalamic-pituitary-adrenal (HPA) axis and stress-responsiveness, critical components
of the pathophysiology of depression. In addition, data support the importance of attenuating sleep 
disturbances to attain and sustain remission in MDD, and further suggest that the sleep enhancing effects 
of OX2R antagonists may be of benefit to patients with MDD.
Clinical data in support of a role for orexin in depression are limited. In depressed human subjects, 
average cerebrospinal fluid (CSF) orexin levels have not been demonstrated to be different from controls, 
nor to correlate with the severity of depressive illness; however, the diurnal variation of CSF orexin levels 
has been shown to be blunted in subjects with depression. Data from a single dose study 
(42847922EDI1002) of JNJ-42847922 in a small number of subjects with MDD showed a trend towards
normalization of morning cortisol levels and a reduction in depressive symptoms. The exploratory 
efficacy results from a multiple dose study (42847922MDD1001) of JNJ-42847922 in a small number of 
subjects with MDD showed an early onset (as early as Day 11 of exposure) and a clinically relevant 
antidepressant effect. The effect of JNJ-42847922 was largely related to an effect on the core symptoms 
of depression and overall unrelated to its effect on sleep-related items. The antidepressant effect was 
sustained at least 14 days after treatment discontinuation.
The present study is being conducted to investigate the antidepressant effects of a range of doses of 
JNJ-42847922 (versus placebo), as adjunctive treatment to standard of care, and to further assess the 
safety and tolerability of JNJ-42847922. The study will utilize the change in the Montgomery-Asberg 
Depression Rating Scale (MADRS; the structured interview guide for the MADRS [SIGMA] will be 
used) total score from baseline to the end of Week 6 for assessment of efficacy. The results of this study 
will be used to select doses and endpoints in subsequent confirmatory Phase 3 and long-term safety 
studies.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Endpoints
Primary

To assess the dose-response relationship of up 
to 3 doses of JNJ-42847922 (20 and 40 mg, 
with 10 mg potentially added at the interim 
analysis) compared to placebo as adjunctive 
therapy to an antidepressant drug in improving 
depressive symptoms in subjects with MDD 
who have had an inadequate response to 
current antidepressant therapy with a selective 
serotonin 
reuptake 
inhibitor 
(SSRI) 
or 
serotonin-norepinephrine reuptake inhibitor 
(SNRI).

Change from baseline to the end of Week 6 in 
the MADRS total score.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
27
Status: Approved, Date: 24 April 2018
Objectives
Endpoints

To assess the safety and tolerability of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant in 
subjects with MDD.

Safety assessments, including adverse events, 
laboratory values, electrocardiogram (ECG), 
vital signs, physical exam, the Columbia 
Suicide Severity Rating Scale (C-SSRS), the 
Arizona Sexual Experiences Scale (ASEX),
and the Physician Withdrawal Checklist 
(PWC).
Secondary

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving depressive 
symptoms in subjects with MDD with 
significant 
insomnia 
symptoms 
(baseline 
Insomnia Severity Index [ISI] score ≥15) 
versus those without significant insomnia 
symptoms (baseline ISI score <15).

Correlation between baseline ISI score as a 
continuous variable and change from baseline 
to the end of Week 6 in the MADRS total 
score.

Change from baseline to the end of Week 6 in 
the MADRS total score in subjects with 
baseline ISI score ≥15 versus subjects with 
baseline ISI score <15.

Shift in ISI score category from baseline to 
the end of Week 6.

To assess the efficacy
of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving:

Response and remission of depressive 
symptoms

Proportion of responders on depressive 
symptoms scale, defined as a ≥50% 
improvement in MADRS total score 
from baseline to the end of Week 6.

Proportion of subjects with remission of 
depressive symptoms, defined as a 
MADRS total score ≤8, ≤10, or ≤12 at 
the end of Week 6.

Anxiety symptoms

Change from baseline to the end of 
Week 6 on the 14-item Hamilton 
Anxiety Rating scale (HAM-A) total 
score.

Response of anxiety symptoms

Proportion of responders on anxiety 
symptoms scale, defined as a ≥50% 
improvement in the HAM-A total score 
from baseline to the end of Week 6.

Clinical severity

Change from baseline to the end of 
Week 
6 
in 
the 
Clinical 
Global 
Impression-Severity (CGI-S) score.

Global functioning (work/school, social 
and family life).

Change from baseline to the end of 
Week 6 in the Sheehan Disability Scale 
(SDS).

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving depressive 
symptoms in the subpopulation of subjects 
with MDD with anxious distress.

Change from baseline to the end of Week 6 in 
the MADRS total score in subjects with MDD 
with anxious distress versus subjects with 
MDD without anxious distress. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
28
Status: Approved, Date: 24 April 2018
Objectives
Endpoints

To evaluate the effect of JNJ-42847922 
exposure on the HPA axis in subjects with 
MDD.

Change from baseline to Weeks 2, 4, and 6 in 
salivary cortisol levels, as measured upon 
awakening.

To assess the exposure of JNJ-42847922 and 
metabolites M12 and M16 in subjects with 
MDD.

Observed 
plasma 
concentrations 
of 
JNJ-42847922 and metabolites and estimated 
exposure parameters for JNJ-42847922 from 
population 
based 
pharmacokinetic 
(PK) 
modeling.

To capture patient-reported assessment of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant.

Change from baseline to the end of Week 6 
in:

Depressive symptoms using the Patient 
Health Questionnaire 9-item (PHQ-9)

Anhedonia using the Snaith-Hamilton 
Pleasure Scale (SHAPS)

Sleep disturbance using the Patient 
Reported 
Outcome 
Measurement 
Information System-Sleep Disturbance 
(PROMIS-SD) Short Form

Fatigue using the PROMIS-Fatigue Short 
Form

Severity of depression using the Patient 
Global Impression-Severity (PGI-S)

Health related quality of life and utility 
using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level 
(EQ-5D-5L) questionnaire

Work productivity and limitations using 
the Work Limitations Questionnaire 
(WLQ) Short Form.
In addition, the exploratory objectives are:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers (HPA axis 
function, biomarkers of immune system activation and oxidative stress) in relation to clinical 
response on depression symptoms upon adjunctive treatment with JNJ-42847922

To explore the exposure/response relationship of JNJ-42847922 in subjects with MDD

To identify genetic factors that may influence the PK, safety, or tolerability of JNJ-42847922

To assess the predictive capability of salivary cortisol levels assessed during the circadian nadir 
(predose in the evening) on the antidepressant effect of JNJ-42847922.
Hypothesis
The hypothesis for this study is that adjunctive treatment with JNJ-42847922 is superior to placebo in 
treating depressive symptoms, as measured by change in MADRS total score from baseline to the end of 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
6 weeks, and exhibits a dose-response relationship, in adult subjects with MDD who have had an 
inadequate response to treatment with an SSRI/SNRI.
OVERVIEW OF STUDY DESIGN
This is a multicenter, double-blind, randomized, parallel-group, placebo-controlled, 6-week adaptive 
dose-finding study to assess the efficacy and safety of JNJ-42847922 as adjunctive therapy in adult 
subjects with MDD who have had an inadequate response to current antidepressant therapy with an 
SSRI/SNRI. Approximately 280 subjects will be randomized.
The doses of JNJ-42847922 that will be studied at the start of the study are 20 and 40 mg. The doses of 
JNJ-42847922 to be studied in subjects randomized after the interim analysis will be adaptively chosen 
based on the dose-response curve observed at the time of the interim analysis. During the interim analysis 
review period, subjects will continue to be randomized to placebo, JNJ-42847922 20 mg, or 
JNJ-42847922 40 mg according to the initial randomization scheme. Regardless of whether subjects are 
randomized before or after the interim analysis, the schedule of events and study procedures will remain 
the same. The final analysis will include all subjects.
The data cutoff for the unblinded interim analysis will be 6 weeks after randomization of 160 subjects. An 
Interim Analysis Committee (IAC) will be established to review the interim data to examine the dose-
response relationship and determine the doses of JNJ-42847922 and the allocation ratio of the doses to be 
used after the interim analysis.

At the start of the study, subjects will be randomly assigned in a 2:1:1 ratio to receive 1 of 
3 treatments: placebo: JNJ-42847922 20 mg: JNJ-42847922 40 mg.

After the interim analysis, subjects will be randomly assigned to receive placebo or one of the 
JNJ-42847922 doses (potential doses include 10 mg, 20 mg, and 40 mg).
For all subjects, the study will consist of 3 phases: a screening phase (up to 4 weeks), a double-blind 
treatment phase (6 weeks), and a posttreatment follow-up phase (2 weeks). The total study duration for 
each subject will be up to approximately 12 weeks (84 days). Subjects will continue to take their baseline 
SSRI/SNRI antidepressant (at the same dose, without change, and at approximately the same time as prior 
to entering the study) throughout the screening, double-blind, and follow-up periods (the entire 12 weeks 
of the study duration).
In order to collect PK and salivary cortisol samples after the Day 1 dose, subjects will stay at the study 
site from at least 1 hour before the bedtime dosing on Day 1 until the morning of Day 2. The PK and 
cortisol samples will be collected from most subjects; however, in some circumstances, subjects may not 
be able to stay overnight on Day 1 for the sample collection. Since the collection of PK and cortisol 
samples does not relate to the primary assessments of safety and efficacy, an exception to the overnight 
stay and collection of samples (PK and cortisol) may be made after discussion with the sponsor’s medical 
monitor. The reason for the exception must be documented in the source documents. Subjects who do not 
stay overnight will take their Day 1 dose at home (at bedtime, approximately 3 hours after the last meal).
SUBJECT POPULATION
The study population will include adult men and women of non-childbearing potential (WONCBP) (aged 
18 to 70 years, inclusive) who meet Diagnostic and Statistical Manual of Mental Disorders-5th Edition 
(DSM-5) diagnostic criteria for MDD (confirmed by the Structured Clinical Interview for DSM-5 Axis I 
Disorders – Clinical Trials Version [SCID-CT]), and who have had an inadequate response to at least 1 
but no more than 3 antidepressants (administered at an adequate dose and duration in the current episode,
as assessed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire 
[MGH-ATRQ]). The current depressive episode must be deemed valid by the SCID Screening 
Questionnaire (SSQ), and each potential subject must have MADRS total score ≥25 at screening and must 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
not demonstrate a clinically significant improvement (ie, an improvement of >20% on their MADRS total 
score) from the screening to baseline visit.
DOSAGE AND ADMINISTRATION
On Day 1 of the double-blind treatment phase, the assigned study drug (blinded placebo or
JNJ-42847922) will be administered at the study site (at bedtime, approximately 3 hours after the last 
meal). For the remainder of the study (from Day 2 to Day 41), the assigned study drug will be self-
administered by the subject at home, at bedtime, approximately 3 hours after the last meal. 
Note: if a subject does not participate in the overnight stay on Day 1, the study drug will be self-
administered at home throughout the double-blind treatment phase (once daily at bedtime, approximately
3 hours after the last meal).
DESCRIPTION OF INTERVENTIONS 
Treatment name
JNJ-42847922
Placebo
Dose per delivery 
(ie, total daily dose)
10 mg, 20 mg or 40 mg
Placebo
Description
Over-encapsulated tablets
Powder-filled capsules
Frequency
Once daily at bedtime, approximately
3 hours after the last meal
Once daily at bedtime, approximately 
3 hours after the last meal
Delivery method
Oral, with 100 mL water
Oral, with 100 mL water
Delivery instructions
Must be swallowed whole and not 
chewed, divided, dissolved or crushed
Must be swallowed whole and not 
chewed, divided, dissolved or crushed
EFFICACY EVALUATIONS
The efficacy of study drug will be evaluated using the MADRS (SIGMA version), HAM-A (SIGH-A
version), CGI-S, SDS, PHQ-9, SHAPS, PROMIS-SD (Short Form), PROMIS-Fatigue (Short Form), 
PGI-S, EQ-5D-5L, and WLQ (Short Form). The Ruminative Response Scale (RRS) will be collected at 
baseline only, and will be evaluated as a potential predictor of treatment outcome.
PHARMACOKINETIC EVALUATIONS
Sparse blood samples will be collected for measurement of plasma concentrations of JNJ-42847922 and 
the active metabolites M12 and M16. These data will be used for population PK analysis of 
JNJ-42847922, and if necessary, analysis of metabolites M12 and M16.
Post-hoc Bayesian estimates of PK parameters will be obtained for JNJ-42847922 from population PK 
modeling (and, if needed, for M12 and M16) and may be used in exploratory exposure-response analysis.
BIOMARKER EVALUATIONS
Saliva samples for the measurement of cortisol concentrations will be collected by using an oral swab 
method just before bedtime (before dosing) on the night before each visit and upon awakening on the day 
of the visits during the double-blind treatment phase. In addition, salivary cortisol samples will be 
collected at the study site at baseline (before study drug administration on Day 1) and prior to each blood 
sample for PK on Days 1, 2, and 8 (note: samples on Days 1 and 2 will only be collected from those 
subjects participating in the Day 1 overnight stay). If a subject does not participate in the overnight stay 
on Day 1, then the cortisol samples on Days 1 and 2 will not be collected.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
Venous blood samples for the assessment of biomarkers related to the immune system activity, growth 
factors, metabolic, and HPA axis activation will be collected on each visit during the double-blind phase. 
Biomarkers may be added or deleted based on scientific information or technical innovations under the 
condition that the total volume of blood collected will not be increased.
PHARMACOGENOMIC AND EPIGENETIC (DNA) EVALUATIONS
Blood samples for genetic research will be collected from subjects who consent separately to this 
component of the study (where local regulations permit) to allow for the identification of genetic and/or 
epigenetic factors that may influence the PK, efficacy, safety, or tolerability of JNJ-42847922 and to 
identify genetic and/or epigenetic factors associated with MDD. Subject participation in genetic research 
is optional. DNA samples collected from Japanese subjects will not be used for research related to MDD.
SAFETY EVALUATIONS
Safety evaluations will include collection of adverse events and concomitant medications, as well as 
assessment with physical examination, body weight, waist circumference, vital signs, 12-lead ECG, urine 
drug screening, alcohol breath test, and clinical laboratory tests (hematology, chemistry panel, lipid panel, 
hemoglobin A1c [HbA1c], thyroid-stimulating hormone [TSH] [screening only], free thyroxine [FT4, for 
subjects with known hypothyroidism who have been on stable treatment for at least 3 months prior to 
screening or for subjects with an elevated TSH], and urinalysis). Pregnancy testing (serum pregnancy test 
at screening and urine pregnancy test thereafter) should be performed as needed per the investigator’s 
judgment. For women of childbearing potential (WOCBP) who enrolled in the study before Amendment 
5 and who continue in the trial, a serum pregnancy test must be performed at screening, and urine 
pregnancy tests must be performed at Day 1, Day 22, Day 42 (End-of Treatment/Early Withdrawal), and 
at the Follow-up Visit to establish absence of pregnancy.
In addition, emergence of suicidal ideation will be assessed using the C-SSRS; potential withdrawal 
effects will be assessed by the clinician using the PWC; and the effect on sexual functioning will be 
measured by the ASEX.
STATISTICAL METHODS
Sample Size Determination
The calculation of the sample size is based on the primary efficacy endpoint (change from baseline to the 
end of Week 6 for the MADRS total score). The assumptions for the effect size were based on published 
literature and the clinically meaningful difference between groups to be detected.
The total sample size is calculated on the basis of the generalized Multiple Comparison Procedure-
Modeling (MCP-Mod) test applied to the placebo and the JNJ-42847922 dose groups at the final analysis. 
Approximately 280 randomized subjects will provide an average weighted power of approximately 85% 
depending on the underlying true dose-response shape, assuming a 1-sided significance level of 0.05, a 
treatment difference from placebo of 4.5 points in change in MADRS total score, a standard deviation of 
10, and a 25% overall dropout rate.
The data cutoff for the unblinded interim analysis will be 6 weeks after randomization of 160 subjects, 
which corresponds to approximately 57% of the sample size of the study. This number of subjects 
provides approximately 93% power to detect a dose-response relationship, depending on the underlying 
true dose-response shape, assuming a treatment difference of 4.5, and a standard deviation of 10 when 
tested by means of the MCP-Mod approach at the 30% significance level (1-sided). 
Efficacy Analysis
The efficacy analyses will be based on the full analysis set (FAS) which consists of all subjects who were 
randomly assigned to study drug and received at least 1 dose of study drug.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
The primary efficacy endpoint will be evaluated at a 1-sided significance level of 0.05 using the 
MCP-Mod approach to test for dose-response. For all other analyses of the primary efficacy endpoint and 
for all other efficacy endpoints, no multiplicity adjustment will be done and nominal 1-sided p-values will 
be presented.
The primary efficacy endpoint is the change in MADRS total score from baseline to the end of Week 6. A 
mixed model for repeated measures (MMRM) analysis of the observed data from the placebo and 
JNJ-42847922 groups will be used as the method of addressing missing data. The final analysis will use 
the generalized MCP-Mod approach, which will be applied towards estimates obtained from the MMRM 
analysis to establish a dose-response signal and to determine dose(s) to be used in the Phase 3 studies. In 
conjunction, the comparison between JNJ-42847922 and placebo will also be performed using the 
appropriate contrasts directly from the MMRM analysis using estimates at the end of Week 6. 
Any secondary efficacy endpoint which is defined as a change from baseline will be analyzed using the 
same MMRM as for the primary efficacy endpoint, with the corresponding baseline as a covariate. The 
secondary endpoint analyses will not be controlled for Type I error and nominal p-values will be 
presented.
Pharmacokinetic Analysis
Concentration-time data will be graphically displayed by dose, visit date and time (relative to dose) for 
JNJ-42847922, M12, and M16 and summarized using descriptive statistics.
A population PK analysis using PK data from a selection of Phase 1 and Phase 2 studies will be 
performed at the completion of the study and at the interim analysis. Using actual sampling and dosing 
times, concentration-time data will be analyzed using population PK modeling. Post-hoc Bayesian 
estimates of PK parameters (ie, area under the concentration-time curve [AUC] and, if allowed by the 
data, maximum drug concentration [Cmax]) will be obtained for JNJ-42847922 from population PK 
modeling, and if necessary, for M12 and M16. As part of the population PK modeling, the effect of 
intrinsic (eg, age, gender, body weight) and extrinsic factors (eg, concomitant medications) affecting the 
PK of JNJ-42847922 may be evaluated if needed. Individual predicted plasma concentration-time profiles 
and/or post-hoc Bayesian estimates of PK parameters for JNJ-42847922 and, if necessary, for M12 and 
M16 may be used for exploratory exposure-response modeling for safety and efficacy endpoints.
Biomarker Analysis
Cortisol levels will be tabulated for each time point and summary statistics will be calculated. 
Posttreatment changes in cortisol levels will be assessed by treatment group. Analysis of variance 
(ANOVA) and t-test will be used to assess differences across groups and time points. Correlations 
between cortisol levels and clinical endpoints will be evaluated.
The additional exploratory biomarkers will be tabulated by treatment and summary statistics will be 
calculated. Posttreatment changes in exploratory biomarkers will be summarized by treatment group. 
Associations between baseline biomarker levels and clinical endpoints may be explored.
Pharmacogenomic Analysis
Individual predicted post-hoc Bayesian estimates of PK parameters will be used in exploratory 
exposure-genetic variant modeling, as appropriate.
Safety Analyses
Safety analyses will be based on the safety analysis set which consists of all subjects who were randomly 
assigned to study drug and received at least 1 dose of study drug. The safety analysis set is the same as the 
FAS.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
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 and adverse events that have 
worsened since baseline (ie, treatment-emergent adverse events [TEAEs]), will be included in the 
analysis. Serious adverse events will be summarized separately.
Laboratory data will be summarized by type of laboratory test and treatment. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from baseline at 
each scheduled time point.
Descriptive statistics of pulse, supine and standing blood pressure (systolic and diastolic), and 
temperature for observed values and changes from baseline will be summarized at each scheduled time 
point by treatment.
Subjects with abnormal findings in physical examination and ECG will be listed. Changes in body weight 
and waist circumference will be summarized descriptively. Results from the C-SSRS, PWC, and ASEX 
will be tabulated by treatment.
Interim Analysis
The primary purpose of the interim analysis will be to examine the dose-response relationship, to 
determine the doses of JNJ-42847922 and the allocation ratio to be used after the interim analysis. The 
IAC will review the outputs from statistical analysis, exposure, exposure-response analysis, and safety for 
this determination. 
The interim analysis will use the generalized MCP-Mod approach to establish a dose-response signal with 
respect to the primary efficacy endpoint. A 1-sided 0.30 significance level will be used to test for 
dose-response using the MCP-Mod approach on the change in MADRS total score to the end of Week 6. 
Unblinded exposure-response analyses will be performed by an independent internal pharmacometrician 
using data available at the interim analysis, with adequate firewalls so the study team will remain blinded. 
At the time of interim analysis, the IAC will review the exposure and exposure-response analyses to assist 
in selection of doses and the allocation ratio to be used after the interim analysis. Post-hoc Bayesian 
exposure data by dose, and exposure-response data will be available at interim analysis to the IAC. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
TIME AND EVENTS SCHEDULE
Phase
Screening
Double-Blind
Follow-upa
End-of-
Treatment/Early 
Withdrawala
Telephone 
Contact
Follow-up 
visit
Study Day
-28 to -3
-1
1b
2
7
8c
21
22
41
42
43
49-56
Study Week
-4 to -1
-1
1
1
1
2
3
4
6
6
7
7-8
Visit (window ± 2 days)
1
-
2
-
-
3
-
4
-
5
-
6
Visit Typed
Out-Patient
Overnight at 
the study site
Out-Patient
Screening/Administrative Procedures
Informed consente
X
ICF for optional genetic research samples
X
Inclusion/exclusion criteriaf
X
X
Demographic information
X
Height
X
Weight and waist circumference
X
X
X
Medical history
X
Psychiatric history
X
SCID-CT
X
ISI
X
X
X
SSQg
X
MGH-ATRQ
X
Prestudy therapy
X
X
Preplanned surgery/procedure(s)
X
TSH and FT4
h,i
X
Urine drug screen
X
X
X
Alcohol (breath) test
X
X
Urine or blood sample for antidepressant 
compliancej
X
X
X
Study Drug Administration
Randomization (Blinded)
X
Dispense study drug
X
X
X
Study drug accountability
X
X
X
Study drug administrationk,b
Continuous
PK Assessments
Blood samplel
Xb
Xb
Xc


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
35
Status: Approved, Date: 24 April 2018
Phase
Screening
Double-Blind
Follow-upa
End-of-
Treatment/Early 
Withdrawala
Telephone 
Contact
Follow-up 
visit
Study Day
-28 to -3
-1
1b
2
7
8c
21
22
41
42
43
49-56
Study Week
-4 to -1
-1
1
1
1
2
3
4
6
6
7
7-8
Visit (window ± 2 days)
1
-
2
-
-
3
-
4
-
5
-
6
Visit Typed
Out-Patient
Overnight at 
the study site
Out-Patient
Pharmacogenomic and epigenetic (DNA) 
Assessments
Blood samplem
X
X
X
X
Biomarker Assessments
Morning blood samplen
X
X
X
X
Menstrual cycle trackingo
X
X
X
Salivary Biomarker (Cortisol) Samples
Morning salivary cortisol samplep,q
X
Xq
Xq
X
X
Evening salivary cortisol samplep,q
X
Xq
X
X
X
Efficacy Assessments
MADRS (SIGMA version)
X
X
X
X
X
HAM-A (SIGH-A version)
X
X
X
X
CGI-S
X
X
X
X
SDS
X
X
X
X
PGI-S
X
X
X
X
SHAPS
X
X
X
X
PROMIS-Fatigue (Short Form)
X
X
X
X
PROMIS-SD (Short Form)
X
X
X
X
WLQ (Short Form)
X
X
X
X
EQ-5D-5L
X
X
X
X
PHQ-9
X
X
X
X
RRS
X
Safety Assessmentsr
Physical examination
X
X
X
12-Lead ECG
X
X
X
Vital signs
X
X
X
X
X
X
Clinical laboratory tests: hematology, 
serum chemistry, and urinalysish
X
X
X
Xs
X
Lipid Panelh
X
X
HbA1ch
X
X


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
36
Status: Approved, Date: 24 April 2018
Phase
Screening
Double-Blind
Follow-upa
End-of-
Treatment/Early 
Withdrawala
Telephone 
Contact
Follow-up 
visit
Study Day
-28 to -3
-1
1b
2
7
8c
21
22
41
42
43
49-56
Study Week
-4 to -1
-1
1
1
1
2
3
4
6
6
7
7-8
Visit (window ± 2 days)
1
-
2
-
-
3
-
4
-
5
-
6
Visit Typed
Out-Patient
Overnight at 
the study site
Out-Patient
Serum/Urine pregnancy testt
Xt
Xt
Xt
Xt
Xt
C-SSRS
X
X
X
X
X
X
ASEX
X
X
PWC
X
X
X
Concomitant medications
Continuous
Adverse events
Continuous
Abbreviations:  
ASEX=Arizona Sexual Experiences Scale, CGI-S=Clinical Global Impression-Severity, C-SSRS=Columbia Suicide Severity Rating Scale, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, FSH=follicle stimulating hormone, FT4= free thyroxine, HbA1c=hemoglobin A1c, EQ-5D-5L=European Quality of Life (EuroQol) Group, 5-Dimension, 
5-Level questionnaire, HAM-A=Hamilton Anxiety Rating Scale, ICF=Informed Consent Form, ISI=Insomnia Severity Index, MADRS=Montgomery-Asberg Depression Rating 
Scale, MGH-ATRQ=Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire, PHQ-9=Patient Health Questionnaire 9-item, PGI-S=Patient Global 
Impression-Severity, PK=pharmacokinetic, PROMIS-SD=Patient Reported Outcome Measurement Information System-Sleep Disturbance, PROMIS-Fatigue=Patient Reported 
Outcome Measurement Information System- Fatigue, PWC=Physician Withdrawal Checklist, RRS=Ruminative Response Scale, SCID-CT=Structured Clinical Interview for DSM-5 
Axis I Disorders– Clinical Trials Version, SDS=Sheehan Disability Scale, SHAPS=Snaith-Hamilton Pleasure Scale, SIGH-A=structured interview guide for the Hamilton Anxiety 
Scale, SIGMA= structured interview guide for the Montgomery-Asberg Depression Rating Scale, SSQ=SCID Screening Questionnaire, TSH=thyroid-stimulating hormone, 
WLQ=Work Limitations Questionnaire, WOCBP=women of childbearing potential, WONCBP=women of non-childbearing potential.
Footnotes:
a.
If a subject discontinues study treatment before the end of Week 6, end-of-treatment and follow-up assessments should be obtained.
b.
The Day 1 dose will be administered at the study site at bedtime, approximately 3 hours after the last meal; subjects will remain overnight in the study site. Three PK samples will be 
obtained after dosing on that day and the following morning (first sample: between 15 minutes to 1.5 hour after dosing, second sample: between 2 to 4 hours after dosing, and third 
sample between 6 to 8 hours after dosing). The exact date and time of the last dose of study drug and PK sample collection will be recorded. Note that there are no dietary restrictions 
or fasting requirements prior to blood collection for PK assessments. Exceptions to the overnight PK sampling on Day 1 may be made if the subject is not able to stay overnight. In 
this case, PK samples will not be collected on Day 1/Day 2.
c.
For all subjects, a single sample will be collected in the early morning on Day 8 between 6 and 12 hours after dosing at night on Day 7. The exact date and time of the last dose of 
study drug and PK sample collection will be recorded. 
d.
Subjects should report to the study site on the morning of Days 1, 8, 22, and 42 in a fasted state (minimum 8 hours, water permitted). On Day 1, after the assessments, subjects may 
remain at the study site or may go home for the afternoon and return later for an overnight stay at the study site. Subjects who prefer to go home will return to the study site 1 hour 
before the evening dosing and will remain overnight at the study site. Subjects will be discharged in the morning on Day 2 (ie, after collection of salivary cortisol and PK samples)
and the site will ensure subjects have appropriate transportation to their home. The remaining visits will be out-patient visits. Note: In some circumstances, subjects may not be able 
to stay overnight on Day 1. An exception to the overnight stay and collection of samples (PK and cortisol) may be made after discussion with the sponsor’s medical monitor. The 
reason for the exception must be documented in the source documents. 
e.
Must be signed before first study-related activity. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
f.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation. Check clinical status again before first 
dose of study medication.
g.
The SSQ will be administered along with the MADRS.
h.
The clinical laboratory assessments (including TSH, hematology, serum chemistry, HbA1c, lipid panel, and urinalysis) should be performed under fasting conditions (with the 
possible exception of screening laboratory tests).
i.
FT4 analysis will be performed for subjects with known hypothyroidism who have been on stable treatment for at least 3 months prior to screening and otherwise for any subject with 
an elevated TSH.
j.
A urine sample will be collected and sent to the central laboratory to assess compliance with the following background antidepressant medications: citalopram, escitalopram, 
fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine. All other SSRI/SNRI background antidepressants qualifying the subject for enrollment will be assayed (urine or 
blood sample) locally at the study site, if possible.
k.
Subjects will administer the assigned study drug once daily at bedtime, approximately 3 hours after the last meal, from Day 1 to Day 41. Subjects are required to record the 
administration of study drug or any missed doses in subject diaries, which will be checked at each scheduled visit.
l.
As this is a blinded study, blood samples for PK will be collected from placebo-dosed subjects, but not analyzed for PK. These samples will be stored and may be analyzed if needed 
(eg, suspicion of an incorrect dose).
m.
Pharmacogenomic and epigenetic blood samples will be collected only from subjects who have consented to provide optional DNA samples for research.
n.
To avoid interference caused by lipid content in morning blood specimens collected for biomarker evaluation, biomarker samples will be collected under fasting conditions.
o.
Start date (first day) of last menstrual period and average length of menstrual cycle (days) will be collected from premenopausal women.
p.
Salivary cortisol samples (morning and evening) will be collected by subjects at home. Evening salivary cortisol samples (ie, on Days -1, 7, 21, and 41) will be collected predose, at 
bedtime. The morning sample will be collected upon awakening (ie, on Days 1, 8, 22, and 42). Subjects should not consume alcoholic beverages for at least 12 hours prior to saliva 
sampling. Food, drinks (except water), and oral care (brushing, flossing, mouthwash) are not permitted 1 hour prior to the saliva collection. 
q.
In addition to the morning and evening salivary cortisol samples mentioned above, salivary cortisol samples will be collected at baseline (before study drug administration on Day 1) 
and prior to each blood sample for PK on Days 1, 2 and 8. These salivary cortisol samples will be collected at the study site. If a subject does not participate in the overnight stay on 
Day 1, then the cortisol samples on Day 1 and Day 2 will not be collected.
r.
If blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, the procedures are recommended to be performed in the following order: ECG, 
vital signs, blood draw.
s.
Hematology samples only.
t.
Serum or urine pregnancy tests may be performed in WONCBP, as determined necessary by the investigator, to establish the absence of pregnancy at any time during the subject’s 
participation in the study. A FSH test may also be performed at investigator judgment to assist in determining if a woman is of non-childbearing potential. For WOCBP enrolled in 
the study before Amendment 5 and who continue in the trial, a serum pregnancy test must be performed at screening, and urine pregnancy tests must be performed at Day 1, Day 22, 
Day 42 (End-of Treatment/Early Withdrawal), and at the Follow-up Visit.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2001 Amendment 5
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Status: Approved, Date: 24 April 2018
ABBREVIATIONS
ADT
antidepressant treatment
ALT
alanine aminotransferase
ASEX
Arizona Sexual Experiences Scale
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
B&L VAS
Bond & Lader visual analogue scale
Β-hCG
β-human chorionic gonadotropin
BMI
body mass index 
Cav
average concentration
Cmax
maximum drug concentration
CGI-S
Clinical Global Impression-Severity 
CNS
central nervous system
CRF
case report form
CSF
cerebrospinal fluid 
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-5th Edition
ECG
electrocardiogram
EQ-5D-5L
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level questionnaire
eDC
electronic data capture
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D6
6-item subscale from the HAM-D17
HAM-D17
Hamilton Depression Rating Scale, 17 items
HbA1c
hemoglobin A1c
HPA
hypothalamic-pituitary-adrenal
IAC
Interim Analysis Committee
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISI
Insomnia Severity Index
IWRS
interactive web response system
LPS
latency to persistent sleep
MADRS
Montgomery-Asberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MCP-Mod
Multiple Comparison Procedure-Modeling
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire
MMRM
mixed model for repeated measures
NOAEL
no observed adverse effect level
NREM
non-rapid eye movement
OX1R
orexin-1 receptor
OX2R
orexin-2 receptor
PD
pharmacodynamic(s)
PGI-S
Patient Global Impression-Severity
PHQ-9
Patient Health Questionnaire 9-item
PI
Package Insert


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PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
PROMIS-SD
Patient Reported Outcome Measurement Information System-Sleep Disturbance
PROMIS-
Fatigue
Patient Reported Outcome Measurement Information System- Fatigue
PWC
Physician Withdrawal Checklist
QIDS-SR14
Quick Inventory of Depressive Symptomatology-Self Report, 14-Items
RBC
red blood cell
REM
Rapid Eye Movement
RRS
Ruminative Response Scale
SAP
Statistical Analysis Plan
SCID-CT
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version
SDLP
standard deviation of lateral position
SDS
Sheehan Disability Scale
SHAPS
Snaith-Hamilton Pleasure Scale
SIGH-A
structured interview guide for the Hamilton Anxiety Scale
SIGMA
structured interview guide for the Montgomery-Asberg Depression Rating Scale
SmPC
Summary of Product Characteristics
SNRI
serotonin-norepinephrine reuptake inhibitor
SSQ
SCID Screening Questionnaire
SSRI
selective serotonin reuptake inhibitor
SSS
Stanford Sleepiness Scale
STAR*D
Sequenced Treatment Alternatives to Relieve Depression 
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
tmax
time to maximum drug concentration
TSH
thyroid-stimulating hormone
TST
total sleep time
ULN
Upper Limit of Normal
US
United States
WBC
white blood cell
WLQ
Work Limitations Questionnaire
WOCBP
women of childbearing potential
WONCBP
women of non-childbearing potential
XR
extended-release
DEFINITIONS OF TERMS
CL/F
Total clearance of drug after extravascular administration, uncorrected for absolute bioavailability, 
calculated as: Dose/AUC.
Vd/F
Apparent volume of distribution after extravascular administration, uncorrected for absolute 
bioavailability.


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1.
INTRODUCTION
Major depressive disorder (MDD) is a common, serious, recurrent disorder, with worldwide 
lifetime prevalence estimates ranging from 1% in the Czech Republic to 17% in the United 
States (US). Its negative impact on role functioning in various settings (eg, school performance, 
marriage, parenting, and the workplace), quality of life, physical health, and life expectancy has 
been well-documented. Loss of work production and absenteeism due to major depressive 
episodes or MDD has been estimated to account for approximately 30 to 50 billion dollars in 
annual human capital.26 In fact, as of October 2015, and with an estimated 350 million sufferers, 
depression has been ranked by the World Health Organization as the leading cause of disability 
worldwide, and the prevalence is rising.63 MDD is associated with significant comorbid medical 
conditions which include diabetes, hypertension, and cardiovascular disease, and there is an 
increased risk of early mortality in patients with MDD.26
Insomnia or hypersomnia is 1 of 9 diagnostic symptoms of MDD, according to Diagnostic and 
Statistical Manual of Mental Disorders-5th Edition (DSM-5) criteria, with sleep disorders being 
one of the most common presenting symptoms of depression. Furthermore, noting an 
approximate 40-fold increase in the risk of MDD among patients with chronic insomnia,16
Johnson and colleagues sought to evaluate the direction of that risk association, and determined 
that chronic insomnia may be prodromal to MDD.25 Recently, insomnia has also been 
determined to play a role in the increasing prevalence of obesity and diabetes, which are 
common comorbid conditions in patients with MDD.27 Ongoing sleep problems may contribute 
to the persistence of depressive episodes or may be a residual symptom of a current depressive 
episode, despite depressive symptoms having responded to treatment.29,43,60 Additionally, chronic 
insomnia is known to increase the risk of depression relapse. Insomnia also has a strong 
association with anxiety, and anxiety is a prominent comorbid condition in patients with MDD.41
In patients with depression with or without anxious distress, ruminative responses are common,37
and a common feature in these conditions is a state of hyperarousal.18
Preliminary data on JNJ-42847922 (seltorexant) suggest that there may be unique additional 
benefits over conventional antidepressants alone with respect to attenuating sleep disturbances, 
 of MDD. JNJ-42847922 is a potent and selective 
antagonist of the human orexin-2 receptor (OX2R, negative log of inhibition constant [pKi]=8) 
that is being developed for the treatment of insomnia and MDD. Orexins promote arousal 
(wakefulness) and are hypothesized to play a role in excessive arousal (eg,
 
 excessive rumination) which occurs in subsets of 
patients with mood disorders. OX2R antagonists may normalize excessive arousal. This is 
hypothesized to have clinical utility in the treatment of such subsets of patients with MDD.
In addition to its potential role in modulating autonomic arousal and hypothalamic-pituitary-
adrenal (HPA) axis hyperactivity, the sleep enhancing effects of a selective OX2R antagonist 
such as JNJ-42847922 are expected to confer benefit in MDD.
Support for a role of orexin receptors, particularly the OX2R, in modulating depressive-like 
behaviors has been derived from preclinical studies. Chronic unpredictable stress increases 
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orexin immunoreactivity in the dorsomedial and perifornical hypothalamic areas in mice.38 The 
dual orexin receptor antagonist (DORA) almorexant showed the ability to prevent stress-induced 
behavioral alterations and reverse glucocorticoid receptor sensitivity back to normal levels in a 
rodent model of chronic stress.39,40 The effect on glucocorticoid receptor sensitivity is likely to 
be mediated via OX2R antagonism, since the OX2R is the orexin receptor expressed in the 
paraventricular nucleus (PVN) of the hypothalamus. Also, intra-cerebroventricular injection of a 
selective OX2R antagonist was shown to attenuate an orexin-induced increase in 
adrenocorticotropic hormone levels in rats.50 Finally, studies using selective orexin antagonists 
and genetic knockout mice showed that administration of selective OX2R antagonists, but not 
selective orexin-1 receptor (OX1R) antagonists, reduced stress-induced adrenocorticotropic 
hormone (ACTH) release in rodents (Janssen R & D, unpublished data). Interestingly, 
sub-chronic corticosterone administration elicits a depressive behavioral phenotype and increases 
orexin immunoreactivity in the lateral hypothalamic area in mice.23 Nevertheless, a small 
increase in depression-like behaviors was measured in mice that did not express the OX2R.52 In 
summary, alterations in the HPA axis, a common finding associated with clinical depression, 
may be linked to the orexin system.
Berridge and colleagues proposed that orexin “may participate in behavioral responding under 
high-arousal aversive conditions”.3 Such a behavioral response consists of both central and 
peripheral components. While this proposition does not shed further light on the receptor 
subtype(s) involved in these responses, various studies suggest that OX2Rs are involved not only 
in wake regulation but, additionally, in autonomic arousal.7 For example, chronic stress increases 
heart rate and blood pressure in rats. Both OX2R and OX1R antagonists significantly attenuate 
stress-induced increases in heart rate and blood pressure.64 Similarly, novelty-induced blood 
pressure increases (but not heart rate increases) were attenuated by an OX2R antagonist.2
Therefore, an OX2R antagonist such as JNJ-42847922 is hypothesized to modulate the 
physiological components of hyperarousal associated with heightened stress-responsiveness, a 
characteristic of patients with depression.
Clinical data in support of a role for orexin in depression are limited. In depressed human 
subjects, average cerebrospinal fluid (CSF) orexin levels have not been demonstrated to be 
different from controls, nor to correlate with the severity of depressive illness,49,51 however, the 
diurnal variation of CSF orexin levels has been shown to be blunted in subjects with 
depression.49 Data from a single dose study (42847922EDI1002) of JNJ-42847922 in a small 
number of subjects with MDD showed a trend towards normalization of morning cortisol levels 
and a reduction in depressive symptoms. The exploratory efficacy results from a multiple dose 
study (42847922MDD1001) of JNJ-42847922 in a small number of subjects with MDD showed 
an early onset (as early as Day 11 of exposure) and a clinically relevant antidepressant effect. 
The effect of JNJ-42847922 was largely related to an effect on the core symptoms of depression 
and overall unrelated to its effect on sleep related items. The antidepressant effect was sustained 
at least 14 days after treatment discontinuation.
For the most comprehensive nonclinical and clinical information regarding JNJ-42847922, refer 
to the latest version of the Investigator's Brochure.22


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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
1.1.1.
Nonclinical Studies
Nonclinical Pharmacology
Single and multiple dose studies in rats at various doses demonstrated that JNJ-42847922 
reduced latency to non-rapid eye movement (NREM) sleep, increased NREM sleep duration, and 
did not impact rapid eye movement (REM) sleep. The reduced sleep onset and increased sleep 
duration were maintained upon 7-day repeated dosing. Unlike DORAs, the physiologic 
NREM/REM sleep ratio is preserved with JNJ-42847922. A single oral dose of JNJ-42847922 
(30 mg/kg) had no effect on motor coordination (Rotarod performance test) at sleep inducing 
doses, in contrast with zolpidem (gold standard for treating insomnia). In addition, the same dose 
of JNJ-42847922 co-administered with alcohol did not modify the ataxic effects of alcohol. 
Pharmacokinetics and Product Metabolism in Animals
JNJ-42847922 was predominantly 
metabolized by cytochrome P450 (CYP) 3A4 and 2C9. 
 
 
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Toxicology
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Further details of nonclinical pharmacology studies can be found in the latest version of the
Investigator’s Brochure.
1.1.2.
Clinical Studies
To date, 11 Phase 1 clinical studies and 1 Phase 2 study have been completed with oral 
suspension and solid dosage formulations of JNJ-42847922 in a total of 239 healthy male and 
female subjects, 68 male and female subjects with MDD, and 28 male and female subjects with 
insomnia. Overall, 271 subjects received at least 1 dose of JNJ-42847922 (Table 1).
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Table 1:
List of Completed Studies
Study Number
Brief Objective
Formulation/
JNJ-42847922 Dose 
(Dose timing)
Population
Total Number of 
Subjects 
(Enrolled/ 
Completed/Dosed 
with 
JNJ-42847922)
Phase 1
42847922EDI1001
Safety, tolerability, and PK.
Oral Suspension/ 10, 20, 
40, and 80 mg (morning, 
fasted), 20 mg (morning, 
fed), and 20 mg (evening, 
at least 4 hours after 
dinner).
Healthy male subjects
57/57/38
42847922EDI1002
Effect of JNJ-42847922 on 
polysomnography (PSG)
measures and depressive 
symptoms.
Oral suspension/ 10, 20 or 
40 mg (bedtime, 4 to 5 
hours after dinner)
Subjects with MDD 
with insomnia who 
are stably treated 
with antidepressants
20/18/20
42847922EDI1003
Safety, tolerability, PK, 
and pharmacodynamics 
(PD)
Oral suspension/5, 10, 20, 
40, and 60 mg (morning, 
1 hour after the start of a 
light breakfast)
Healthy subjects
40/39/30
42847922EDI1004
Bioavailability, food effect, 
safety and tolerability.
Oral suspension vs 
tablet/20 mg (morning, 
fasted)
Healthy male 
subjects
18/17/18
42847922EDI1005
Effect of itraconazole on 
PK, safety and tolerability 
of JNJ-42847922.
Suspension/5 mg
(morning, fasted)
Healthy male 
subjects
16/16/16
42847922EDI1006
Effect of rabeprazole on 
PK, safety and tolerability 
of JNJ-42847922.
Tablet/ 20 mg (morning, 
fasted)
Healthy male 
subjects
16/16/16
42847922EDI1009
Effect of rifampin on PK, 
safety and tolerability of 
JNJ-42847922.
Tablet/40 mg (morning, 
fasted)
Healthy subjects
14/14/14
42847922EDI1010
Effect of JNJ-42847922 on 
PK, safety, and tolerability 
of midazolam and 
warfarin; and PD of 
warfarin.
Tablet/20 mg (morning, 
fasted)
Healthy subjects
18/17/17
42847922EDI1011
Duration of effects of 
JNJ-42847922, zolpidem, 
and placebo on simulated 
car driving and cognitive 
performance.
Tablet/40 mg (bedtime, 
4 hours after a standard 
dinner)
Healthy subjects
36/35/35
42847922ISM1002
Safety, tolerability and 
pharmacokinetics of 
JNJ-42847922 in healthy 
Japanese subjects.
Tablet/5, 20 or 40 mg
(morning, fasted)
Healthy Japanese 
male subjects
24/24/18
42847922MDD1001
Safety, efficacy and 
biomarker study with 
JNJ-42847922.
Tablet/20 mg (bedtime, 
3 to 5 hours after dinner)
Subjects with Major 
Depressive Disorder
48/47/22
Phase 2
42847922ISM2002
Efficacy, safety and 
tolerability of 
JNJ-42847922.
Tablet/40 mg (bedtime,
3 to 5 hours after dinner)
Subjects with 
insomnia disorder 
without psychiatric 
comorbidity
28/27/27
Pharmacokinetics (PK)
Following oral administration (as a suspension), JNJ-42847922 was rapidly absorbed, with time 
to maximum drug concentration (tmax) ranging from 0.3 to 1.5 hours. After tmax, plasma 


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concentrations of JNJ-42847922 declined mono-exponentially, with a mean half-life of 2 to
3 hours. Cmax and AUC∞of JNJ-42847922 increased with increasing doses, but values were less 
than dose proportional both after single (10 to 80 mg), and multiple (5 to 60 mg, once daily) 
doses, which may be due to a decrease in oral bioavailability. Mean Cmax and AUC on Days 1, 5, 
and 10 were similar, with a mean accumulation ratio close to 1 (0.911 to 1.26). Less than 0.02% 
of the administered dose was excreted in the urine as unchanged drug, suggesting that 
JNJ-42847922 was mainly eliminated via non-renal clearance. 
 
 
 
 
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Pharmacodynamics (PD)
In study 42847922EDI1001 (healthy subjects), subjects who received 10 mg, 20 mg (in fed 
state), and 80 mg JNJ-42847922 exhibited significantly less alertness using the Bond & Lader 
visual analogue scale (B&L VAS) at the first postdose time point of 2 hours. Significantly higher 
Stanford Sleepiness Scale (SSS) scores (reflecting greater sleepiness) were observed for actively 
treated subjects relative to placebo for all daytime cohorts at the first postdose time point of 
2 hours. No significant treatment effects were observed at later time points.
In studies 42847922EDI1002 (subjects with MDD) and 42847922EDI1003 (healthy subjects), no 
differences were found between JNJ-42847922 and placebo in task performance and subject 
measures of alertness, suggesting that the risk for next-day residual effects is minimal. All 
subjects reported normal responses for suicidal ideation/behavior at baseline and at all 
post-baseline assessments as measured by the Columbia Suicide Severity Rating Scale (C-SSRS)
in study 42847922EDI1003. One subject reported a suicidal ideation adverse event after 
administration of 20-mg JNJ-49847922 in Study 42847922EDI1002; this event was deemed mild 
in intensity and not related to treatment. Suicidal ideation was also reported predose and 
considered as a part of the underlying condition (MDD).
JNJ-42847922 showed a significant reduction in latency to persistent sleep (LPS) versus placebo, 
as measured by PSG in subjects with MDD (42847922EDI1002). The total sleep time (TST) was 
significantly longer in all of the JNJ-42847922 dose groups than in the placebo group. Sleep 
efficiency was also significantly improved in subjects with MDD who were treated with 
JNJ-42847922 compared with placebo. Treatment with JNJ-42847922 showed a trend towards a 
decrease in depressive symptoms compared to placebo, as measured by the Quick Inventory of 
Depressive Symptomatology-Self Report, 14 item scale (QIDS-SR14). Mean decreases in the 
QIDS-SR14 total score from Day 1 to Day 2 were -0.7, -1.4, -1.3, and -2.1 points in the placebo, 
JNJ-42847922 10 mg, JNJ-42847922 20 mg, and JNJ-42847922 40 mg treatment groups, 
respectively.
In the single ascending dose study in healthy Japanese male subjects (42847922ISM1002), no 
consistent dose-related trends were observed in SSS and B&L VAS results. Subjects in the 
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40-mg group reported greater sleepiness and subjects in the 20- and 40-mg groups reported less 
alertness than subjects in the placebo group at the 2 hours postdose timepoint, but these effects 
were not observed at any other timepoints.
In the multiple dose study in subjects with MDD (42847922MDD1001), a larger improvement in 
clinician-rated depression symptoms (Hamilton Depression Rating Scale, 17 items [HAM-D17]
total and adjusted total scores and 6-item subscale from the HAM-D17 [HAM-D6]) was 
observed in subjects randomized to treatment with JNJ-42847922 compared with placebo and 
diphenhydramine (HAM-D17 adjusted scores were calculated by summing the item scores 
excluding the 3 insomnia questions ie, 4-Insomnia Early, 5-Insomnia Middle and 6-Insomnia 
Late. The 6 items in the HAM-D6 were: depressed mood, guilt feelings, work and interests, 
psychomotor retardation, psychic anxiety, and general somatics [tiredness and pains]). The 
assessment for symptoms of depression showed that self-rated symptoms (QIDS-SR16) of 
depression followed the same overall trend as clinician-rated symptoms. However, a larger 
placebo effect was measured, especially in women of childbearing potential (WOCBP). In this 
study, the effect of JNJ-42847922 was largely related to an effect on the core symptoms of 
depression and overall unrelated to its effect on sleep related items.
In the multiple dose study in subjects with insomnia disorder without psychiatric comorbidity 
(42847922ISM2002), sleep efficiency was significantly higher in the 40-mg JNJ-42847922 dose 
group compared with placebo at both Day 1/2 and Day 5/6 timepoints. Both objective (per PSG) 
and subjective sleep parameters (TST, Sleep Onset Latency [SOL], Wake after Sleep Onset 
[WASO] and Number of Awakenings) were similarly improved by treatment with 
JNJ-42847922. In addition, treatment with JNJ-42847922 decreased LPS and REM latency times 
on both study days and increased the overall time spent in REM sleep.
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Safety and Tolerability
In healthy subjects, the most commonly reported treatment-emergent adverse event (TEAE) with 
JNJ-42847922 
in 
morning-dosing 
studies 
42847922EDI1001, 
42847922EDI1003, 
42847922EDI1004, 
42847922EDI1005, 
42847922EDI1009, 
42847922EDI1010, 
and 
42847922ISM1002 was somnolence. 
In the single dose drug-interaction study with rabeprazole (42847922EDI1006), the most 
frequently reported TEAE (≥2 subjects) by preferred term was fatigue (7 subjects [43.8%]) with 
all other TEAEs being reported as single incidents.
In healthy Japanese male subjects (42847922ISM1002), a single dose of JNJ-42847922 (5, 20, or 
40 mg) was observed to be safe and well tolerated with no new safety findings of clinical 
concern.
In subjects with MDD receiving single doses of JNJ-42847922 (42847922EDI1002), the most 
common TEAEs during the double-blind phase were headache, dizziness, somnolence, 
disturbance in attention, hypoesthesia, nausea, feeling hot, and nasopharyngitis. 
In subjects with MDD receiving multiple doses of JNJ-42847922 (20 mg) or placebo 
(42847922MDD1001), the most common TEAEs in WOCBP dosed over 10 days were 
influenza, nasopharyngitis, fatigue, insomnia, nightmare, and headache; in the JNJ-42847922 
treatment arm (n=10), no TEAE was reported by more than 1 subject. For men and women of 
non-childbearing potential who were dosed over 28 days, the most common TEAEs were 
headache, dizziness, somnolence, abdominal discomfort, diarrhea, nausea, nasopharyngitis, and 
fatigue; the most common TEAE in the JNJ-42847922 treatment group was somnolence 
(3 [25%] of 12 subjects in the JNJ-42847922 group, 0 of 6 subjects in the placebo group, and 
0 of 7 subjects in the diphenhydramine group).  
In subjects with insomnia disorder without psychiatric comorbidity (42847922ISM2002), the 
most common TEAEs during the double-blind phase were headache and somnolence.
There were no deaths or serious adverse events reported in subjects dosed with JNJ-42847922. 
There were no clinically significant, consistent, treatment-related effects in clinical laboratory 
parameters (hematology, biochemistry, coagulation profile and urinalysis); neurologic and 
physical examinations; vital signs; or electrocardiogram (ECG) measurements.
Sleep paralysis, Abnormal dreams, and Somnolence were classified as adverse drug reactions:

Sleep paralysis was classified as an adverse drug reaction based on 3 reported incidences; 
1 each from studies 42847922EDI1001 (80 mg dose), 42847922EDI1006 (20 mg dose), and 
42847922ISM2002 (40 mg dose).

Abnormal dreams was classified as an adverse drug reaction based on 4 reported incidences
that were predominantly described as “vivid” dreams: 2 from 42847922EDI1010 (20 mg 
dose) and 2 from 42847922ISM2002 (40 mg dose). 


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
Based on its mechanism of action, JNJ-42847922 is being developed as a treatment for 
insomnia. Thus, somnolence is an expected ADR. Among these events of somnolence were 
events of “next day” somnolence that occurred 6 to 12 hours after the evening dose in 
7 subjects from Studies 42847922ISM2002 (3 subjects) and 42847922MDD1001 
(4 subjects).
Refer to the latest version of the Investigator's Brochure for additional details on the adverse 
events seen in studies with JNJ-42847922 conducted thus far.
1.2.
Overall Rationale for the Study
MDD is characterized by low mood, anhedonia, feelings of guilt and worthlessness, low energy, 
and other emotional and physical symptoms. In severe cases, MDD can result in suicide. 
Effective treatment of patients with MDD not responding adequately to first-line antidepressant 
treatment (ADT) remains an important unmet need. Partial response to pharmacologic treatment 
is common. In the National Institute of Mental Health (NIMH)-sponsored Sequenced Treatment 
Alternatives to Relieve Depression (STAR*D) trial, only 28% of subjects achieved remission 
(defined as a score of ≤7 on the HAM-D17) during first-line treatment with a selective serotonin 
reuptake inhibitor (SSRI).46 For inadequate response to an optimized trial of first-line ADT, 
current guidelines recommend switching the ADT, adding a second ADT or adding adjunctive 
therapy with a non-ADT.8,42,57 Adjunctive second generation antipsychotic therapies such as 
olanzapine, quetiapine, and aripiprazole are associated with significant improvements in 
treatment response and remission; however, their side effect profile may limit use in clinical 
practice.57 Thus, there is ongoing interest in identifying adjunctive strategies that offer better 
efficacy and tolerability.
Preclinical evidence supports a role for the orexin system in modulating the HPA-axis and 
stress-responsiveness, critical components of the pathophysiology of depression. In addition, 
data support the importance of attenuating sleep disturbances to attain and sustain remission in 
MDD, and further suggest that the sleep enhancing effects of OX2R antagonists may be of 
benefit to patients with MDD. At present, about two-thirds of patients with depression take sleep 
medications in addition to their antidepressant regimen. The drugs prescribed for this purpose 
include benzodiazepines, atypical antipsychotics, trazodone, antihistamines, non-benzodiazepine 
sleep agents such as zolpidem, as well as non-prescription sleep aids. Some of the most common 
side effects of these medications include cognitive impairment, risk of dependence and abuse, 
risk of respiratory depression, dependence in association with alcohol use and/or sleep apnea, 
next day sedation, and weight gain. Whereas some of the drugs used to treat insomnia in MDD 
have intrinsic antidepressant effects (eg, trazodone, tricyclic antidepressants), the doses used to 
relieve insomnia symptoms are usually lower than typical antidepressant doses and their use does 
not always help to improve depressive symptoms. Hypnotics have also shown inconsistent 
effects on depressive symptoms when used adjunctively with antidepressants in patients with 
MDD. For example, whereas no improvement in depressive symptoms was measured after 
8 weeks of treatment with zolpidem in combination with escitalopram,13 a small but significant 
effect was observed after treatment with eszopiclone in combination with fluoxetine.14 In these 
studies, depressed subjects with sleep problems were included, but subjects were not selected for 
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 The 
present study is being conducted to investigate the antidepressant effects of a range of doses of 
JNJ-42847922 (versus placebo), as adjunctive treatment to standard of care, and to further assess 
the safety and tolerability of JNJ-42847922. The study will utilize the change in the 
Montgomery-Asberg Depression Rating Scale (MADRS; the structured interview guide for the 
MADRS [SIGMA] will be used) total score from baseline to the end of Week 6 for assessment 
of efficacy. The results of this study will be used to select doses and endpoints in subsequent 
confirmatory Phase 3 and long-term safety studies.
1.3.
Overall Risk and Benefit Assessment
As further described in Section 1 and the rationale for this study (Section 1.2), MDD is a 
common, serious, recurrent mental disorder. MDD is the leading cause of disability, and its 
prevalence is rising.63
Current therapies commonly used as first-line ADT in patients with MDD (eg, SSRIs and 
SNRIs) are sub-optimally effective in some patients who require adjunctive treatment, or who 
are otherwise poorly compliant because of their associated adverse events, such as weight gain 
and sexual side effects. Currently approved adjunctive treatments are limited to the atypical 
antipsychotic drug class, which also present considerable tolerability concerns (eg, metabolic 
syndrome, akathisia, and extrapyramidal symptoms [EPS]). The orexin-receptor antagonist class 
offers a novel mechanism of action that may prove to be a valuable alternative in the adjunctive 
treatment of MDD, but without the side effects observed with other medications commonly used 
in this setting such as weight gain, sexual side effects, akathisia, or EPS. The preliminary data 
regarding effects on cortisol and stress-response suggest that JNJ-42847922 may have clear 
advantages over the standard of care in patients with certain co-morbid medical conditions 
typically associated with dysregulation of the HPA axis. 
The currently available data (see Section 1.1.2, Clinical Studies, and the JNJ-42847922 
Investigator’s Brochure22) support this clinical study that investigates the efficacy and safety of 
JNJ-42847922 in adult subjects with MDD who have responded inadequately to commonly used 
ADTs.
The antidepressant effect of JNJ-42847922 was clinically relevant as early as Day 11 of exposure 
and was sustained at least 14 days after treatment discontinuation. The effect of JNJ-42847922 
was largely related to an effect on the core symptoms of depression, and overall unrelated to its 
effect on sleep related events. 
Additionally, the safety and tolerability data so far accumulated for JNJ-42847922 in both 
healthy subjects and subjects with MDD and/or insomnia were generally acceptable based on a 
thorough review of the safety information from completed clinical studies. No death or SAEs
were reported after subjects received JNJ-42847922. The most commonly reported TEAEs were 
somnolence, headache, and dizziness with most TEAEs being mild or moderate in intensity. 
Adverse drug reactions attributed to JNJ-42847922 were sleep paralysis, somnolence, and 
abnormal dreams. Few subjects reported these events at doses planned for this study and all were 
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self-limited and mild or moderate in intensity. Based on the short half-life of JNJ-42847922, no 
accumulation of study drug is expected. (Refer to Section 1.1.2, Clinical Studies, and the 
JNJ-42847922 Investigator’s Brochure22 for additional details). 
To ensure safe use of the study drug, besides routine safety monitoring and subject management, 
this protocol also includes specific risk mitigation strategies, including: exclusion of WOCBP,
since a female rat fertility study suggested that JNJ-42847922 reduced female fertility rates at all 
doses studied (however, WOCBP subjects who are currently enrolled in this study may continue 
study participation following discussion between the subject and the investigator of the new rat 
fertility study results, if they have a negative pregnancy test, and are using reliable 
contraception). Other risk mitigation strategies include: restrictions on driving, operating 
machinery, or engaging in hazardous activity when subjects have had less than 6 hours sleep the 
night before (Section 4.3, Prohibition and Restrictions); overnight in-house observation of 
subjects at study sites after the first dose administration of study drug (see Time and Events 
Schedule); paying special attention to clinically significant adverse events that are known to have 
been reported in drugs of the same pharmacological class (Section 9.6, Safety 
Evaluations/Adverse Events of Special Interest); and reducing suicidality risk inherent in the 
underlying depression by excluding high risk subjects (Section 4.2, Exclusion Criteria) and 
performing C-SSRS at every site visit (Section 9.6, Safety Evaluations/C-SSRS). 
The information obtained to date regarding JNJ-42847922 suggests that the potential benefits to 
patients with MDD in fulfilling an unmet medical need outweigh the identified (ie, ADRs) and 
potential risks (see Adverse Events of Special Interest in Section 9.6, Safety Evaluations) at the 
doses selected for further investigation.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the dose-response relationship of up 
to 3 doses of JNJ-42847922 (20, and 40 mg,
with 10 mg potentially added at the interim 
analysis) compared to placebo as adjunctive 
therapy to an antidepressant drug in improving 
depressive symptoms in subjects with MDD 
who have had an inadequate response to current 
antidepressant therapy with a selective serotonin 
reuptake 
inhibitor 
(SSRI)
or 
serotonin-
norepinephrine reuptake inhibitor (SNRI).

Change from baseline to the end of Week 6 
in the MADRS total score.

To assess the safety and tolerability of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant in 
subjects with MDD.

Safety 
assessments,
including 
adverse 
events, laboratory values, ECG, vital signs, 
physical exam, the C-SSRS, the Arizona 
Sexual Experiences Scale (ASEX), and the 
Physician Withdrawal Checklist (PWC).


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Objectives
Endpoints
Secondary

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to an 
antidepressant 
in 
improving 
depressive 
symptoms 
in 
subjects 
with 
MDD 
with 
significant 
insomnia 
symptoms 
(baseline 
Insomnia Severity Index [ISI] score ≥15) versus 
those without significant insomnia symptoms 
(baseline ISI score <15).

Correlation between baseline ISI score as a 
continuous 
variable 
and 
change 
from 
baseline to the end of Week 6 in the 
MADRS total score.

Change from baseline to the end of Week 6 
in the MADRS total score in subjects with 
baseline ISI score ≥15 versus subjects with 
baseline ISI score <15.

Shift in ISI score category from baseline to 
the end of Week 6.

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to an 
antidepressant in improving:

Response and remission of depressive 
symptoms

Proportion of responders on depressive 
symptoms scale, defined as a ≥50% 
improvement in MADRS total score 
from baseline to the end of Week 6.

Proportion of subjects with remission of 
depressive symptoms, defined as a 
MADRS total score ≤8, ≤10, or ≤12 at 
the end of Week 6.

Anxiety symptoms

Change from baseline to the end of 
Week 6 on the 14-item Hamilton 
Anxiety Rating scale (HAM-A) total 
score.

Response of anxiety symptoms

Proportion of responders on anxiety 
symptoms scale, defined as a ≥50% 
improvement in the HAM-A total score 
from baseline to the end of Week 6.

Clinical severity

Change from baseline to the end of 
Week 
6 
in 
the 
Clinical 
Global 
Impression-Severity (CGI-S) score.

Global functioning (work/school, social 
and family life).

Change from baseline to the end of 
Week 6 in the Sheehan Disability Scale 
(SDS).

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to an 
antidepressant 
in 
improving 
depressive 
symptoms in the subpopulation of subjects with 
MDD with anxious distress.

Change from baseline to the end of Week 6 
in the MADRS total score in subjects with 
MDD with anxious distress versus subjects 
with MDD without anxious distress. 

To evaluate the effect of JNJ-42847922 
exposure on the HPA axis in subjects with 
MDD.

Change from baseline to Weeks 2, 4, and 6 
in salivary cortisol levels, as measured upon 
awakening.


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Objectives
Endpoints

To assess the exposure of JNJ-42847922 and 
metabolites M12 and M16 in subjects with 
MDD.

Observed 
plasma 
concentrations 
of 
JNJ-42847922 and metabolites and estimated 
exposure parameters for JNJ-42847922 from 
population based PK modeling.

To capture patient-reported
assessment of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant.

Change from baseline to the end of Week 6 
in:

Depressive symptoms using the Patient 
Health Questionnaire 9-item (PHQ-9)

Anhedonia using the Snaith-Hamilton 
Pleasure Scale (SHAPS)

Sleep disturbance using the Patient 
Reported 
Outcome 
Measurement 
Information System-Sleep Disturbance 
(PROMIS-SD) Short Form

Fatigue using the PROMIS-Fatigue
Short Form

Severity of depression using the Patient 
Global Impression-Severity (PGI-S)

Health related quality of life and utility 
using the European Quality of Life 
(EuroQol) 
Group, 
5-Dimension, 
5-Level (EQ-5D-5L) questionnaire

Work productivity and limitations using 
the Work Limitations Questionnaire 
(WLQ) Short Form.
In addition, the exploratory objectives are:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers 
(HPA axis function, biomarkers of immune system activation and oxidative stress) in 
relation to clinical response on depression symptoms upon adjunctive treatment with 
JNJ-42847922

To explore the exposure/response relationship of JNJ-42847922 in subjects with MDD

To identify genetic factors that may influence the PK, safety, or tolerability of 
JNJ-42847922

To assess the predictive capability of salivary cortisol levels assessed during the circadian 
nadir (predose in the evening) on the antidepressant effect of JNJ-42847922.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.


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2.2.
Hypothesis
The hypothesis for this study is that adjunctive treatment with JNJ-42847922 is superior to 
placebo in treating depressive symptoms, as measured by change in MADRS total score from 
baseline to the end of 6 weeks, and exhibits a dose-response relationship, in adult subjects with 
MDD who have had an inadequate response to treatment with an SSRI/SNRI.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, double-blind, randomized, parallel-group, placebo-controlled, 6-week 
adaptive dose-finding study to assess the efficacy and safety of JNJ-42847922 as adjunctive 
therapy in adult subjects with MDD who have had an inadequate response to current 
antidepressant therapy with an SSRI/SNRI. Approximately 280 subjects will be randomized.
The doses of JNJ-42847922 that will be studied prior to the interim analysis are known (ie,
20 and 40 mg), whereas the doses of JNJ-42847922 to be studied after the interim analysis will 
be adaptively chosen based on the dose-response curve observed at the interim analysis. During 
the interim analysis review period, subjects will continue to be randomized, according to the 
initial randomization scheme. Regardless of whether subjects are randomized before or after the 
interim analysis, the schedule of events and study procedures will remain the same. The final 
analysis will include all subjects.
Initially, the study will assess the efficacy, dose- and exposure-response relationship, safety, and 
tolerability of JNJ-42847922 20 and 40 mg doses compared to placebo, when administered as 
adjunctive therapy to an SSRI/SNRI antidepressant. At the start of the study, subjects will be 
randomized in a 2:1:1 ratio to receive 1 of 3 treatments: placebo: JNJ-42847922 20 mg: 
JNJ-42847922 40 mg.
The data cutoff for the unblinded interim analysis will be 6 weeks after randomization of 
160 subjects. An Interim Analysis Committee (IAC) will be established to review the interim 
data to examine the dose-response relationship and determine the doses of JNJ-42847922 and the 
allocation ratio of the doses to be used after the interim analysis. See Section 11.8 for additional 
details on interim analysis. 
After the interim analysis, subjects will be randomly assigned to study drug (placebo or one of 
the JNJ-42847922 doses [potential doses include 10 mg, 20 mg, 40 mg]), with the allocation 
ratio adapted according to the dose-response curve seen at the interim analysis. 


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A schematic overview of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study Design
Abbreviations: IA=interim analysis, MDD=major depressive disorder, PK=pharmacokinetics, QD=once daily, 
SSRI= selective serotonin reuptake inhibitor, SNRI=serotonin-norepinephrine reuptake inhibitor.
For all subjects, the study will consist of 3 phases: a screening phase (up to 4 weeks), a double-
blind treatment phase (6 weeks), and a posttreatment follow-up phase (2 weeks). Subjects will 
continue to take their baseline SSRI/SNRI antidepressant (at the same dose, without change, and 
at approximately the same time as prior to entering the study) throughout the screening, 
double-blind, and follow-up periods (the entire 12 weeks of the study duration).
In order to collect PK and salivary cortisol samples after the Day 1 dose, subjects will stay at the 
study site from at least 1 hour before the bedtime dosing on Day 1 until the morning of Day 2.
The PK and cortisol samples will be collected from most subjects; however, in some 
circumstances, subjects may not be able to stay overnight on Day 1 for the sample collection. 
Since the collection of PK and cortisol samples does not relate to the primary assessments of 
safety and efficacy, an exception to the overnight stay and collection of samples (PK and 
cortisol) may be made after discussion with the sponsor’s medical monitor. The reason for the 
exception must be documented in the source documents. Subjects who do not stay overnight will 
take their Day 1 dose at home (at bedtime, approximately 3 hours after the last meal).


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Screening Phase
After providing written informed consent and within 4 weeks prior to randomization, outpatient 
subjects experiencing a major depressive episode will be screened to evaluate their eligibility for 
study participation. In order to be eligible for the study, subjects must meet the following 
criteria:

DSM-5 diagnostic criteria for MDD, without psychotic features, based upon clinical 
assessment and confirmed by the Structured Clinical Interview for DSM-5 Axis I Disorders–
Clinical Trials Version (SCID-CT).

The current depressive episode must be deemed valid by the SCID Screening Questionnaire 
(SSQ).

MADRS total score ≥25 at screening and must not demonstrate a clinically significant 
improvement (ie, an improvement of >20% on their MADRS total score) from the screening 
to baseline visit.

Inadequate response to at least 1 but no more than 3 antidepressants, administered at an 
adequate dose and duration in the current episode of depression, as assessed by the 
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ).
See Section 9.1.2, Screening Phase, for additional details on screening procedures.
Double-Blind Treatment Phase
As mentioned above, at the start of the study, subjects will be randomly assigned in a 2:1:1 ratio 
to receive 1 of 3 treatments: placebo: JNJ-42847922 20 mg: JNJ-42847922 40 mg. Subjects 
randomized after the interim analysis will be assigned to receive placebo or one of the 
JNJ-42847922 doses, with the allocation ratio adapted according to the dose-response curve seen
at the interim analysis (potential doses of JNJ-42847922 include 10 mg, 20 mg, 40 mg). All other 
study procedures during the double-blind treatment phase will remain the same for subjects 
randomized either before or after the interim analysis, and will occur as per the Time and Events 
Schedule.
On Day 1 of the double-blind treatment phase, the assigned study drug (blinded placebo or
JNJ-42847922) will be administered at the study site (at bedtime, approximately 3 hours after the 
last meal), and PK and salivary cortisol samples will be collected at the study site in subjects 
participating in the overnight stay. For the remainder of the study (from Day 2 to Day 41), the 
assigned study drug will be self-administered by the subject at home at bedtime, approximately
3 hours after the last meal. For subjects who don’t participate in the overnight stay on Day 1, the 
study drug will be self-administered at home throughout the double-blind treatment phase (from 
Day 1 to Day 41 [once daily at bedtime, approximately 3 hours after the last meal]). 
See Section 9.1.3, Double-blind Treatment Phase for additional details.


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Posttreatment (Follow-up) Phase
One day after completion of the double-blind phase, on Day 43 (Week 7), a telephone contact 
will be made for follow-up safety assessments. During this call, the PWC will be administered 
and information on adverse events and concomitant medications will be collected.
In addition, all subjects will complete a follow-up visit within 7 to 14 days after completion of 
the double-blind phase. If a subject discontinues study treatment before the end of Week 6, 
end-of-treatment and follow-up assessments should be obtained.
The total study duration for each subject will be up to approximately 12 weeks (84 days). The 
study will be considered completed after the final study visit for the last subject participating in 
the study.
See Section 9.1.4, Posttreatment Phase (Follow-up) for additional details.
Study Evaluations
The efficacy of study drug will be evaluated using the MADRS (SIGMA version), HAM-A
(SIGH-A version), CGI-S, SDS, PHQ-9, SHAPS, PROMIS-SD (Short Form), PROMIS-Fatigue
(Short Form), PGI-S, EQ-5D-5L, and WLQ (Short Form). These evaluations will be performed 
at the time points specified in the Time and Events Schedule. The Ruminative Response Scale 
(RRS) will be collected at baseline only, and will be evaluated as a potential predictor of 
treatment outcome.
The safety and tolerability of the study drug will be evaluated throughout the study. In addition 
to standard/routine assessments, the safety assessment in this study will include the ASEX, 
C-SSRS, and PWC.
Blood samples for PK and biomarker evaluation will be collected on the study visits specified in 
the Time and Events Schedule. Evening and morning salivary cortisol samples will be collected 
as specified in the Time and Events Schedule.
Blood samples for genetic research will be collected from subjects who consent separately to this 
component of the study (where local regulations permit) to allow for the identification of genetic
and/or epigenetic factors that may influence the PK, efficacy, safety, or tolerability of 
JNJ-42847922 and to identify genetic and/or epigenetic factors associated with MDD. Subject 
participation in genetic research is optional. DNA samples collected from Japanese subjects will 
only be used for research related to JNJ-42847922 and will not be used for research related to 
MDD.
3.2.
Study Design Rationale
Study Population
In the context of mood disorders, sleep disturbances (both insomnia and hypersomnia) have been 
associated with a suboptimal response to antidepressant drug therapy, an increased risk for 
relapse (in antidepressant-responsive patients), and prodromal depression.4,5,24,25,59 While the 


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orexin system promotes wakefulness, increasingly it is also associated with hyperarousal3 and 
motivational behaviors.48 Hyperarousal characterizes a major subgroup of patients with MDD.18
OX2R antagonists may have utility to normalize hyperarousal in patients with MDD and thereby 
have an antidepressant effect independent from their utility as hypnotics. It is proposed that in 
many patients a cycle exists that involves rumination/dysphoric arousal leading to sleep 
problems, thereby perpetuating/exacerbating a depressive episode.37
Therefore, OX2R
antagonists, such as JNJ-42847922 may have clinical efficacy in the treatment of MDD, 
particularly in patients with such symptoms, and especially as an adjunctive therapy to 
conventional antidepressant drug therapy.
The study population will include adult men and WONCBP (aged 18 to 70 years, inclusive) who 
meet DSM-5 diagnostic criteria for MDD (confirmed by the SCID-CT), 15 and who have had an 
inadequate response to current antidepressant therapy with an SSRI/SNRI (administered at an 
adequate dose and duration in the current episode). The diagnosis of MDD will be validated by 
the SSQ. The SSQ criteria identify subjects who, despite meeting DSM criteria, would be poor 
candidates for drug trials and whose exclusion from the study may increase the likelihood of 
separation between novel antidepressant treatments and placebo.
Unlike many other mental disorders, the age of onset of depression has a wide range, with a 
median onset of early to mid-20s, although significant proportions of patients may experience 
onset between late adolescence to late adulthood. Hence, the age of the study population in this 
protocol is intentionally broad. Women have a two-fold increased risk of depression over men, 
and separation and divorce are additional risk factors across the sexes.26
Definitive GLP studies in pregnant rats and rabbits to evaluate the effects of JNJ-42847922 on 
embryo-fetal development have been completed.
JNJ-42847922 did not induce any 
developmental alterations (external, visceral, and skeletal) in the fetuses. However, a female rat 
fertility study suggested a reduction in female fertility. Since it is not known what the relevance 
of these findings are to a woman’s ability to become pregnant after taking JNJ-42847922, no 
new WOCBP will be included in this study until more is learned about the effect of 
JNJ-42847922 on female reproduction. WOCBP subjects, who are currently enrolled in this
study, may continue study participation following discussion between the subject and the 
investigator of the new rat fertility study results, if they have a negative pregnancy test, and are 
using reliable contraception. 
Blinding, Control, and Treatment Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment. Randomization will be used to 
minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that 
known and unknown subject attributes (eg, 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.


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To test the hypothesis that JNJ-42847922 improves depressive symptoms in subjects with and 
without significant insomnia, randomization will be stratified and roughly balanced between
subjects with a baseline insomnia severity index (ISI) score <15 (subclinical or no clinically 
significant insomnia) and ≥15 (moderate to severe insomnia). This distribution will essentially 
mimic the prevalence of significant insomnia in representative samples of subjects with MDD 
reported in the literature, where mean ISI scores are reported to be approximately 14 (Kenter 
201666: mean ISI score =13.8; SEM 6.3) or 15 (Mason 201467: mean ISI score=14.70; 
SEM=0.92).
Adaptive Design and Interim Analysis
An adaptive design will be used in order to better characterize the shape of the dose-response 
curve. At the start of study enrollment, subjects will be randomly assigned in a 2:1:1 ratio to 
receive 1 of 3 treatments: placebo: JNJ-42847922 20 mg: JNJ-42847922 40 mg.
The doses of JNJ-42847922 to be studied and allocation ratio after the interim analysis will be 
adaptively chosen based on the dose-response relationship established at the time of the interim 
analysis (potential doses of JNJ-42847922 include 10 mg, 20 mg, 40 mg).
The primary purpose of the interim analysis will be to determine the doses of JNJ-42847922 to 
be used after the interim analysis and the allocation ratio of these doses to be used in subjects 
randomized after the interim analysis. The interim analysis will use the generalized Multiple 
Comparison Procedure-Modeling (MCP-Mod) approach to establish a dose-response signal with 
respect to the primary efficacy endpoint. 
Dose and Dose Administration Interval
The JNJ-42847922 doses selected at the start of the study are 20 and 40 mg, and the 
JNJ-42847922 doses selected after the interim analysis are one or more of the following potential 
doses: 10 mg, 20, and/or 40 mg. The doses chosen are within the range shown to be 
well-tolerated in the Phase 1 studies. Additionally, in study 42847922MDD1001, a clinically 
relevant antidepressant effect was shown after daily administrations of the 20 mg dose in the 
evening (for 10 days in WOCBP and 28 days in women of non-childbearing potential and men).
There was also a suggestion of efficacy and a reduction in morning cortisol levels in the 
42847922EDI1002 study, in which single doses of 10 to 40 mg were studied.
The present study will begin with the JNJ-42847922 20 and 40 mg doses in order to obtain 
preliminary information regarding the dose-response curve. An interim analysis will then be 
performed to optimize allocation up to a total of 3 possible active dose levels in the study after 
interim analysis, in order to fully characterize the shape of the dose-response curve.
The proposed dose range for this study (10 mg up to 40 mg) was selected based on anticipated 
efficacious dose levels, plasma exposures in relation to the NOAEL in GLP toxicology studies, 
the clinical safety and tolerability profile, and anticipated plasma exposures across the selected 
dose levels.


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JNJ-42847922 has been studied as a single evening dose of 10, 20 and 40 mg in subjects with 
MDD with insomnia who were stable on their current antidepressant treatment (Study 
42847922EDI1002). Treatment with JNJ-42847922 showed a trend towards a decrease in 
depressive symptoms compared to placebo, as measured by the QIDS-SR14. The largest mean 
change from Day 1 to Day 2 in the QIDS-SR14 total score was observed in the 40-mg 
JNJ-42847922 treatment group (-2.1 points). Mean changes in the 10- and 20-mg JNJ-42847922 
treatment groups were similar in magnitude (-1.4 and -1.3 points, respectively). The smallest 
mean change was observed in the placebo group (-0.7 points). In study 42847922MDD1001, 
subjects with moderate to severe MDD who were either antidepressant naive or being treated 
with a maximum of 2 concurrent antidepressants were randomized to 1 of 3 treatment groups 
(JNJ-42847922 20 mg, diphenhydramine 25 mg, or placebo) in a ratio of 2:1:1. All doses were 
administered at nighttime. The double-blind treatment period was a maximum 10 days for 
WOCBP and 28 days for all other subjects. Overall, a larger improvement in clinician-rated 
depression symptoms was observed from subjects randomized to treatment with JNJ-42847922 
compared with placebo and diphenhydramine. The observed change in the HAM-D17 scores in 
the JNJ-42847922 treatment group was not related to a preferential effect of JNJ-42847922 on 
sleep items, but to an improvement in the core symptoms of depression. In both studies, the 
doses of JNJ-42847922 were well tolerated in the target population.
While there were no reports of severe somnolence reported in subjects exposed to 
JNJ-42847922, 1 subject receiving 60 mg morning dose in Study 42847922EDI1003 was 
reported to have insomnia and somnolence on Day 3 and Day 4 and was discontinued from the 
study due to the events on Day 5. Based on the apparent dose-limiting tolerability, 40 mg was
selected as the upper dose limit in this study to evaluate the efficacy of JNJ-42847922 in the 
adjunctive treatment of MDD.
The doses of JNJ-42847922 to be studied after the interim analysis will be adaptively chosen 
based on the dose-response relationship established at the time of the interim analysis. The 
lowest potential dose of JNJ-42847922 in this study is 10 mg. It is considered unlikely that doses 
lower than 10 mg will be clinically effective. Therefore, a dose range of 10 to 40 mg was 
selected for this study in order to preserve a good safety ratio relative to GLP toxicology 
exposures and to maximize the chance of observing an efficacy effect.
 
 
 
DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in drug distribution and response and can also serve as a marker for disease 
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to a drug. The goal of the pharmacogenomic component is to collect DNA to allow 
the identification of genetic and/or epigenetic factors that may influence the PK, efficacy, safety, 
or tolerability of JNJ-42847922 and to identify genetic and/or epigenetic factors associated with 
CCI


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MDD. Specifically, genetic and epigenetic changes in genes known to be in pathways relevant to 
depression (HPA axis, inflammation, growth factors, monoamine transporters, ion channels, 
circadian rhythm) will be evaluated.
Increasingly, it is recognized that psychiatric disorders may be associated with altered 
immune/metabolic activation patterns. Blood and saliva samples will be collected to explore 
biomarkers related to immune system activity, HPA axis activation, and neurotropic factors 
(including but not limited to growth factors, inflammation, or endocrine markers). Many of these 
factors may be influenced by stage of menstrual cycle in women; therefore menstrual cycle will 
be tracked in premenopausal women during the study, by the subject’s verbal report. Biomarker 
samples may help to explain interindividual variability in clinical outcomes or identify 
population subgroups that respond differently to JNJ-42847922.
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.
Efficacy Measures
Primary Efficacy Measure
MADRS: The 10-item clinician-administered MADRS was designed to be used in subjects with 
MDD to measure the overall severity of depressive symptoms.35 The MADRS scale has been 
selected as a primary endpoint for this study because it is validated, reliable, and acceptable to 
regulatory health authorities as a primary scale to determine efficacy in major depression. The 
structure interview guide version (SIGMA) will be used in this study. The SIGMA has been 
shown to achieve high reliability of MADRS scores in evaluating patients with depression.61
Secondary Efficacy Measures
HAM-A: The original 14-item clinician-administered HAM-A scale assesses the severity of 
different anxiety-related symptoms. It is a commonly used, validated scale in clinical trials 
assessing anxiety.20,21 However, the original HAM-A lacks instructions for administration and 
clear anchor points for the assignment of severity ratings. For this reason, the structured 
interview guide (SIGH-A) version will be used in this study. The SIGH-A has been shown to 
have high inter-rater and test-retest reliability and produced similar but consistently higher (+4.2) 
scores compared to the original HAM-A. Correlation with a self-report measure of overall
anxiety has also been shown to be high.62
SDS: The SDS has been widely used and accepted for assessment of functional impairment and 
associated disability.30,54
PROMIS-SD and PROMIS-Fatigue: These measures were developed using state of the art 
psychometric techniques such as Item Response Theory Models and have been shown to 
adequately represent sleep disturbance and fatigue domains. These measures provide high total 
test information with high validity and reliability.44,65 Short form versions (consisting of 8 items)
of the PROMIS-SD and PROMIS-Fatigue will be used in this study.


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CGI-S and PGI-S: The CGI-S and PGI-S will be used to allow assessment of minimal clinically 
important difference using an anchor based approach calculated from the global impressions of
the clinician and the subject.6,17
PHQ-9: The PHQ-9 will be used as a patient-reported measure of depressive symptomatology.55
Construct validity and criterion validity have been assessed and the PHQ-9 proved to be a 
reliable and valid measure of depression severity.28
SHAPS: The SHAPS is a reliable, valid, and unidimensional instrument to assess hedonic 
capacity in adults with MDD.36
EQ-5D-5L: The EQ-5D-5L is included as a standardized patient-completed instrument for use as 
a measure of health-related quality of life and health status.11,12
WLQ: The WLQ is a patient-reported outcome (PRO) tool to assess the on-the-job impact of 
chronic health problems and/or treatment. Its content validity has been established through 
condition-specific focus groups and its measurement properties are documented as strong.31,32,33
A short form version consisting of 8 items will be used in this study.
RRS: The RRS will be collected at baseline only, and will be evaluated as a potential predictor 
of treatment outcome.37
For additional details on efficacy measures, see Section 9.2.
Pharmacokinetic Assessments
A population PK analysis using PK data from a selection of Phase 1 and Phase 2 studies will be 
performed at the completion of the study and at the interim analysis. The purpose of the planned 
population PK analysis will be to assess the PK of JNJ-42847922 (and, if needed, of metabolites 
M12 and M16) in the target patient population, and the potential impact of covariates. PK 
collection will also enable the evaluation of the relationship between parent drug concentration 
and metabolites M12 and M16, and the exploration of the correlation of exposure to efficacy or 
safety measures. These analyses will be helpful in identifying optimal doses and dosing regimens 
to evaluate in subsequent studies. 
Safety Evaluations
Standard safety evaluations including collection of adverse events and concomitant medications, 
physical examination, body weight, waist circumference, vital signs, 12-lead ECG, urine drug 
screening, alcohol breath test, and clinical laboratory tests will be performed to monitor subject 
safety throughout the study. Pregnancy testing (serum pregnancy test at screening and urine 
pregnancy test thereafter) should be performed as needed per the investigator’s judgment. For 
WOCBP, who enrolled in the study before Amendment 5 and who continue in the trial, a serum 
pregnancy test must be performed at screening, and urine pregnancy tests must be performed at 
Day 1, Day 22, Day 42 (End-of Treatment/Early Withdrawal), and at the Follow-up Visit to 
establish absence of pregnancy.


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Emergence of suicidal ideation will be assessed using the C-SSRS. The C-SSRS has been used 
frequently in clinical studies and it is a standard measure for suicidal ideation assessment; its use 
is in accordance with Food and Drug Administration (FDA) guidance.58
The effect on sexual functioning will be measured by the ASEX. The ASEX has shown 
satisfactory reliability and validity.34
In addition, potential withdrawal effects will be assessed by the clinician using the PWC. The 
PWC is a reliable and sensitive instrument for the assessment of discontinuation symptoms.47
Adverse Events of Special Interest
Prior studies with DORAs (eg, suvorexant) suggest that such agents may precipitate cataplexy 
(sudden, transient episode of muscle weakness accompanied by conscious awareness) and sleep 
paralysis (the experience of not being able to move, react, or speak when falling 
asleep/awakening). Animal studies suggest that cataplexy may be a liability for DORAs, but not 
for OX2R-selective antagonists.9 To date, 3 cases of sleep paralysis have been observed with 
JNJ-42847922: 1 each from studies 42847922EDI1001 (80 mg dose), 42847922EDI1006 (20 mg 
dose), and 42847922ISM2002 (40 mg dose). Complex, sleep-related behaviors/parasomnias such 
as confusional arousals, somnambulism (sleep walking), sleep terrors, bruxism (teeth grinding), 
sleep sex, sleep-related eating disorder, 
sleep behavior disorder, and catathrenia 
(REM-associated end-inspiratory apnea/breath holding) have been noted with exposure to 
hypnotic drugs. For these reasons, cataplexy, sleep paralysis, and complex, sleep-related 
behaviors (parasomnias) are considered adverse events of special interest in this study.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before administration of the 
study drug.
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 must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. Exceptional and limited 
retesting of abnormal screening values that lead to exclusion may be allowed after discussion and 
approval by the sponsor during the screening period (to reassess eligibility). This should only be 
considered if there is no anticipated impact on subject safety.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.


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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
1.1. Criterion Modified per Amendments 1 and 5
1.2 Men or WONCBP, aged 18 to 70 years (inclusive). Note: Subjects should be at 
least 18 years of age or older as per the legal age of consent in the jurisdiction in 
which the study is taking place.
A WONCBP is defined as: 
o
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) 
level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.
o
Permanently sterile
Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
If reproductive status is questionable, additional evaluation should be 
considered.
2.
2.1 Criterion Modified per Amendments 1, 2, and 5
2.3 Meet DSM-5 diagnostic criteria for MDD, without psychotic features (DSM-5 
296.22, 296.23, 296.32, or 296.33), based upon clinical assessment and confirmed 
by the SCID-CT. In addition, their major depressive episode must be deemed 
“valid” using the SSQ interview administered by remote, independent raters. The 
length of the current depressive episode must be ≤18 months.
3.
3.1 Criterion Modified per Amendments 1, 3, and 5
3.3 Have had an inadequate response to at least 1 but no more than 3 antidepressants 
(see the inclusion criterion below), administered at an adequate dose and duration 
in the current episode of depression, as measured by the MGH-ATRQ. An 
inadequate response is defined as <50% reduction in depressive symptom 
severity, as assessed by the MGH-ATRQ. An adequate trial is defined as an 
antidepressant treatment for at least 4 weeks at or above the minimum therapeutic
dose specified in the MGH-ATRQ, for any particular antidepressant. The 
inadequate response must include the subject’s current antidepressant treatment.
4.
4.1 Criterion Modified per Amendments 1, 2, 3, and 5
4.4 Is receiving monotherapy treatment for depressive symptoms with one of the 
following SSRI/SNRI antidepressants, in any formulation: citalopram, duloxetine, 
escitalopram, fluvoxamine, fluoxetine, milnacipran, levomilnacipran, paroxetine, 
sertraline, venlafaxine, desvenlafaxine, vilazodone, or vortioxetine at a stable dose 
(at or above the minimum therapeutic dose level) for at least 4 weeks, and for no 


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greater than 12 months, at screening. Modification of an effective preexisting 
therapy should not be made for the explicit purpose of entering a subject into the 
study.
Note: Dose and duration of treatment should be verified by the investigator using 
the medical or pharmacy records. The investigator will use this information to 
complete the MGH-ATRQ, which will then be corroborated by the independent 
rater.
5.
5.1 Criterion Modified per Amendments 1 and 3
5.2 Have a MADRS total score ≥25 (performed by independent, centralized remote 
raters) at screening and must not demonstrate a clinically significant improvement 
(ie, an improvement of >20% on their MADRS total score) from the screening to 
baseline visit.
6.
Criterion Modified per Amendment 3
6.1 Body 
mass 
index 
(BMI)
between 
18 
and 
35
kg/m2
inclusive 
(BMI=weight/height2).
7.
Must be an outpatient at screening.
8.
Criterion Modified per Amendment 3
8.1 Must be otherwise healthy on the basis of physical examination, medical history, 
vital signs, 12-lead ECG, and clinical laboratory tests performed at screening. If the 
results of the clinical laboratory tests are outside the normal reference ranges, the 
subject may be included only if the investigator judges the abnormalities or deviations 
from normal to be not clinically significant or to be appropriate and reasonable for the 
population under study. This determination must be recorded in the subject's source 
documents and initialed by the investigator.
9.
9.1 Criterion Modified per Amendments 2 and 3
9.2 Must sign an informed consent form (ICF) indicating that he or she understands 
the purpose of and procedures required for the study and be willing to participate 
in the study.
10.
Criterion Deleted per Amendment 5
11.
Criterion Deleted per Amendment 5
12.
Criterion Modified per Amendment 5
12.1 A woman must agree not to donate eggs (ova, oocytes) for the purposes of 
assisted reproduction during the study and for a period of at least 1 month after 
receiving the last dose of study drug.


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13.
13.1 Criterion Modified per Amendments 1 and 5
13.2 During the study and for a minimum of 1 spermatogenesis cycle (defined as
approximately 3 months) after receiving the last dose of study drug, a man:

who is sexually active with a woman of childbearing potential must agree to 
use a barrier method of contraception (eg, condom with spermicidal 
foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a condom

must agree not to donate sperm.
14.
Be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol.
15.
Must sign a separate informed consent form (or their legally-acceptable representative 
must sign) if he or she agrees to provide optional DNA samples for research (where 
local regulations permit). Refusal to give consent for the optional DNA research 
samples does not exclude a subject from participation in the study.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
1.1 Criterion Modified per Amendments 3 and 5
1.2 Has a history of, or current signs and symptoms of, severe renal insufficiency 
(creatinine clearance <30 mL/min); moderate to severe hepatic insufficiency (Child-
Pugh Score 7-9), significant or unstable cardiovascular, respiratory, gastrointestinal, 
neurologic (including narcolepsy),
hematologic, rheumatologic, immunologic or 
endocrine disorders (including uncontrolled hypo- or hyperthyroidism or diabetes, or 
insulin-dependent diabetes mellitus). Subjects with non-insulin dependent diabetes 
mellitus who are well-controlled (hemoglobin A1C [HbA1C] ≤7.5% and fasting glucose 
<126 mg/dL at screening) may be eligible to participate if otherwise medically healthy, 
and if on a stable regimen of glucose-lowering medications for at least 2 months prior to 
screening.
2.
Criterion Modified per Amendment 1
2.1 Has current signs/symptoms of hypothyroidism or hyperthyroidism (Subjects with 
known hypothyroidism who have been on stable treatment for at least 3 months 
prior to screening are required to have thyroid-stimulating hormone [TSH] and free 
thyroxine [FT4] obtained. Any subject with an elevated TSH should also have FT4
measured. In any case where the TSH value is out of range, but FT4 is normal, the 
findings should be discussed directly with the medical monitor before the subject is 
enrolled. If the FT4 value is out of range, the subject is not eligible. Subjects taking 
thyroid supplementation for antidepressant purposes are not allowed in the study).


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3.
Has signs and symptoms of Cushing’s Disease, Addison’s Disease, primary 
amenorrhea, or other evidence of significant medical disorders of the HPA axis.
4.
Criterion Modified per Amendment 1
4.1 Has a current or recent history of serious suicidal ideation within the past 6 months, 
corresponding to a positive response on item 4 (active suicidal ideation with some 
intent to act, without specific plan) or item 5 (active suicidal ideation with specific 
plan and intent) for ideation on the 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 of any sort, or prior serious suicidal ideation/plan within the 
past 6 months, should be carefully screened for current suicidal ideation and only 
subjects with non-serious items (1-3 of the suicidal ideation section of the C-SSRS) 
may be included at the discretion of the investigator.
5.
5.1 Criterion Modified per Amendments 3 and 5
5.2 Has a history of lack of response to to 3 or more adequate antidepressant 
treatments, as indicated by no or minimal (≤25% improvement in symptoms) when 
treated with an antidepressant of adequate dose (per MGH-ATRQ) and duration (at 
least 4 weeks).
6.
Has a history or evidence of noncompliance with current antidepressant therapy.
7.
7.1 Criterion Modified per Amendments 1 and 3
7.2 Has taken a known moderate or strong inhibitor/inducer of CYP3A4 and CYP2C9 
or a dual inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days (or after 
washout ie, duration of 5 times the drug’s half-life) before the first study drug 
administration on Day 1. See Attachment 1 for examples of moderate and strong 
inhibitor/inducer of CYP3A4 and CYP2C9 or a dual inhibitor of CYP3A4 and 
CYP2C9.
8.
Criterion Modified per Amendment 1
8.1 Has a primary DSM-5 diagnosis of panic disorder, generalized anxiety disorder, 
social anxiety disorder, or specific phobia which has been the primary focus of 
psychiatric treatment within the past 2 years. Current or lifetime history of 
obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or 
bulimia nervosa is exclusionary.
9.
Criterion Modified per Amendment 3
9.1 Has history or current diagnosis of a psychotic disorder, bipolar disorder, mental 
retardation, autism
spectrum disorder, or borderline personality disorder, 
somatoform disorders, chronic fatigue syndrome or fibromyalgia.
10. Has any significant primary sleep disorder, including but not limited to obstructive sleep 
apnea, restless leg syndrome, or parasomnias.


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11. Criterion Modified per Amendment 3
11.1 Has significant hypersomnia that is not related to insomnia disorder (based on 
clinical judgment of the investigator).
12. Is a night-shift worker.
13. Has a history of substance or alcohol use disorder according to DSM-5 criteria within 
6 months before screening or positive test result(s) for alcohol and/or drugs of abuse 
(opiates 
[including 
methadone], 
cocaine, 
amphetamines, 
methamphetamines, 
cannabinoids, 
barbiturates, 
3,4-Methylenedioxymethamphetamine
[XTC] 
and 
benzodiazepines) at screening or at baseline.
14. Had a clinically significant acute illness within 7 days before the first dose of study 
drug.
15. Criterion Deleted per Amendment 3.
16. Has a known malignancy or history of malignancy within 5 years before screening 
(exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of 
the cervix, or malignancy that in the opinion of the investigator, with concurrence with 
the sponsor's medical monitor, is considered cured with minimal risk of recurrence).
17. 17.1 Criterion Modified per Amendments 1 and 3
17.2 Has clinically significant ECG abnormalities at screening or Day 1 prior to 
randomization defined as:
–
QT interval corrected according to Fridericia’s formula (QTcF): ≥450 msec 
(males); ≥470 msec (females)
–
Evidence of 2nd
and 3rd
degree atrioventricular block, or 1st
degree 
atrioventricular block with PR interval >200 msec, left bundle branch block 
(LBBB). 
–
At screening, history of additional risk factors for torsades des pointes (eg, heart 
failure, hypokalemia, family history of long QT syndrome, or the use of 
concomitant medications that prolong the QT/QTc interval)
–
Features of new ischemia
–
Valvular heart disease including mitral regurgitation and aortic stenosis
–
Other clinically important arrhythmia.
Note: Subjects with right bundle branch block (RBBB) may be allowed provided 
confirmation that RBBB is not associated with underlying cardiac/lung diseases.
18. Previous exposure to the study drug, JNJ-42847922.
19. Criterion Deleted per Amendment 3.
20. Criterion Modified per Amendment 3


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20.1 Has received any prior treatment with electroconvulsive therapy, vagal nerve 
stimulation, a deep brain stimulation device, or transcranial magnetic stimulation.
21. Criterion Deleted per Amendment 3.
22. Ongoing psychological treatments (eg, Cognitive Behavior Therapy, Interpersonal 
Psychotherapy, Psychodynamic Psychotherapy etc.), initiated within 2 months prior to 
start of the double-blind treatment phase. A subject who has been receiving ongoing 
psychological treatment for a period of greater than 2 months is eligible, if the 
investigator deems the psychological treatment to be of stable duration and frequency. 
23. Criterion Modified per Amendment 3
23.1 Has known allergies, hypersensitivity, intolerance or any contraindication to 
JNJ-42847922 or its excipients (refer to Investigator's Brochure for JNJ-42847922).
24. Criterion Deleted per Amendment 1.
25. Donation of 1 or more units (approximately 450 mL) of blood or acute loss of an 
equivalent amount of blood within 60 days before the first dose of study drug.
26. Has cognitive impairment that would render the informed consent invalid, or limit the 
ability of the subject to comply with the study requirements.
27. Has any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the subject (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
28. Has taken any disallowed therapies as noted in Section 8, Prestudy and Concomitant 
Therapy before the planned first dose of study drug. 
29. Has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 3 months before the planned first dose of 
study drug or is currently enrolled in an investigational study.
30. Criterion Modified per Amendment 5
30.1 Is pregnant, or breastfeeding, while enrolled in this study or within 1 month after 
the last dose of study drug.
31. Has plans to father a child while enrolled in this study or within 3 months after the last 
dose of study drug.
32. Has had major surgery, (eg, requiring general anesthesia) within 2 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.
Note: Subjects with planned surgical procedures to be conducted under local anesthesia 


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may participate.
33. Employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes significantly (including any available laboratory results or 
receipt of additional medical records) after screening but before the first dose of study drug is 
given such that he or she no longer meets all eligibility criteria, then the subject should be 
excluded from participation in the study. Section 17.4, Source Documentation, describes the 
required documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8, Prestudy and Concomitant Therapy for details regarding prohibited 
and restricted therapy during the study.
2.
2.1  Criterion Modified per Amendments 1 and 5
2.2  Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
Women of childbearing potential (WOCBP), enrolled in the study prior to 
Amendment 5 and who choose to continue in the trial need to adhere to all 
previously-stated contraceptive requirements (as described below):

A WOCBP must be:
o
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly)
Examples of highly effective contraceptives include
- user-independent methods:
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the subject.)
- user-dependent methods:
combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: oral, 


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intravaginal, and transdermal; progestogen-only hormone 
contraception associated with inhibition of ovulation: oral and 
injectable
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies.
The efficacy of the contraceptive method when given in combination with 
JNJ-42847922 has not been studied. 
o
agrees to remain on a highly effective method throughout the study and for 
at least 1 month after the last dose of study drug.
o
A woman using oral contraceptives must use an additional birth control 
method, such as a barrier method (male condom or diaphragm, or cervical 
cap with or without spermicide).
Note: If the childbearing potential changes after start of the study or the risk of 
pregnancy changes (eg, a woman who is not heterosexually active becomes 
active) a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria. If reproductive status is 
questionable, additional evaluation should be considered.
3.
Criterion Deleted per Amendment 1.
4.
The use of limited amounts of alcohol (up to 1 unit daily eg, half a pint of ordinary 
strength beer, lager or cider [3 to 4% alcohol by volume]; or a small pub measure 
[25 mL] of spirits (40% alcohol by volume); or a standard pub measure [50 mL] of 
fortified wine [20% alcohol by volume], 0.5 Go [90 mL] of Japanese sake, or 0.3 Go 
[55 mL] of Shochu) will be allowed during the study, with the exception of the evenings 
before study visits and 12 hours before salivary cortisol sample collections.
5.
Criterion Modified per Amendment 3
5.1 Subjects are advised not to change the frequency or level of exercise during the 
study.
6.
Subjects will be advised not to donate blood during the study and for at least 3 months
after completion of the study.
7.
Criterion Modified per Amendment 1
7.1 Subjects should be cautioned not to drive a car or operate machinery or engage in 
any potentially hazardous activities if they have had less than a full night’s sleep (6-
8 hours) following administration of the study drug or at any time during the study 
if the subject feels that his or her baseline capacity is impaired.
Note: At any point during the study, if subjects manifest significant next-day 
sleepiness, they are advised to inform the investigator. Such subjects may be 
discontinued or advised not to drive or operate machinery.


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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned 
based on a computer-generated randomization schedule prepared before the study by or under 
the supervision of the sponsor.
At the start of study enrollment, subjects will be randomly assigned in a 2:1:1 ratio to receive 
1 of 3 treatments: placebo: JNJ-42847922 20 mg: JNJ-42847922 40 mg.
After the interim analysis, subjects will be randomly assigned to study drug, with the allocation 
ratio adapted according to the dose-response curve observed at the time of the interim analysis. 
Subjects will be assigned to receive placebo or one of the JNJ-42847922 doses (potential doses 
include 10 mg, 20 mg, 40 mg).
The randomization will be balanced by using randomly permuted blocks and will be stratified by
region (US, EU, and Japan) and by insomnia status (significant insomnia symptoms [ISI score 
≥15]1 at baseline versus no significant insomnia symptoms [ISI score <15] at baseline). In order 
to randomize approximately equal proportions of subjects with and without significant insomnia 
symptoms at baseline, the number randomized in either stratum will be capped at 60% of the 
planned total sample size.
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
Blinding
To maintain the study blind, the study drug container will have a label containing the study 
name, study drug number, and reference number. The label will not identify the study drug in the 
container. However, if it is necessary for a subject's safety, the study blind may be broken and 
the identity of the study drug ascertained. The study drug number will be entered in the case 
report form (CRF) when the study drug is dispensed. The study drugs will be identical in 
appearance and will be packaged in identical containers.
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, study drug concentrations, study 
drug preparation/accountability data, treatment allocation, and biomarker or other specific 
laboratory data) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 


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such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding. In particular, data regarding 
cortisol and other biomarkers will not be made available to the investigational team and the 
sponsor study team until after the database lock. 
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 IWRS. It is recommended that the investigator contact the sponsor or 
its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented in the appropriate section of the CRF, and in 
the source document. The documentation received from the IWRS indicating the code break 
must be retained with the subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded are required to return for 
end-of-treatment/follow-up visits.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, for the interim analysis, 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.
See Section 11.8 Interim Analysis for details.
6.
DOSAGE AND ADMINISTRATION
JNJ-42847922 supplied for this study is formulated as over-encapsulated tablets of 10 and 
20 mg. The 40-mg dose will consist of two 20 mg tablets. All other JNJ-42847922 doses will 
consist of 1 active and 1 placebo capsule each. The placebo doses will consist of 2 placebo 
capsules (Table 2).
All tablets will be over-encapsulated to ensure blinding, and placebo will be supplied as 
matching capsules.
Table 2:
Dose Description
Dose Level
Capsules
10 mg
10 mg and placebo
20 mg
20 mg and placebo
40 mg
20 mg and 20 mg
Placebo
2 matching placebo capsules
On Day 1 of the double-blind treatment phase, the assigned study drug (blinded placebo or
JNJ-42847922) will be administered at the study site (at bedtime, approximately 3 hours after the
last meal). For the remainder of the study (from Day 2 to Day 41), the assigned study drug will 
be self-administered by the subject at home at bedtime, approximately 3 hours after the last meal.


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Note: if a subject does not participate in the overnight stay on Day 1, the study drug will be self-
administered at home throughout the double-blind treatment phase (from Day 1 to Day 41) (once 
daily at bedtime, approximately 3 hours after the last meal). 
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed
(see Table 1 for description of interventions). The IWRS randomization system will assign the 
numbers of the blister packs to be used by a subject (see Section 5 for details on treatment 
allocation). Subjects will administer the assigned study drug once daily at bedtime, 
approximately 3 hours after the last meal, from Day 1 to Day 41. Subjects are required to record 
the administration of study drug or any missed doses in subject diaries, which will be checked at 
each scheduled visit.
If a scheduled (ie, at bedtime) dose is missed, subjects are advised not to take the dose in the 
morning and not to administer 2 doses at a time the next evening. The dose will be skipped. 
Information about the missing dose should be recorded in subject diaries, which will be checked 
at each scheduled visit.
Subjects will continue to take their baseline SSRI/SNRI antidepressant (at the same dose, 
without change, and at approximately the same time as prior to entering the study) throughout 
the screening, double-blind, and follow-up periods (the entire 12 weeks of the study duration).
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol. See Section 14.4 for details.
Table 3:
Description of Interventions
Treatment name
JNJ-42847922
Placebo
Dose per delivery 
(ie, total daily dose)
10 mg, 20 mg or 40 mg
Placebo
Description
Over-encapsulated tablets
Powder-filled capsules
Frequency
Once daily at bedtime, approximately 
3 hours after the last meal
Once daily at bedtime, approximately
3 hours after the last meal
Delivery method
Oral, with 100 mL water
Oral, with 100 mL water
Delivery instructions
Must be swallowed whole and not 
chewed, divided, dissolved or crushed
Must be swallowed whole and not 
chewed, divided, dissolved or crushed
For this study, any dose of JNJ-42847922 greater than the number of capsules assigned for each 
day will be considered an overdose (see Section 12.2, Special Reporting Situations for reporting 
requirements).
7.
TREATMENT COMPLIANCE
On Day 1, subjects will receive their first dose of study drug during an overnight stay at the 
study site. For the remainder of the study, the assigned study drug will be self-administered by 
the subject at home. If a subject does not participate in the overnight stay on Day 1, the study 


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drug will be self-administered by the subject at home throughout the double-blind treatment 
period.
The number of study drug capsules dispensed for self-administration by subjects at home will be 
recorded and compared with the number returned during each scheduled visit. Subjects are 
required to record the administration of study drug in subject diaries, which will be checked at 
each scheduled visit.
For subjects taking part in the overnight stay on Day 1, the administration of study drug on 
Day 1 will be witnessed by the investigator or a properly trained designee. The exact date and 
time of drug administration will be recorded.
If appropriate, additional details may be provided in a site investigational product manual that is 
provided separately and noted in Section 15, Study-Specific Materials.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before the screening visit and any ongoing 
therapies must be recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with signing of the 
informed consent (ie, screening) until the follow-up visit. Concomitant therapies should also be 
recorded beyond this time only in conjunction with new or worsening adverse events, or serious 
adverse events that meet the criteria outlined in Section 12.3.2 (Serious Adverse Events). For 
subjects who fail screening, concomitant therapies do not need to be recorded unless there is an 
adverse 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. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication. Prior to study entry, modification of an effective 
preexisting therapy should not be made for the explicit purpose of entering a subject into the 
study.
Subjects will continue to take their baseline antidepressant as described in Section 6.
For safety reasons, the use of hypnotic drugs is prohibited during the study (see further details 
below). JNJ-42847922 has hypnotic properties and potential PD interactions with other hypnotic 
drugs have not been investigated yet. Apart from hypnotic drugs, no necessary medication will 
be stopped or modified for the sole purpose of making subjects eligible for enrollment in the 
study. Rebound effects of stopping prestudy sleep medication should be prevented.
The use of acetaminophen or paracetamol is preferred over ibuprofen or aspirin for occasional 
use to treat minor pain because multiple biomarkers related to inflammatory mechanisms 


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implicated in mood disorders are being assessed in this study, and these measures are affected by 
the use of medications with anti-inflammatory properties.
Subjects must not use the following medication or food supplements during the study:

Monoamine oxidase inhibitors (MAOIs) within 4 weeks before Baseline (Day 1) until the 
follow-up visit.

Antipsychotic drugs (D2-antagonists and D2 partial agonists) within 4 weeks before Baseline 
(Day 1) until the follow-up visit.

Benzodiazepines, hypnotics (eg, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant,
and ramelteon), sedating antidepressants (eg, mirtazapine, doxepin, trazodone, and tricyclic 
antidepressants), sedating antihistamines
including over-the-counter hypnotics (eg, 
diphenhydramine, doxylamine, and hydroxyzine), and melatonin from at least 7 days before 
Baseline (Day 1) until the follow-up visit. Sleep medication should be tapered off to prevent 
rebound insomnia.

S-adenosyl methionine (SAMe), opiates, bupropion, lithium and anticonvulsants from at 
least 7 days before Baseline (Day 1) until the follow-up visit.

Stimulants (dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic 
steroids, 
decongestants 
and 
appetite 
suppressants 
(such 
as 
ephedrine), 
and 
isoxsuprine from at least 7 days before Baseline (Day 1) until the follow-up visit.

A known moderate or strong inhibitor/inducer of CYP3A4 and CYP2C9 or a dual 
inhibitor/inducer of CYP3A4 and CYP2C9 within 14 days (or after washout; ie, duration of 
5 times the drug’s half-life) before the first study drug administration on Day 1 until the 
follow-up visit. See Attachment 1 for examples of moderate and strong inhibitor/inducer of 
CYP3A4 and CYP2C9 or a dual inhibitor of CYP3A4 and CYP2C9.

St. John’s Wort, ephedra, ginkgo, ginseng, Chinese herbal medicine, or kava from at least 
7 days before Baseline (Day 1) until the follow-up visit.

For ketamine or esketamine, any previous history of use for depression or use during the 
study is prohibited
When discontinuing a prohibited medication, the investigators should consider the time needed 
to sufficiently eliminate a drug from body system, eg, 5 half-lives of the drug. The sponsor must 
be notified in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, biomarker, 
pharmacogenomic, and safety measurements applicable to this study.


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Throughout the study, subjects will complete self-assessments (PRO) at the study site. Where 
multiple procedures are scheduled for the same visit, procedures are recommended to be 
performed in the following order: salivary cortisol samples, ECGs, vital signs, blood samples, 
PRO assessments and then other procedures. All scheduled morning salivary cortisol samples 
should be collected upon awakening and evening salivary cortisol samples should be collected at 
bedtime. The salivary cortisol samples scheduled at the time of PK samples (ie, Day 1 night, Day 
2 morning, and Day 8 morning) should be collected before any blood samples are drawn.
Blood collections for PK, biomarker, and pharmacogenomic and epigenetic (DNA) assessments 
should be kept as close to the specified time as possible. Actual dates and times of assessments 
will be recorded in the source documentation.
Serum or urine pregnancy tests may be performed, as determined necessary by the investigator to 
establish the absence of pregnancy at any time during the subject's participation in the study. For 
WOCBP, who enrolled in the study before Amendment 5 and who continue in the trial, a serum 
pregnancy test must be performed at screening, and urine pregnancy tests must be performed at 
Day 1, Day 22, Day 42 (End-of Treatment/Early Withdrawal), and at the Follow-up Visit to 
establish absence of pregnancy.
The total blood volume to be collected from each subject will be approximately 190 mL. Repeat 
or unscheduled samples may be taken for safety reasons or for technical issues with the samples.
The maximum amount of blood drawn (including retesting) from each subject in this study will 
not exceed 300 mL. 
9.1.2.
Screening Phase
After providing written informed consent and within 4 weeks prior to randomization, outpatient 
subjects experiencing a major depressive episode will be screened to evaluate their eligibility for 
study participation. Subjects must meet DSM-5 diagnostic criteria for MDD, without psychotic 
features, based upon clinical assessment and confirmed by the SCID-CT. In addition, the current 
depressive episode must be deemed valid by the SSQ interview, which will be administered by 
independent, remote (ie, not at clinical site) raters. (Note: The SSQ will be administered along 
with the MADRS). The duration of the current depressive episode must be ≤18 months.
Eligible subjects must have a MADRS total score ≥25 at screening and must not demonstrate a 
clinically significant improvement (ie, an improvement of >20% on their MADRS total score) 
from the screening to baseline visit. Rating of the MADRS will be performed by independent, 
remote raters. Subjects must have had an inadequate response to at least 1 but no more than 
3 antidepressants, administered at an adequate dose and duration in the current episode of 
depression, documented by medication history based upon the MGH-ATRQ. An inadequate 
response is defined as <50% reduction in depressive symptom severity, as assessed by the 
MGH-ATRQ. An adequate trial is defined as an antidepressant treatment for at least 4 weeks at 
or above the minimum therapeutic dose specified in the MGH-ATRQ. The inadequate response 
must include the subject’s current antidepressant treatment.


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In addition, the eligibility screening examination will consist of the following general health 
assessments:

Complete medical history, psychiatric history, and demography

Review of inclusion/exclusion criteria

Review of prestudy medications

Review of preplanned surgery/procedure(s)

Physical examination (including height, body weight, and waist circumference)

Vital signs (systolic and diastolic blood pressure, pulse, temperature) 

12-lead ECG

Clinical safety laboratory assessments under fasted conditions (including HbA1c, TSH, FT4
[for subjects with known hypothyroidism who have been on stable treatment for at least 
3 months prior to screening or for any subjects with an elevated TSH], hematology, serum 
chemistry, and urinalysis)

Alcohol (breath) test

Urine drug screen

Serum pregnancy testing (per investigator’s judgment for WONCBP; mandatory for 
WOCBP)

Menstrual cycle tracking (premenopausal women only)

Recording of adverse events and concomitant medication

C-SSRS

ISI

A urine sample will be collected and sent to the central laboratory to assess compliance with 
the 
following 
background 
antidepressant 
medications: 
citalopram, 
escitalopram, 
fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine. All other SSRI/SNRI 
background antidepressants qualifying the subject for enrollment will be assayed (urine or 
blood sample) locally at the study site, if possible.
Investigators should be aware that subjects with seizures are not excluded, but subjects are 
excluded if they take anticonvulsant medications (see Section 8, Prestudy and Concomitant 
Therapy). In deciding to include a subject with seizures or history of seizures, investigators 
should be aware that convulsions were observed in a small number of dogs at high exposure 
levels in nonclinical studies (see Section 1.1.1, Nonclinical Studies). In each case, the animals 
with convulsions had substantially higher exposures than those without, and exposures in these 
animals were 20- to 40-fold higher than the mean Cmax levels in humans at a dose of 40 mg/day 
(the highest dose to be studied in this study). The group mean Cmax levels at the dose where 
convulsions were seen in the 9-month dog study were >6.5-fold higher (or >68-fold when 
adjusted for plasma protein binding) than the mean Cmax levels in humans at a dose of 40 
mg/day. No convulsions were seen in the 1- or 3-month dog studies at similar doses or in other 
species in the preclinical program. To date, no convulsions or seizures have been seen in humans 


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exposed to JNJ-42847922. The investigators should carefully weigh the risks and benefits of 
including subjects with a known history of seizures or seizure disorder, particularly considering 
exclusion criterion 1 of this study that exclude subjects with significant and/or unstable 
neurological conditions. 
Exceptional and limited retesting of abnormal screening values that lead to exclusion may be 
allowed after discussion and approval by the sponsor during the screening period (to reassess 
eligibility). This should only be considered if there is no anticipated impact on subject safety.
Subjects must discontinue all prohibited psychotropic medications as described in Section 8, 
Prestudy and Concomitant therapy, before Day 1 of the study.
9.1.3.
Double-Blind Treatment Phase
Subjects will be randomized after completion of all screening procedures and after assessment of 
qualification for study participation based on inclusion/exclusion criteria. The doses of 
JNJ-42847922 that will be studied at the beginning of the study are known (ie, 20 and 40 mg), 
whereas the doses of JNJ-42847922 to be studied after the interim analysis will be adaptively 
chosen based on the dose-response curve seen at the time of the interim analysis.
At the start of the study on Day 1 of the double-blind treatment phase, subjects will be randomly 
assigned in a 2:1:1 ratio to receive 1 of 3 treatments: placebo: JNJ-42847922 20 mg:
JNJ-42847922 40 mg.
After the interim analysis, subjects will be randomly assigned to study drug (placebo or one of 
the JNJ-42847922 doses [potential doses include 10 mg, 20 mg, 40 mg]), with the allocation 
ratio adapted according to the dose-response curve observed at the time of the interim analysis. 
Regardless of whether subjects are randomized before or after the interim analysis, the schedule 
of events and study procedures will remain the same. Study procedures during the double-blind 
treatment phase to assess safety, tolerability, efficacy, compliance, and other evaluations (eg, PK 
and biomarkers) will occur as per the Time and Events Schedule. Subjects will report to the 
study site in the morning on Days 1 (Week 1), 8 (Week 2), 22 (Week 4), and 42 (end of Week 6)
in a fasted state.
On Day 1 of the double-blind treatment phase, the assigned study drug (blinded placebo or
JNJ-42847922) will be administered at the study site (at bedtime, approximately 3 hours after the 
last meal), and PK and salivary cortisol samples will be collected at the site. For the remainder of 
the study (from Day 2 to Day 41), the assigned study drug dose will be self-administered by the 
subject at home at bedtime, approximately 3 hours after the last meal.
Note: On Day 1, subjects should report to the study site in the morning for the assessments. After 
the assessments, subjects may remain at the study site or may go home for the afternoon and 
return later for an overnight stay at the study site. Subjects who prefer to go home will return to 
the study site 1 hour before the evening dosing and will remain overnight at the study site. 


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Subjects will be discharged in the morning on Day 2 (ie, after collection of salivary cortisol and
PK samples) and the site will ensure subjects have appropriate transportation to their home.
Note: In some circumstances, subjects may not be able to stay overnight on Day 1 for the sample 
collection. Since the collection of PK and cortisol samples does not relate to the primary 
assessments of safety and efficacy, an exception to the overnight stay and collection of samples 
(PK and cortisol) may be made after discussion with the sponsor’s medical monitor. The reason 
for the exception must be documented in the source documents. Subjects who do not stay 
overnight will take their Day 1 dose at home (at bedtime, approximately 3 hours after the last 
meal).
9.1.4.
Posttreatment Phase (Follow-Up)
Telephone Contact
One day after completion of the double-blind phase, on Day 43 (Week 7), a telephone contact 
will be made for follow-up safety assessments. During this call, the PWC will be administered,
and information on adverse events and concomitant medications will be collected.
Follow-up Visit
All subjects will complete a follow-up visit within 7 to 14 days after completion of the 
double-blind phase. Evaluations to be performed at the follow-up visit are described in the Time 
and Events Schedule.
If a subject discontinues study treatment before the end of Week 6, end-of-treatment and follow-
up assessments should be obtained.
The duration of participation in the study for an individual subject (including screening and 
follow-up visit) will be up to approximately 12 weeks (84 days).
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug and that they should return to their primary physician to 
determine standard of care.
9.2.
Efficacy Evaluations
The following efficacy assessments will be performed at the time points indicated in the Time 
and Events Schedule. The MADRS (SIGMA) and CGI-S will be administered by independent, 
centralized remote raters over the telephone; the HAM-A (SIGH-A) will be administered by the 
investigators or designee; and the EQ-5D-5L, PGI-S, PHQ-9, PROMIS-SD (Short Form), 
PROMIS-Fatigue (Short Form), SDS, SHAPS, RRS, and WLQ (Short Form) will be completed
by the subjects.
9.2.1.
Montgomery-Asberg Depression Rating Scale (MADRS)
The MADRS will be performed by independent, centralized remote raters during the study. The 
MADRS is a clinician-administered scale designed to measure depression severity and detects 
changes due to antidepressant treatment.35 The scale consists of 10 items, each of which is scored 


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from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a 
total possible score of 60. Higher scores represent a more severe condition. The MADRS 
evaluates apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, 
concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. 
The test exhibits high inter-rater reliability. The typical recall period for the MADRS is 7 days. 
9.2.2.
Sheehan Disability Scale (SDS)
The SDS is a 5 item questionnaire which has been widely used and accepted for assessment of 
functional impairment and associated disability.30,54 The first 3 items assess disruption of 
(1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating 
scale. The scores for the first 3 items are summed to create a total score of 0-30 where a higher 
score indicates greater impairment. It also has 1 item on days lost from school or work and 
1 item on days when underproductive. Its completion time is estimated to be around 1 to 
2 minutes. The recall period for this study is 7 days.
9.2.3.
Hamilton Anxiety Rating Scale (HAM-A)
The original 14-item clinician-administered HAM-A scale assesses the severity of different 
anxiety-related symptoms. It is a commonly used, validated scale in clinical trials assessing 
anxiety.20,21 However, the original HAM-A lacks instructions for administration and clear anchor 
points for the assignment of severity ratings. For this reason, the structured interview guide 
version (SIGH-A) will be used in this study.62 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.62
9.2.4.
Patient Reported Outcomes Measurement Information System-Sleep 
Disturbance (PROMIS-SD) and Fatigue (PROMIS-Fatigue) Short Form
Developed under a National Institutes of Health (NIH) initiative, the Patient Reported Outcomes 
Measurement Information System captures self-reported, qualitative health aspects in the 
domains of physical, mental, and social health.65
The PROMIS-SD Short Form subscale consists of a static 8-item questionnaire. Using a recall 
period of the past 7 days, it assesses the concepts of sleep initiation (2 items), quality of sleep 
(3 items), early morning feelings (2 items) and worrying about sleep (1 item). Five-point Likert 
scales are provided to capture the subject’s impressions ranging from “very poor” to “very good”
and “not at all” to “very much”. Its completion time is estimated to be less than 5 minutes.
The PROMIS-Fatigue Short Form subscale consists of a static 8-item questionnaire. Using a 
recall period of the past 7 days, it assesses a range of symptoms from mild subjective feelings of 
tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely 
decreases one’s ability to execute daily activities and function normally in family or social roles. 
Ratings are done on a 5 item Likert scale ranging from “not at all” to “very much” and “never”
to “always”. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) 


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and the impact of fatigue on physical, mental, and social activities. The fatigue short form is 
generic rather than disease-specific. Its completion time is estimated to be less than 5 minutes.
9.2.5.
Clinical Global Impression of Severity (CGI-S)
The CGI-S will be completed by independent, centralized remote raters during the study. The 
CGI-S provides an overall clinician-determined summary measure of the severity of the subject’s 
illness that takes into account all available information, including knowledge of the subject’s 
history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
subject’s ability to function.19 The CGI-S evaluates the severity of psychopathology on a scale of 
1 to 7. Considering total clinical experience with the depression population, a subject is assessed 
on severity of illness at the time of rating according to: 1=normal (not at all ill); 2=borderline ill; 
3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill 
patients. The CGI-S permits a global evaluation of the subject's condition at a given time. For an 
experienced rater, the time required to complete the CGI-S is less than 1 minute.
9.2.6.
Patient Global Impression of Severity (PGI-S)
The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 
4=severe). Considering all aspects of depression, subjects will rate their severity on the PGI-S.
Its completion time is less than 1 minute.
9.2.7.
Patient Health Questionnaire, 9-Item (PHQ-9)
The PHQ-9 is a 9-item, PRO measure to assess depressive symptoms.55 The scale scores each of 
the 9 symptom domains of the DSM-5 MDD criteria and it has been used both as a screening 
tool and a measure of response to treatment for depression. Each item is rated on a 4-point scale 
(0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The subject’s 
item responses are summed to provide a total score (range of 0 to 27), with higher scores 
indicating greater severity of depressive symptoms. The recall period is 2 weeks and its 
completion time is less than 5 minutes.
9.2.8.
Snaith-Hamilton Pleasure Scale (SHAPS)
The SHAPS is a reliable, valid, and unidimensional instrument to assess hedonic capacity in 
adults with MDD. It is a 14-item, self-report tool with a completion time below 5 minutes. Each 
of the items has a set of 4 response categories-Definitely Agree/Strongly Agree, Agree, Disagree, 
and Strongly Disagree, with either of the Disagree responses receiving a score of 1 and either of 
the Agree responses receiving a score of 0. A higher total SHAPS score indicates higher levels of 
current anhedonia.36
9.2.9.
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level 
(EQ-5D-5L) Questionnaire
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
Mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 


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anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).11,12
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 to 100. 
The time taken to complete the questionnaire varies with age, health status, and setting but is 
likely to be around 1 minute. 
9.2.10.
Work Limitations Questionnaire (WLQ) Short Form
The objective of the WLQ is to assess the on-the-job impact of chronic health problems and/or 
treatment (“work limitations”) in adults. It is a PRO tool, consisting of 8 items in the short form 
version. Likert scales are provided to capture the subject’s impressions. The recall period is 
2 weeks and its completion time has been reported to be less than 5 minutes. Its content validity 
has been established through condition-specific focus groups and its measurement properties are 
documented as strong.31,32,33
9.2.11.
Ruminative Response Scale (RRS)
The RRS assesses rumination as the process of “compulsively focused attention on the symptoms 
of one’s distress, and on its possible causes and consequences, as opposed to its solutions” as 
established by Nolen-Hoeksema in 1998. The measure consists of 22 items and provides 4 point 
Likert scales ranging from “almost never” to “almost always”. Its completion time is about
5 minutes. The tool is understood as very straightforward, as all items are summed to provide the 
final score.37
9.3.
Pharmacokinetics
9.3.1.
Evaluations
Blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of JNJ-42847922 and the metabolites M12 and M16 as described below:

Day 1 Night and Day 2 Morning PK sampling:

Three blood samples will be collected on the following time points:
o
Sample 1: between 15 minutes to 1.5 hour after dosing
o
Sample 2: between 2 to 4 hours after dosing
o
Sample 3: between 6 to 8 hours after dosing.

Day 8 PK sampling 

A single sample will be collected in the early morning on Day 8 between 6 and 12 hours 
after dosing at night on Day 7.


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Plasma samples may be collected using an indwelling catheter. As this is a blinded study, blood 
samples for PK will be collected from placebo-dosed subjects, but not analyzed for PK. These 
samples will be stored and may be analyzed if needed (eg, suspicion of an incorrect dose).
Genetic analyses will not be performed on these plasma samples. Note that there are no dietary 
restrictions or fasting requirements prior to blood collection for PK assessments.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.
The exact time of PK blood sample collection must be recorded, along with all concomitant 
medications (dose, drug, start and stop date). The exact date and time of the last administration 
of study drug before the PK sample will be recorded.
9.3.2.
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to measure concentrations of JNJ-42847922 and the metabolite 
M12 using a validated, specific, and sensitive liquid chromatography/mass spectrometry/mass 
spectrometry (LC-MS/MS) method by or under the supervision of the sponsor. The metabolite 
M16 will be analyzed using a scientifically validated method.
9.3.3.
Pharmacokinetic Parameters
Concentration-time data will be graphically displayed by dose, visit date and time (relative to 
dose) for JNJ-42847922, M12, and M16 and summarized using descriptive statistics.
A population PK analysis using PK data from a selection of Phase 1 and Phase 2 studies will be 
performed at the completion of the study and at the interim analysis. Using actual sampling and 
dosing times, concentration-time data will be analyzed using population PK modeling. Post-hoc 
Bayesian estimates of PK parameters (ie, AUC and, if allowed by the data, Cmax) will be obtained 
for JNJ-42847922 from population PK modeling and if needed, for M12 and M16. As part of the 
population PK modeling, the effect of intrinsic (eg, age, gender, body weight) and extrinsic 
factors (eg, concomitant medications) affecting the PK of JNJ-42847922 may be evaluated if 
needed.
Individual predicted plasma concentration-time profiles and/or post-hoc Bayesian estimates of 
PK parameters for JNJ-42847922 and, if necessary, for M12 and M16 may be used for 
exploratory exposure-response modeling for safety and efficacy endpoints.
9.4.
Biomarkers Evaluations
Venous blood samples will be collected for the assessment of biomarkers as indicated in the 
Time and Events Schedule. To avoid interference caused by lipid content in blood specimens 
collected for biomarker evaluation, biomarker samples will be collected under fasting conditions 
(for a minimum of 8 hours, water permitted). 


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Saliva samples for the measurement of cortisol concentrations will be collected by using an oral 
swab method just before bedtime (before dosing) on the night before each visit and upon 
awakening on the day of the visits indicated in the Time and Events Schedule. In addition, 
salivary cortisol samples will be collected at the study site at baseline (before study drug 
administration on Day 1) and prior to each blood sample for PK on Days 1, 2, and 8 
(Note: samples on Days 1 and 2 will only be collected from those subjects participating in the 
Day 1 overnight stay). (Note: order of samples: salivary cortisol followed by biomarker blood 
samples and then PK samples; exact time of all samples should be recorded). Cortisol 
concentration has a strong diurnal pattern, with peak concentrations present upon awakening and 
low concentrations in the evening hours. Collection of saliva cortisol samples (which correlate 
well with serum concentrations) allows for collection at home with a low subject burden. 
Subjects should not consume alcoholic beverages for at least 12 hours prior to saliva sampling. 
Food, drinks (except water), and oral care (brushing, flossing, mouthwash) are not permitted 
1 hour prior to the saliva collection.
Biomarker analyses will include (but are not limited to) markers related to the immune system 
activity, growth factors, metabolic, and HPA axis activation, to allow for exploratory assessment 
of drug-clinical response relationship, to explain interindividual variability in clinical outcomes, 
and to identify population subgroups that respond differently to treatment.
Biomarkers may be added or deleted based on scientific information or technical innovations 
under the condition that the total volume of blood collected will not be increased.
All biomarker data obtained during this study may be included in ongoing cross-study analyses 
to investigate the relationship between depression severity and phenotypes and biomarkers.
Fasting status at the time of biomarker blood collection will be noted on the laboratory 
requisition form and/or the CRF, along with any incidence of illness or allergy during the 
previous 2 weeks. Information about alcohol consumption within 12 hours prior to saliva 
sampling (including amount/type of alcohol consumed) will be recorded on the CRF. In addition, 
for premenopausal women, the average length of menstrual cycle (days) and first day of last 
period will be recorded on the CRF.
9.5.
Pharmacogenomic and Epigenetic (DNA) Evaluations
A pharmacogenomic blood sample will be collected to allow for pharmacogenomic research 
where local regulations permit. DNA samples will be analyzed for the identification of genetic 
and/or epigenetic factors that may influence the PK, efficacy, safety, or tolerability of 
JNJ-42847922 and to identify genetic and/or epigenetic factors associated with MDD. Epigenetic 
changes in genes known to be relevant to depression (HPA axis, inflammation, growth factors, 
monoamine transporters, ion channels, circadian rhythm) may be evaluated. Additional analyses 
may be conducted if it is hypothesized that this may help resolve issues with the clinical data. 
Subject participation in the pharmacogenomic research is optional. DNA samples will be used 
for research related to JNJ-42847922 and MDD. They may also be used to develop tests/assays 
related to JNJ-42847922 and MDD. Pharmacogenomic research may consist of the analysis of 


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1 or more candidate genes or of the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate) in relation to JNJ-42847922 and MDD clinical 
endpoints. Analyses may be performed across multiple studies. DNA samples collected from 
Japanese subjects will not be used for research related to MDD.
9.6.
Safety Evaluations
The collection of adverse events and concomitant medications will start after the informed 
consent has been signed and will continue until the follow-up visit. All safety assessments listed 
below will be performed as specified in the Time and Events Schedule.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting.
As with any CNS-active medication, investigators should monitor carefully and document any 
CNS-related adverse event including tremor, ataxia, abnormal sensation, confusion, or possibility 
of seizure.
Adverse Events of Special Interest
The following adverse events are considered to be of special interest in this study:

Cataplexy (sudden, transient episode of muscle weakness accompanied by conscious 
awareness)

Sleep paralysis (the experience of not being able to move, react, or speak when falling 
asleep/awakening)

Complex, sleep-related behaviors/parasomnias such as confusional arousals, somnambulism 
(sleep walking), sleep terrors, bruxism (teeth grinding), sleep sex, sleep-related eating 
disorder, sleep behavior disorder, and catathrenia (REM-associated end-inspiratory 
apnea/breath holding).
Investigators are instructed to inquire about the occurrence of such events during the collection 
of adverse events at each visit. When reported, the investigator will be required to complete a 
detailed summary of the event and its clinical course utilizing the AE of special interest narrative 
form as soon as information on the outcome (recovered, resolving, or ongoing) is available. In 
addition, the AE should be marked as an AE of special interest in the CRF. Note: If the event 


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meets the seriousness criteria (see Section 12.1.1), the Serious Adverse Events Form must also 
be completed according to the serious adverse events reporting timeline described in 
Section 12.3.2, ie, within 24 hours of having become aware of the event, even if all details are 
not available.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected. The investigator must review the laboratory results, 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. Clinical laboratory 
assessments (including TSH, hematology, serum chemistry, HbA1c, lipid panel, and urinalysis) 
should be performed under fasting conditions.
The following tests will be performed during the study:

Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-percent reticulocytes
-red blood cell (RBC) count
-white blood cell (WBC) count with differential
Note: A WBC evaluation may include any abnormal cells, which will then be reported by 
the laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC 
parameters, or RBC morphology, which will then be reported by the laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.

Serum Chemistry Panel
-sodium
-alkaline phosphatase
-potassium
-creatine phosphokinase (CPK)
-chloride
-lactic acid dehydrogenase (LDH)
-bicarbonate
-uric acid
-blood urea nitrogen (BUN)
-calcium
-creatinine
-phosphate
-glucose
-albumin
-insulin
-total protein
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)
-gamma-glutamyltransferase (GGT)
-total and direct bilirubin

Lipid Panel
-total cholesterol
-high-density lipoprotein cholesterol 
-triglycerides
-low-density lipoprotein cholesterol


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
Urinalysis
Dipstick
Sediment if dipstick result is abnormal
-specific gravity
-red blood cells
-pH
-white blood cells
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
Note: If dipstick result is abnormal, flow cytometry will be used to measure sediment. In 
case of discordance between the dipstick results and the flow cytometric results, the 
sediment will be examined microscopically.

Serum and urine pregnancy testing, at any time during the study as needed per the 
investigator’s judgment. For WOCBP, who enrolled in the study before Amendment 5 and 
who continue in the trial, a serum pregnancy test must be performed at screening, and urine 
pregnancy tests must be performed at Day 1, Day 22, Day 42 (End-of Treatment/Early 
Withdrawal), and at the Follow-up Visit to establish absence of pregnancy.

Urine 
drug 
screen:
opiates 
(including 
methadone), 
cocaine, 
amphetamines, 
methamphetamines, cannabinoids, barbiturates, XTC and benzodiazepines. Urine drug 
screens will be done by the site using a dipstick

TSH (screening only) and FT4 (for subjects with known hypothyroidism who have been on 
stable treatment for at least 3 months prior to screening or for any subjects with an elevated 
TSH)

Alcohol breath test

HbA1c
Electrocardiogram (ECG)
Twelve-lead ECGs, intended for safety monitoring, will be recorded in a supine position so that 
the different ECG intervals (RR, PR, QRS, QT) can be measured. The ECG will be recorded 
until 4 regular consecutive complexes are available in good readable quality.
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, it is 
recommended that the procedures be performed in the following order: ECG, vital signs, blood 
draw.


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Vital Signs (Pulse/Heart Rate, Blood Pressure, Temperature)
Blood pressure and pulse/heart rate measurements will be assessed in supine and standing 
positions with a completely automated device. Manual techniques will be used only if an 
automated device is not available.
Supine blood pressure and pulse/heart rate measurements should be preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones), and standing 
measurements should follow. Standing measurements are to be taken after at least a full minute 
of standing.
In addition, oral or tympanic temperature will be measured. In the places where oral or tympanic 
temperature are not standard practice, axillary temperature can be used. The same temperature 
measure should be used throughout the study.
Physical Examination 
The study investigator, or other authorized and appropriately qualified designee, will perform the 
physical examinations. Height will be measured at screening only. Body weight and waist 
circumference will be measured at screening, Day 1, and end-of-treatment/early withdrawal visit.
Body weight will be measured using a calibrated scale at each visit. Subjects will be weighed at 
approximately the same time of day on the same scale, wearing underwear and a gown and 
without shoes; they will be instructed to empty their bladders before being weighed. (Note: if 
disrobing for weighing is logistically impossible, the subject should be dressed as lightly as 
possible, with consistency from visit to visit). 
When measuring waist circumference, the study-site personnel must ensure that the subject 
stands and the examiner places a measuring tape in a horizontal plane around the abdomen at the 
level of the umbilicus. The measuring tape should be snug, but does not compress the skin, is 
parallel to the floor, and is not twisted. The measurement should be taken at the end of a normal 
respiratory expiration. The measurement should be recorded in centimeters to the first decimal 
point.  
Physician Withdrawal Checklist (PWC)
Potential withdrawal effects will be assessed by the PWC.47
The Physician Withdrawal Checklist (20 items; PWC-20) is a simple and accurate method 
used to assess potential withdrawal symptoms following cessation of treatment. The PWC-20 is a 
reliable and sensitive instrument for the assessment of discontinuation symptoms.
Columbia Suicide Severity Rating Scale (C-SSRS)
Emergence of suicidal ideation will be assessed using the C-SSRS. The C-SSRS has been used 
frequently in clinical studies, is a standard measure for suicidal ideation assessment, and its use 
is in accordance with FDAguidance.58


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Arizona Sexual Experiences Scale (ASEX)
Effect on sexual functioning will be assessed using the ASEX. The ASEX is a five-item rating 
scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach 
orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher 
scores indicating more sexual dysfunction. The scale has shown satisfactory reliability and 
validity.34
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. If blood samples are collected via an indwelling cannula, an appropriate 
amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume of the lock 
will be removed from the cannula and discarded before each blood sample is taken. After blood 
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (USP) (or equivalent) or sodium heparin of 10 U/mL and charged with a volume 
equal to the dead space volume of the lock. If a mandarin (obturator) is used, blood loss due to 
discard is not expected.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the Laboratory Manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the double-blind phase if he or she has 
completed assessments at the end of Week 6 (ie, Day 42) of the double-blind phase (end-
of-treatment visit).
A subject will be considered to have completed the follow-up phase if he or she has completed 
assessments at the follow-up visit (ie, the visit Days 49-56).
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.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death


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
Noncompliance with study drug administration (ie, missing either 4 or more consecutive 
doses of study medication or a total of 8 or more doses during the 6-week period)

Investigator's impression of noncompliance with background antidepressant therapy

Discontinuation of study treatment for any reason. A subject's study treatment will be 
automatically discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse 
event) it is in the best interest of the subject to discontinue study treatment

The subject becomes pregnant 

The subject shows signals of acute suicidal ideation with a clear plan at any time during
the study; the subject should be referred to appropriate medical/psychiatric care

AST and/or ALT exceeds 5 x Upper Limit of Normal (ULN) (confirmed by repeat 
testing)

AST and/or ALT exceeds 3 x ULN and total bilirubin exceeds 1.5 x ULN (confirmed 
by repeat testing).
If a subject withdraws from the study before the end of the double-blind phase (ie, Day 42), 
end-of-treatment and follow-up assessments should be obtained.
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. Subjects who withdraw will not be replaced.
10.3.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional 
research samples:

The collected samples will be retained and used in accordance with the subject's original 
separate informed consent for optional research samples.

The subject may withdraw consent for optional research samples, in which case the samples 
will be destroyed and no further testing will take place. To initiate the sample destruction 
process, the investigator must notify the sponsor study site contact of withdrawal of consent 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.


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Withdrawal From the Optional Research Samples While Remaining in the Main Study
The subject may withdraw consent for optional research samples while remaining in the study. In 
such a case, the optional research samples will be destroyed. The sample destruction process will 
proceed as described above.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future 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. However, if the subject 
withdraws consent after the study is over, it is possible that the investigator may have already 
discarded the subject’s medical records that link the subject’s name to his or her study number. 
In this case, the subject’s samples would no longer be linked to the subject, and it would not be 
possible to find the subject’s samples for destruction. Details of the sample retention for research 
are presented in the main ICF and in the separate ICF for optional research samples.
11.
STATISTICAL METHODS
Statistical analysis will be performed by the sponsor or under the authority of the sponsor. A 
general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).
11.1.
Subject Information
The efficacy analyses will be based on the full analysis set (FAS) which consists of all subjects 
who were randomly assigned to study drug and received at least 1 dose of study drug.
Safety analyses will be based on the safety analysis set, which consists of all subjects who were 
randomly assigned to study drug and received at least 1 dose of study drug. The safety analysis 
set is the same as the FAS.
Data for all subjects who have received JNJ-42847922 and have at least 1 evaluable PK sample 
will be included in the population PK analysis.
For all subjects who are randomly assigned to study drug, descriptive statistics (eg, study 
completion/withdrawal information, demographic and baseline data) will be provided. 
11.2.
Sample Size Determination
The calculation of the sample size is based on the primary efficacy endpoint (change from 
baseline to the end of Week 6 for the MADRS total score). The assumptions for the effect size 
were based on published literature and the clinically meaningful difference between groups to be 
detected.
The total sample size is calculated on the basis of the generalized Multiple Comparison 
Procedure-Modeling (MCP-Mod) test45 applied to the placebo and the JNJ-42847922 dose 
groups at the final analysis. Approximately 280 randomized subjects will provide an average 
weighted power of approximately 85% depending on the underling true dose-response shape, 


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assuming a 1-sided significance level of 0.05, a treatment difference from placebo of 4.5 points 
in change in MADRS total score, a standard deviation of 10, and a 25% overall dropout rate. 
The data cutoff for the unblinded interim analysis will be 6 weeks after randomization of 
160 subjects, which corresponds to approximately 57% of the sample size of the study. This 
number of subjects provides approximately 93% power to detect a dose-response relationship, 
depending on the underlying true dose-response shape, assuming a treatment difference of 4.5, 
and a standard deviation of 10 when tested by means of the MCP-Mod approach at the 
30% significance level (1-sided). 
11.3.
Efficacy Analyses
Primary estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 3 components:
Population: subjects with MDD who have had an inadequate response to current antidepressant 
therapy with an SSRI/SNRI.
Endpoint: change in MADRS total score from baseline to the end of Week 6.
Measure of Intervention: the effect of the initially randomized treatment together with the oral 
SSRI/SNRI antidepressant that would have been observed had all subjects remained on their 
treatment throughout the double-blind phase.
The primary analysis will be based on the FAS and the MADRS total scores collected during the 
double-blind phase.
The primary efficacy endpoint will be evaluated at a 1-sided significance level of 0.05 using the 
MCP-Mod approach to test for dose-response. For all other analyses of the primary efficacy 
endpoint and for all other efficacy endpoints, no multiplicity adjustment will be done and 
nominal 1-sided p-values will be presented.
Primary efficacy endpoint 
The primary efficacy endpoint is the change in MADRS total score from baseline to the end of 
Week 6. A mixed model for repeated measures (MMRM) analysis of the observed data from the 
placebo and JNJ-42847922 groups will be used as the method of addressing missing data. The 
MMRM will include region, time, treatment (placebo and JNJ-42847922 dose groups), baseline 
insomnia status (present/absent), and treatment-by-time interaction as factors and baseline 
MADRS total score as a covariate. An unstructured variance-covariance matrix will be used. 
Subjects in the FAS who do not have complete data will still contribute to the estimates at the 
end of Week 6, but will have less weight in the analysis than those subjects with complete data. 
The final analysis will use the generalized MCP-Mod approach45 (a hybrid methodology that 
combines multiple comparison procedures with modeling techniques), which will be applied 
towards estimates obtained from the MMRM analysis to establish a dose-response signal and to 


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determine dose(s) to be used in the Phase 3 studies. MCP-Mod has been qualified by the 
European Medicines Agency.10
In conjunction, the comparison between JNJ-42847922 and placebo will also be performed using 
the appropriate contrasts directly from the MMRM analysis using estimates at the end of 
Week 6. 
Secondary efficacy endpoints
Any secondary efficacy endpoint which is defined as a change from baseline will be analyzed 
using the same MMRM as for the primary efficacy endpoint, with the corresponding baseline as 
a covariate. Frequency distributions will be provided for CGI-S, PGI-S, and for the number of 
responders and remitters. 
The correlation between baseline ISI score as a continuous variable and change from baseline to 
the end of Week 6 in the MADRS total score will be evaluated by means of a scatter plot and if 
appropriate, regression analysis. In addition, subjects will be dichotomized based on their 
baseline ISI score (≥15 versus <15) to evaluate whether there are differences in these subgroups 
(ie, evaluating change from baseline to the end of Week 6 in the MADRS total score in subjects 
with ISI score ≥15 versus subjects with ISI score <15). The shift in ISI score category (score 
0-7=no 
clinically 
significant 
insomnia; 
score 
8-14=sub-threshold 
insomnia; 
score 
15-21=moderate insomnia, and score 22-28=clinically severe insomnia) from baseline to the end 
of Week 6 will be presented.
Subjects will also be dichotomized based on whether they have MDD with anxious distress or 
MDD without anxious distress to evaluate whether there are differences in these subgroups (ie, 
evaluating change from baseline to the end of Week 6 in the MADRS total score in subjects with 
and without anxious distress).
The secondary endpoint analyses will not be controlled for Type I error and nominal p-values 
will be presented.
The analyses for the other secondary and exploratory efficacy endpoints will be described in the 
SAP.
11.4.
Pharmacokinetic Analyses
Plasma concentrations for JNJ-42847922, M12, and M16 (if applicable) will be analyzed and 
summarized by dose, day and time point, using descriptive statistics. A population based PK 
analysis using PK data from a selection of Phase 1 and Phase 2 studies will be performed at the 
completion of the study and at the interim analysis. Post-hoc Bayesian estimates of PK 
parameters for JNJ-42847922 (and, if necessary, for metabolites M12 and M16) from the 
population PK analysis may be used for exploratory exposure-response analyses.
Population PK analysis of plasma concentration-time data of JNJ-42847922 will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
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(demographics, laboratory variables, genotypes, race, etc.) will be included in the model as 
necessary. Post-hoc Bayesian individual estimates of PK parameters will be generated from the 
population PK analysis for potential use in exposure-response analysis. An interim population 
PK and exposure-response analysis will be conducted. A snapshot date for PK samples to be 
analyzed will be defined, if required. Samples collected before this date will be analyzed for 
JNJ-42847922, M12, and M16 (if applicable) and included in the population PK analysis. 
Samples collected after the snapshot date will be analyzed at a later date, and may be included in 
a population PK re-analysis when they become available after database lock. Details for the 
population PK and exposure-response analysis will be described in a standalone analysis plan 
and the results of the population PK and exposure-response analysis will be presented in a
separate report.
Data will be listed for all subjects with available plasma concentrations per treatment group. 
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study drug; missing information of dosing and 
sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
For each treatment group, descriptive statistics will be calculated for all individual derived PK 
parameters including exposure information of JNJ-42847922 and, if needed, M12, and M16.
11.5.
Biomarker Analysis
Cortisol levels will be tabulated for each time point and summary statistics will be calculated. 
Posttreatment changes in cortisol levels will be assessed by treatment group. Analysis of 
variance (ANOVA) and t-test will be used to assess differences across groups and time points. 
Correlations between cortisol levels and clinical endpoints will be evaluated.
The additional exploratory biomarkers will be tabulated by treatment and summary statistics will 
be calculated. Posttreatment changes in exploratory biomarkers will be summarized by treatment 
group. Associations between baseline biomarker levels and clinical endpoints may be explored. 
Additional exploratory analyses may also be performed. Results of all exploratory analysis will 
be presented in a separate report.
All biomarker data obtained from this study may also be included in an ongoing cross-study 
analysis to investigate the relationship between depression severity, phenotypes, and biomarkers.
11.6.
Pharmacogenomic Analyses
Individual predicted post-hoc Bayesian estimates of PK parameters will be used in exploratory 
exposure-genetic 
variant 
modeling, 
as 
appropriate.
Results 
of 
other 
exploratory 
genetic/epigenetic analyses will be presented in a separate report.


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Pharmacogenomic data obtained from this study may be included in a cross-study analysis to 
investigate the relationship between phenotypes and depression severity, biomarkers, and 
exposure.
11.7.
Safety Analyses
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). Treatment-emergent adverse 
events are adverse events with onset during the double-blind treatment phase or that are a 
consequence of a preexisting condition that has worsened since baseline. All reported 
treatment-emergent adverse events will be included in the analysis. For each treatment-emergent 
adverse event, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for any
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
Adverse events of special interest are cataplexy, sleep paralysis, and complex, sleep-related 
behaviors (parasomnias). Subjects with adverse events of special interest may be presented 
separately.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test and treatment. Reference ranges 
and markedly abnormal results (specified in the SAP) will be used in the summary of laboratory 
data. Descriptive statistics will be calculated for each laboratory analyte at baseline and for 
observed values and changes from baseline at each scheduled time point. A listing of subjects 
with any laboratory results outside the reference ranges will be provided. A listing of subjects 
with any markedly abnormal laboratory results will also be provided.
Electrocardiogram (ECG)
A listing of subjects with abnormal ECG findings will be presented.
Vital Signs
Descriptive statistics of pulse, supine and standing blood pressure (systolic and diastolic), and 
temperature for observed values and changes from baseline will be summarized at each 
scheduled time point by treatment. The percentage of subjects with values beyond clinically 
important limits will be summarized.
Physical Examination
Physical examination findings will be summarized at each scheduled time point. Changes in 
body weight and waist circumference will be summarized descriptively. Subjects with abnormal 
findings in physical examination will be presented in a data listing.


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Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment.
Withdrawal Effects
Results from the PWC will be tabulated by treatment.
Arizona Sexual Experiences Scale (ASEX)
Results from the ASEX will be tabulated by treatment.
11.8.
Interim Analysis
An internal IAC will be established to review the interim data and formulate recommended 
decisions/actions in accordance with the objectives of the interim analysis. The IAC consists of 
2 clinicians (or a clinician and a scientist), a clinical pharmacologist, and a statistician, one of 
whom will chair the committee, and other members as required. The IAC will not include 
sponsor study team members; however, it will include other sponsor employees, who are not 
affiliated with the study team, as deemed appropriate for the membership.
The primary purpose of the interim analysis will be to examine the dose-response relationship, to 
determine the doses of JNJ-42847922 and the allocation ratio of these doses to be used in
subjects randomized after the interim analysis. The IAC will review the outputs from statistical 
analysis, exposure, exposure-response analysis, and safety for this determination.
The interim analysis will use the generalized MCP-Mod approach to establish a dose-response 
signal with respect to the primary efficacy endpoint. A 1-sided 0.30 significance level will be 
used to test for dose-response using the MCP-Mod approach on the change in MADRS total 
score to the end of Week 6. 
Unblinded exposure-response analyses will be performed by an independent internal 
pharmacometrician using data available at the interim analysis, with adequate firewalls so the 
study team will remain blinded. At the time of interim analysis, the IAC will review the exposure 
and exposure-response analyses to assist in selection of doses and the allocation ratio to be used 
after the interim analysis. To ensure timely availability of data for modeling, dosing information, 
drug concentration data, efficacy data for MADRS, safety data for next-day somnolence and 
sleep paralysis, and demographic information will also be accessed by the unblinded 
pharmacometrician prior to the time of the interim analysis, while keeping the study team 
blinded. 
As this Phase 2b study is not a confirmatory trial, no adjustment to the significance level will be 
performed for the interim analysis.
Further details regarding the interim analysis will be specified in a separate charter and interim 
SAP.


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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 in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH]).
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*


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*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 (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For JNJ-42847922, the expectedness of an 
adverse event will be determined by whether or not it is listed in the Investigator's Brochure. 
For baseline antidepressant therapies (eg, citalopram, duloxetine, escitalopram, fluvoxamine, 
fluoxetine, milnacipran, levomilnacipran, sertraline, paroxetine, venlafaxine, desvenlafaxine, 
vilazodone, or vortioxetine) with marketing authorization, the expectedness of an adverse event 
will be determined by whether or not it is listed in the locally approved Summary of Product 
Characteristics (SmPC)/Package Insert (PI).
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, Attribution Definitions.
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, eg, 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, 
eg, 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 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).


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Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, 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 (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
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

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug during pregnancy or breastfeeding
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 


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evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
All 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 2.
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 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
respiratory infection”). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the investigational institute where required). 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


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12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered 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.
The cause of death of a subject in a study within 30 days of the last dose of study drug, 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 


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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.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
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 in the Contact Information 
page(s), which will be provided to the investigators 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, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours 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 in the Contact Information page(s), which will be 
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-42847922 supplied for this study is formulated as over-encapsulated tablets of 10 and 
20 mg. The 40-mg dose will consist of two 20 mg tablets. All other JNJ-42847922 doses will 
consist of 1 active and 1 placebo capsule each. It will be manufactured and provided under the 
responsibility of the sponsor. Refer to the Investigator's Brochure for a list of excipients.
The placebo doses will consist of 2 placebo capsules. 
All tablets will be over-encapsulated to ensure blinding, and placebo will be supplied as 
matching capsules.
14.2.
Packaging
Study drug will be supplied in blister packs identified by a number. The blister packs are 
considered child resistant.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study drug must be stored at controlled temperatures as indicated on the product-specific 
labeling.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
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. All study drug will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of the study drug containers.
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.


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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. Whenever a subject brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. 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 the following supplies:

Investigator's Brochure for JNJ-42847922

Pharmacy manual/study site investigational product manual

Laboratory manual and materials

A binder containing all patient- and investigator-administered questionnaires and scales, 
along with completion guidelines

Electronic data capture (eDC) Manual

Sample ICF

IWRS Manual

Subject recruitment materials

Pre-printed labels for blood samples

Subject diaries.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The primary ethical concern is that some subjects who could potentially benefit from adjunctive 
treatment with JNJ-42847922 will be randomized to placebo or to a dose of study drug that is 
either not efficacious or where the risks exceed the benefits for that subject. This will be partially 
mitigated by continued background antidepressant therapy throughout the study. Moreover, the 
duration of study is considered to be relatively short. Since the female rat fertility study 
suggested a reduction in female fertility, and it is not known what the relevance of these findings 
are to a woman’s ability to become pregnant after taking JNJ-42847922, WOCBP will not be 
included in this study until more is learned about the effect of JNJ-42847922 on female 


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reproduction. However, WOCBP subjects, who are currently enrolled in this study, may continue 
study participation following discussion between the subject and the investigator of the new rat 
fertility study results, if they have a negative pregnancy test, and are using reliable contraception.
JNJ-42847922 has been administered to humans before in single and multiple ascending dose 
studies in healthy subjects and subjects suffering from depression and/or insomnia. The highest 
dose tested in the multiple dose study was 60 mg over 10 days (Study 42847922EDI1003). All 
doses tested to date have proven to be well-tolerated in healthy subjects and in subjects suffering 
from depression with comorbid insomnia and in subjects with insomnia without comorbid 
psychiatric diseases.
 
 
 
 
 
 
 
 
 
 
 
 
 This is consistent with the reported involvement of the orexinergic system in the 
hypothalamo-pituitary-adrenal axis through control of the gonadotrophic hormones.70,71,72 A 
study to assess reversibility has not been conducted with JNJ-42847922 but similar effects 
induced by several approved drugs were shown to be reversible.73,74
 
 
In this study adult men and WONCBP with MDD who have had an inadequate response to 
current antidepressant therapy with an SSRI/SNRI will be selected. The age of the study 
population in this protocol is intentionally broad, as unlike many other mental disorders, the age 
of onset of depression has a wide range, with a median onset of early to mid-20s, although 
significant proportions of patients may experience onset between late adolescence to late 
adulthood. In addition, women have a two-fold increased risk of depression over men, and 
separation and divorce are additional risk factors across the sexes. Subjects with MDD who have 
had an inadequate response to current antidepressant therapy with an SSRI/SNRI will be 
selected, as it is expected that this population will be representative for the targeted subject 
population for future clinical trials. Also, subjects might benefit from the clinical evaluations and 
the information collected as part of this study. The results of the investigation of JNJ-42847922 
may help future patients with MDD.
CCI
CCI


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The sponsor will monitor the study site and records to ensure compliance with the protocol, and 
that current ICH guidelines on Good Clinical Practice (GCP) are followed, and applicable 
regulatory requirements are adhered to.
Subjects will be monitored for safety and tolerability throughout the study, in accordance with 
the Time and Events Schedule. In addition, to ensure subject safety, subjects should be cautioned
not to drive or operate machinery or engage in any potentially hazardous activities if they have 
had less than a full night’s sleep (6-8 hours) following administration of the study drug or at any 
time during the study if the subject feels that his or her baseline capacity is impaired. At any 
point during the study, if subjects manifest significant next day sleepiness, they are advised to 
inform the investigator. Such subjects may be discontinued or advised not to drive or operate 
machinery.
The maximum amount of blood drawn (including retesting) from each subject in this study will 
not exceed 300 mL, that is considered to be safe and acceptable in comparison to a Red Cross 
blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on 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)


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
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, unless required locally), 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.
Approval for the collection of optional samples for genetic research and for the corresponding 
ICF must be obtained from the IEC/IRB. Approval for the protocol can be obtained independent 
of this optional research component.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject 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 the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. 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 is authorizing such access. It also denotes that the subject agrees to 
allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, and subsequent disease-related treatments, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for separate consent to provide optional samples for genetic research 
(where local regulations permit). After informed consent for the study is appropriately obtained, 
the subject (or his or her legally acceptable representative) will be asked to sign and personally 
date a separate ICF indicating agreement to participate in the optional genetic research 
component. Refusal to participate in the optional research will not result in ineligibility for the 
study. A copy of this signed ICF will be given to the subject.


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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 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 DNA, biomarker, and PK research is not conducted under standards appropriate for 
the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-42847922, to 
understand MDD, to understand differential drug responders, and to develop tests/assays related 
to JNJ-42847922 and MDD (Note: DNA samples collected from Japanese subjects will not be 
used for research related to MDD). The research may begin at any time during the study or the 
post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research).


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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 if the need for the product persists, 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 
IEC/IRB (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 listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 


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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
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.


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17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
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. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data: 

Race

History of smoking

Blood pressure, pulse/heart rate, and temperature

Height, weight, and waist circumference

Details of physical examination
The following investigator-completed scales and assessments will be recorded on worksheets 
and then entered into the CRF. The worksheets will be considered source data:

HAM-A [SIGH-A version], PWC, ISI, SCID-CT, MGH-ATRQ, and C-SSRS
The following PROs are completed by the subject using the questionnaires provided. These 
patient-completed documents are considered source documents:

PHQ-9, EQ-5D-5L, PROMIS-Fatigue [Short Form], PROMIS-SD [Short Form], SHAPS, 
PGI-S, SDS, WLQ [Short Form], ASEX, and RRS 
The following scales will be completed electronically by the central rater: 

MADRS (SIGMA version), CGI-S and SSQ.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site


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
Discharge summaries.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If electronic source is utilized, references made to the CRF in 
the protocol include the electronic source system but information collected through electronic 
source may not be limited to that found in the CRF. Data in this system may be considered 
source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
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 documents. Data must be entered into 
CRF in English. The CRF must be completed 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 (eg, clinician-completed questionnaires) will be completed by the 
same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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, and direct 


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transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRF 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 CRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the CRF
with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the CRF are known to the sponsor and study-site personnel and are 


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accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the final study visit 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 visit at that study site, in the time frame specified in the Clinical 
Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of 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 


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records, including source documents, for inspection. 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-42847922 or the 
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data, including pharmacogenomic or 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-42847922, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. 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 


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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 disclose the existence of and the results of clinical studies as 
required by law.


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March 2018.


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Attachment 1: Examples of Concomitant Drugs to be Avoided (Moderate or Strong 
Inhibitor/Inducer of CYP3A4 or CYP2C9 or Dual Inhibitor/Inducer of CYP3A4 and 
CYP2C9)
Enzymes
Inhibitors
Inducers
Dual Inhibitors 
or Inducers of 
CYP3A4 and 
CYP2C9
Strong
Moderate
Strong
Moderate
CYP2C9
None known
Amiodarone, 
fluconazole, 
miconazole, 
oxandrolone
None known
Carbamazepine, 
rifampin.
Amiodarone, 
fluconazole, 
carbamazepine, 
rifampin, 
aprepitant, 
bosentan
CYP3A4
Boceprevir,
clarithromycin, 
conivaptan, 
indinavir, 
itraconazole, 
ketoconazole,
lopinavir/ritonavir,
mibefradil, 
nefazodone, 
nelfinavir,
posaconazole, 
ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Amprenavir, 
aprepitant, 
atazanavir, 
ciprofloxacin, 
crizotinib, 
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, 
fosamprenavir,
imatinib, verapamil
Avasimibe, 
carbamazepine, 
phenytoin, 
rifampin, St. 
John’s wort
Bosentan, 
efavirenz, 
etravirine, 
modafinil, 
nafcillin.
Notes:

This is not an exhaustive list.

No “strong CYP2C9” inducers or inhibitors are known, but if any were to emerge, those should be excluded as 
well.
Source: USFDA - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm. Accessed 04 November 2015


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Attachment 2: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease-related) or background regimen.
For the purposes of this study the following events will be considered anticipated events: 

Suicidal thinking, ideation/ behavior,

Sleep changes/difficulty sleeping, reduced sleep, abnormal sleep, tiredness, fatigue, reduced energy,

Difficulty in sexual desire, performance or satisfaction,

Reduced appetite, weight changes (loss or increase),

Irritability, anger, impulsive behavior,

Agitation, feeling anxious/anxiety, tension, panic attacks, phobia.
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor 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, except for Japan (no events will be designated as anticipated 
events in Japan). 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.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).


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Status: Approved, Date: 24 April 2018
INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
1
Approved, Date: 6 February 2019
Janssen Research & Development *
Statistical Analysis Plan
Amendment 2
A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Adaptive 
Dose-Finding Study to Evaluate the Efficacy and Safety of JNJ-42847922 as Adjunctive 
Therapy to Antidepressants in Adult Subjects With Major Depressive Disorder Who Have 
Responded Inadequately to Antidepressant Therapy
Protocol 42847922MDD2001; Phase 2b
JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
NCT03227224


2
Approved, Date: 6 February 2019
Status:
Approved
Date:
6 February 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-133786387 3.0
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.


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2001
3
Approved, Date: 6 February 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ........................................................................................................................................ 8
1.
INTRODUCTION.................................................................................................................................. 9
1.1.
Trial Objectives ................................................................................................................................ 9
1.2.
Trial Design .................................................................................................................................... 11
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Sample Size Justification ............................................................................................................... 13
1.5.
Randomization and Blinding .......................................................................................................... 14
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 15
2.1.
Study Reference Start and End Dates........................................................................................... 15
2.2.
Analysis Phases............................................................................................................................. 15
2.3.
Study Day....................................................................................................................................... 15
2.4.
Baseline and End Point (DB) ......................................................................................................... 16
2.5.
Visit Windows................................................................................................................................. 16
2.6.
Pooling Algorithm for Analysis Centers.......................................................................................... 19
2.7.
Analysis Sets.................................................................................................................................. 19
2.7.1.
All Randomized Analysis Set...................................................................................................... 19
2.7.2.
Efficacy Analysis Set .................................................................................................................. 19
2.7.2.1.
Full Analysis Set ...................................................................................................................... 19
2.7.3.
Safety Analysis Set..................................................................................................................... 19
2.8.
Definition of Subgroups.................................................................................................................. 19
2.9.
Imputation Rules for Missing Adverse Event (AE) Dates .............................................................. 21
2.10.
Imputation Rules for Missing Prior/Concomitant Medication Dates............................................... 22
2.10.1.
Prior Medications ........................................................................................................................ 22
2.10.2.
Concomitant Medications Taken During the Double-blind Phase.............................................. 23
2.10.3.
Concomitant Medications Taken During the Follow-up Phase................................................... 24
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 25
4.
SUBJECT INFORMATION................................................................................................................ 25
4.1.
Demographics and Baseline Characteristics ................................................................................. 25
4.2.
Disposition Information................................................................................................................... 26
4.3.
Treatment Compliance................................................................................................................... 27
4.3.1.
Treatment Compliance With Study Drug.................................................................................... 27
4.3.2.
Treatment Compliance With Baseline SSRI/SNRI Antidepressant............................................ 27
4.4.
Extent of Exposure......................................................................................................................... 28
4.5.
Protocol Deviations ........................................................................................................................ 28
4.6.
Prior and Concomitant Medications ............................................................................................... 28
5.
EFFICACY ......................................................................................................................................... 29
5.1.
Analysis Specifications................................................................................................................... 30
5.1.1.
Level of Significance................................................................................................................... 30
5.1.2.
Data Handling Rules................................................................................................................... 31
5.1.3.
Imputation Methods for Missing Items........................................................................................ 31
5.2.
Primary Efficacy Endpoint.............................................................................................................. 31
5.2.1.
Definition..................................................................................................................................... 31
5.2.2.
Primary Estimand ....................................................................................................................... 32
5.2.3.
Analysis Methods........................................................................................................................ 32
5.2.3.1.
MCP-Mod Analysis .................................................................................................................. 32
5.2.3.2.
MMRM Pairwise Comparisons ................................................................................................ 35
5.2.3.3.
Sensitivity Analysis – ANCOVA with LOCF............................................................................. 35


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5.2.3.4.
Mediation Analysis................................................................................................................... 35
5.2.3.5.
Subgroup Analyses ................................................................................................................. 36
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 37
5.3.1.
Response of Depressive Symptoms .......................................................................................... 37
5.3.1.1.
Definition.................................................................................................................................. 37
5.3.1.2.
Utility Estimand........................................................................................................................ 38
5.3.1.3.
Analysis Methods .................................................................................................................... 38
5.3.2.
Remission of Depressive Symptoms.......................................................................................... 39
5.3.2.1.
Definition.................................................................................................................................. 39
5.3.2.2.
Analysis Methods .................................................................................................................... 39
5.3.3.
Shift in Insomnia Severity Index (ISI) Score Category ............................................................... 39
5.3.3.1.
Definition.................................................................................................................................. 39
5.3.3.2.
Analysis Methods .................................................................................................................... 39
5.3.4.
Change in Hamilton Anxiety Rating Scale (HAM-A)................................................................... 40
5.3.4.1.
Definition.................................................................................................................................. 40
5.3.4.2.
Analysis Methods .................................................................................................................... 40
5.3.5.
Response of Anxiety Symptoms................................................................................................. 41
5.3.5.1.
Definition.................................................................................................................................. 41
5.3.5.2.
Analysis Methods .................................................................................................................... 41
5.3.6.
Clinical Global Impression-Severity (CGI-S) .............................................................................. 41
5.3.6.1.
Definition.................................................................................................................................. 41
5.3.6.2.
Analysis Methods .................................................................................................................... 42
5.3.7.
Sheehan Disability Scale (SDS) ................................................................................................. 42
5.3.7.1.
Definition.................................................................................................................................. 42
5.3.7.2.
Analysis Methods .................................................................................................................... 42
5.3.8.
Patient Health Questionnaire 9-item (PHQ-9) ............................................................................ 43
5.3.8.1.
Definition.................................................................................................................................. 43
5.3.8.2.
Analysis Methods .................................................................................................................... 43
5.3.9.
Snaith-Hamilton Pleasure Scale (SHAPS) ................................................................................. 44
5.3.9.1.
Definition.................................................................................................................................. 44
5.3.9.2.
Analysis Methods .................................................................................................................... 44
5.3.10.
Patient Reported Outcome Measurement Information System-Sleep Disturbance 
(PROMIS-SD) ............................................................................................................................. 45
5.3.10.1.
Definition.................................................................................................................................. 45
5.3.10.2.
Analysis Methods .................................................................................................................... 46
5.3.11.
Patient Reported Outcome Measurement Information System- Fatigue (PROMIS-
Fatigue)....................................................................................................................................... 46
5.3.11.1.
Definition.................................................................................................................................. 46
5.3.11.2.
Analysis Methods .................................................................................................................... 47
5.3.12.
Patient Global Impression-Severity (PGI-S)............................................................................... 48
5.3.12.1.
Definition.................................................................................................................................. 48
5.3.12.2.
Analysis Methods .................................................................................................................... 48
5.3.13.
European Quality of Life (EuroQol) Group, 5 Dimension, 5-Level questionnaire (EQ-5D-
5L)............................................................................................................................................... 48
5.3.13.1.
Definition.................................................................................................................................. 48
5.3.13.2.
Analysis Methods .................................................................................................................... 49
5.3.14.
Work Limitations Questionnaire (WLQ)...................................................................................... 49
5.3.14.1.
Definition.................................................................................................................................. 49
5.3.14.2.
Analysis Methods .................................................................................................................... 53
5.3.15.
MADRS-6.................................................................................................................................... 53
5.3.15.1.
Definition.................................................................................................................................. 53
5.3.15.2.
Analysis Methods .................................................................................................................... 53
6.
SAFETY............................................................................................................................................. 53
6.1.
Adverse Events .............................................................................................................................. 54
6.2.
Clinical Laboratory Tests................................................................................................................ 55
6.2.1.
Homeostatic Assessment (HOMA) Modeling.......................................................................... 56
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 57


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
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6.4.
Electrocardiogram.......................................................................................................................... 58
6.5.
Other Safety Parameters ............................................................................................................... 60
6.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 60
6.5.2.
Physicians Withdrawal Checklist (PWC) .................................................................................... 61
6.5.3.
Arizona Sexual Experiences Scale (ASEX)................................................................................ 61
7.
SUMMARY OF PLASMA CONCENTRATIONS FOR JNJ-42847922, M12, AND M16 .................. 62
8.
BIOMARKERS................................................................................................................................... 62
REFERENCES............................................................................................................................................ 63
ATTACHMENTS......................................................................................................................................... 64


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2001
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Approved, Date: 6 February 2019
AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
21 May 2018
Amendment 1
10 Jan. 2019
Amendment 2
6 Feb. 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (6 Feb. 2019)
The overall reason for the amendment:    removed analysis windows for salivary cortisol; added sensitivity 
analysis for MCP-Mod; added conversion rules for lab values and added analysis for plasma concentrations  
Applicable Section(s)
Description of Change (s)
Section 2.5                            Removed analysis windows for salivary cortisol from Table 1 (this is moved to a 
separate biomarker SAP)
Section 2.8
Removed association analysis between cortisol and efficacy outcome (this is 
moved to a separate biomarker SAP)
Section 5.2.3.1
Added sensitivity analysis using the model based on the maximum of the candidate 
model trend test statistics; added sensitivity analysis using bootstrap for MCP-Mod 
CI
Section 6.2 
Added conversion rules for chemistry laboratory values
Section 7
Added that Plasma concentrations for JNJ-42847922, M12, and M16 will be 
summarized using descriptive statistics.
Attachment 3
Updated conversion factor for Triglycerides
Amendment 1 (10 Jan. 2019)
The overall reason for the amendment:  added MADRS-6, remission/response analyses for observed case, 
descriptive analyses for ISI and SDS; clarified definitions for sustained response, Hy’s law and identifications of 
treatment-emergent abnormal ECGs; and removed biomarker analysis from the SAP.  
Applicable Section(s)
Description of Change (s)
Section 2.5                            Table 1 minor edits to the analysis windows
Section 2.8
Added prior medication use of adjunctive antipsychotics based on concomitant 
medication and MGH (Yes/No) to subgroup
Section 4.1
Added WOCBP vs. WONCBP vs Men to demographic categorical variables in 
Table 2; added baseline ISI per IWRS and per eDC to baseline categorical variables 
in Table 3.
Section 4.6
Clarified that prior medications will be summarized by base preferred term.
Section 5 
Added MADRS-6 Total score to the efficacy variable. Added section 5.3.15.
Section 5.1.2, 5.3.1.1, 
5.3.2.1, 5.3.5.1 and 5.3.8.2
Added observed case analyses for remission/response analyses.  
Section 5.2.3.2
Added a sensitivity analysis to exclude major protocol deviations.
Section 5.3.1.3
Clarified sustained response definitions 
Section 5.3.3.2  
Added that descriptive statistics will also be provided for change from baseline in 
ISI total score by baseline ISI score (≥15 versus <15)


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Section 5.3.7.2
Added that the percentage of subjects who have not worked/studied at all during 
the past 7 days will be summarized.
Section 6.1
Removed the definition of next-day somnolence AE
Section 6.2
Clarified Hy’s law with AST included to the criteria.
Section 6.4
Clarified the identification of treatment-emergent abnormal ECG values
Section 6.5.2
Added PWC-20 total score 
Section 8
Biomarker analysis are moved out to a separate document.


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ABBREVIATIONS
AE
adverse event
AIC
Akaike Information Criterion
ANCOVA
analysis of covariance
ASEX
Arizona Sexual Experiences Scale
CGI-S
Clinical Global Impression-Severity 
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition
ECG
electrocardiogram
EQ-5D-5L
European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level questionnaire
HAM-A 
Hamilton Anxiety Rating Scale 
HbA1c
hemoglobin A1c
HPA
hypothalamic-pituitary-adrenal
HSI
Health Status Index
IAC
Interim Analysis Committee
ISI
Insomnia Severity Index
IWRS
interactive web response system
LOCF
last observation carried forward
LS
least-squares
MADRS
Montgomery-Asberg Depression Rating Scale
MCP-Mod
Multiple Comparison Procedure-Modeling
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire
MMRM
mixed model for repeated measures
PD
pharmacodynamic(s)
PGI-S
Patient Global Impression-Severity
PHQ-9
Patient Health Questionnaire 9-item
PK
pharmacokinetic(s)
PRO
patient-reported outcome(s)
PROMIS-SD
Patient Reported Outcome Measurement Information System-Sleep Disturbance
PROMIS-Fatigue
Patient Reported Outcome Measurement Information System- Fatigue
PWC
Physician Withdrawal Checklist
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
RRS
Ruminative Response Scale
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID-CT
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version
SD
standard deviation
SDS
Sheehan Disability Scale
SHAPS
Snaith-Hamilton Pleasure Scale
SIGH-A
structured interview guide for the Hamilton Anxiety Scale
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
US
United States
WHO-DD
World Health Organization Drug Dictionary
WLQ
Work Limitations Questionnaire
WOCBP
women of childbearing potential
WONCBP 
women of non-childbearing potential


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for all planned analyses for the clinical study report (CSR) for study 
42847922MDD2001.
This SAP does not include planned analyses on biomarkers or pharmacogenomics data or on 
population pharmacokinetic (PK), pharmacodynamics (PD) and exposure/response analyses, 
which will be specified as appropriate in separate documents.
1.1.
Trial Objectives
Objectives
Endpoints
Primary

To assess the dose-response relationship of up 
to 3 doses of JNJ-42847922 (20 and 40 mg, 
with 10 mg potentially added at the interim 
analysis) compared to placebo as adjunctive 
therapy to an antidepressant drug in improving 
depressive symptoms in subjects with major 
depressive disorder (MDD) who have had an 
inadequate response to current antidepressant 
therapy with a selective serotonin reuptake 
inhibitor (SSRI) or serotonin-norepinephrine 
reuptake inhibitor (SNRI).

Change from baseline to the end of Week 6 in 
the Montgomery-Asberg Depression Rating 
Scale (MADRS) total score.

To assess the safety and tolerability of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant in 
subjects with MDD.

Safety assessments, including adverse events
(AEs), laboratory values, electrocardiogram 
(ECG), vital signs, physical exam, the 
Columbia Suicide Severity Rating Scale (C-
SSRS), the Arizona Sexual Experiences Scale 
(ASEX), and the Physician Withdrawal 
Checklist (PWC).


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Objectives
Endpoints
Secondary

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving depressive 
symptoms in subjects with MDD with 
significant 
insomnia 
symptoms 
(baseline 
Insomnia Severity Index [ISI] score ≥15) 
versus those without significant insomnia 
symptoms (baseline ISI score <15).

Correlation between baseline ISI score as a 
continuous variable and change from baseline 
to the end of Week 6 in the MADRS total 
score.

Change from baseline to the end of Week 6 in 
the MADRS total score in subjects with 
baseline ISI score ≥15 versus subjects with 
baseline ISI score <15.

Shift in ISI score category from baseline to 
the end of Week 6.

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving:

Response and remission of depressive 
symptoms

Proportion of responders on depressive 
symptoms scale, defined as a ≥50% 
improvement in MADRS total score 
from baseline to the end of Week 6.

Proportion of subjects with remission of 
depressive symptoms, defined as a 
MADRS total score ≤8, ≤10, or ≤12 at 
the end of Week 6.

Anxiety symptoms

Change from baseline to the end of 
Week 6 on the 14-item Hamilton 
Anxiety Rating scale (HAM-A) total 
score.

Response of anxiety symptoms

Proportion of responders on anxiety 
symptoms scale, defined as a ≥50% 
improvement in the HAM-A total score 
from baseline to the end of Week 6.

Clinical severity

Change from baseline to the end of 
Week 
6 
in 
the 
Clinical 
Global 
Impression-Severity (CGI-S) score.

Global functioning (work/school, social 
and family life).

Change from baseline to the end of 
Week 6 in the Sheehan Disability Scale 
(SDS).

To assess the efficacy of JNJ-42847922 
compared to placebo as adjunctive therapy to 
an antidepressant in improving depressive 
symptoms in the subpopulation of subjects 
with MDD with anxious distress.

Change from baseline to the end of Week 6 in 
the MADRS total score in subjects with MDD 
with anxious distress versus subjects with 
MDD without anxious distress.

To evaluate the effect of JNJ-42847922 
exposure on the hypothalamic-pituitary-adrenal 
(HPA) axis in subjects with MDD.

Change from baseline to Days 8, 22, and 42 in 
salivary cortisol levels, as measured upon 
awakening.

To assess the exposure of JNJ-42847922 and 
metabolites M12 and M16 in subjects with 
MDD.

Observed 
plasma 
concentrations 
of 
JNJ-42847922 and metabolites and estimated 
exposure parameters for JNJ-42847922 from 
population based PK modeling.


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Objectives
Endpoints

To capture patient-reported assessment of 
JNJ-42847922 
compared 
to 
placebo 
as 
adjunctive therapy to an antidepressant.

Change from baseline to the end of Week 6 
in:

Depressive symptoms using the Patient 
Health Questionnaire 9-item (PHQ-9)

Anhedonia using the Snaith-Hamilton 
Pleasure Scale (SHAPS)

Sleep disturbance using the Patient 
Reported 
Outcome 
Measurement 
Information System-Sleep Disturbance 
(PROMIS-SD) Short Form

Fatigue using the PROMIS-Fatigue Short 
Form

Severity of depression using the Patient 
Global Impression-Severity (PGI-S)

Health related quality of life and utility 
using the European Quality of Life 
(EuroQol) Group, 5-Dimension, 5-Level 
(EQ-5D-5L) questionnaire

Work productivity and limitations using 
the
Work Limitations Questionnaire 
(WLQ) Short Form.
In addition, the exploratory objectives are:

To identify diagnostic biomarkers and to investigate changes in MDD-related biomarkers 
(HPA axis function, biomarkers of immune system activation and oxidative stress) in 
relation to clinical response on depression symptoms upon adjunctive treatment with JNJ-
42847922

To explore the exposure/response relationship of JNJ-42847922 in subjects with MDD

To identify genetic factors that may influence the PK, safety, or tolerability of JNJ-
42847922

To assess the predictive capability of salivary cortisol levels assessed during the circadian 
nadir (predose in the evening) on the antidepressant effect of JNJ-42847922.
1.2.
Trial Design
This is a multicenter, double-blind, randomized, parallel-group, placebo-controlled, 6-week 
adaptive dose-finding study to assess the efficacy and safety of JNJ-42847922 as adjunctive 
therapy in adult subjects with MDD who have had an inadequate response to current 
antidepressant therapy with an SSRI/SNRI. Approximately 280 subjects will be randomized.


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The doses of JNJ-42847922 that will be studied prior to the interim analysis are known (i.e., 20 
and 40 mg), whereas the doses of JNJ-42847922 to be studied after the interim analysis will be 
adaptively chosen based on the dose-response curve observed at the interim analysis. During the 
interim analysis review period, subjects will continue to be randomized according to the initial 
randomization scheme. Regardless of whether subjects are randomized before or after the interim 
analysis, the schedule of events and study procedures will remain the same. The final analysis 
will include all subjects.
Initially, the study will assess the efficacy, dose- and exposure-response relationship, safety, and 
tolerability of JNJ-42847922 20 and 40 mg doses compared to placebo, when administered as 
adjunctive therapy to an SSRI/SNRI antidepressant. At the start of the study, subjects will be 
randomized in a 2:1:1 ratio to receive 1 of 3 treatments: placebo: JNJ-42847922 20 mg: JNJ-
42847922 40 mg.
The data cutoff for the interim analysis will be 6 weeks after randomization of 160 subjects. An 
Interim Analysis Committee (IAC) will be established to review the interim data to examine the 
dose-response relationship and determine the doses of JNJ-42847922 and the allocation ratio of 
the doses to be used after the interim analysis. 
After the interim analysis, subjects will be randomly assigned to study drug (placebo or 1 of the 
JNJ-42847922 doses [potential doses include 10 mg, 20 mg, 40 mg]), with the allocation ratio 
adapted according to the dose-response curve seen at the interim analysis.
For all subjects, the study will consist of 3 phases: a screening phase (up to 4 weeks), a double-
blind treatment phase (6 weeks), and a posttreatment follow-up phase (2 weeks). The planned 
total study duration for each subject will be approximately 12 weeks (84 days). Subjects will 
continue to take their baseline SSRI/SNRI antidepressant (at the same dose, without change, and 
at approximately the same time as prior to entering the study) throughout the screening, double-
blind, and follow-up periods (the entire 12 weeks of the study duration).
In order to collect PK and salivary cortisol samples after the Day 1 dose, subjects will stay at the 
study site from at least 1 hour before the bedtime dosing on Day 1 until the morning of Day 2.
A schematic overview of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study Design
Abbreviations: IA=interim analysis, MDD=major depressive disorder, PK=pharmacokinetics, QD=once daily, 
SSRI= selective serotonin reuptake inhibitor, SNRI=serotonin-norepinephrine reuptake inhibitor.
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is the change from baseline to the end of Week 6 in the MADRS
total score.  The null hypothesis to be tested to address the primary objective of the study is that 
there is no difference between any of the JNJ-42847922 doses (10, 20 and/or 40 mg) and 
placebo, as adjunctive treatment to an SSRI/SNRI, in the improvement of depressive symptoms 
of MDD, based on the primary efficacy endpoint.
1.4.
Sample Size Justification
The calculation of the sample size is based on the primary efficacy endpoint (change from 
baseline to the end of Week 6 for the MADRS total score). The assumptions for the effect size 
were based on published literature and the clinically meaningful difference between groups to be 
detected.
The total sample size is calculated on the basis of the generalized Multiple Comparison 
Procedure-Modeling (MCP-Mod)4 test applied to the placebo and the JNJ-42847922 dose groups 
at the final analysis. Approximately 280 randomized subjects will provide an average weighted 
power of approximately 85% depending on the underlying true dose-response shape, assuming a 
1-sided significance level of 0.05, a treatment difference from placebo of 4.5 points in change in 
MADRS total score, a standard deviation of 10, and a 25% overall dropout rate.
The data cutoff for the interim analysis will be 6 weeks after randomization of 160 subjects, 
which corresponds to approximately 57% of the sample size of the study. This number of 
subjects provides approximately 93% power to detect a dose-response relationship, depending on 
Interim Analysis (IA): The data cutoff for the unblinded IA will be 
6 weeks after randomization of 160 subjects. To determine the 
doses and allocation ratio of the doses to be used after the IA.


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the underlying true dose-response shape, assuming a treatment difference of 4.5, and a standard 
deviation of 10 when tested by means of the MCP-Mod approach at the 30% significance level 
(1-sided). 
Further details regarding the interim analysis will be specified in a separate charter and interim 
analysis SAP.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned 
based on a computer-generated randomization schedule prepared before the study by or under 
the supervision of the sponsor.
At the start of study enrollment, subjects will be randomly assigned to receive 1 of 3 treatments 
in a 2:1:1 ratio to placebo:JNJ-42847922 20 mg:JNJ-42847922 40 mg.
After the interim analysis, subjects will be randomly assigned to study drug, with the allocation 
ratio adapted according to the dose-response curve observed at the time of the interim analysis. 
Subjects will be assigned to receive placebo or one of the JNJ-42847922 doses (potential doses 
include 10 mg, 20 mg, 40 mg). 
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
region (United States [US], Europe, and Japan) and by insomnia status (significant insomnia 
symptoms [ISI score ≥15] at baseline versus no significant insomnia symptoms [ISI score <15] at 
baseline).  In order to randomize approximately equal proportions of subjects with and without 
significant insomnia symptoms at baseline, the number randomized in either stratum will be 
capped at 60% of the planned total sample size.
The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
To maintain the study blind, the study drug container will have a label containing the study 
name, study drug number, and reference number. The label will not identify the study drug in the 
container. However, if it is necessary for a subject's safety, the study blind may be broken and 
the identity of the study drug ascertained. The study drugs will be identical in appearance and 
will be packaged in identical containers.
In general, randomization codes will be disclosed fully only when the study is completed and the 
clinical database is closed. However, for the interim analysis, the randomization codes and 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.
Study Reference Start and End Dates
The overall reference start date for the study is defined as the date of the first dose of double-
blind medication (the date is missing for screened subjects who did not receive a dose of double-
blind medication). The overall reference end date for the study is the end of trial date including 
the last follow-up visit, i.e., the study reference end date is the maximum of the date of the last 
visit in the double-blind treatment phase, or date of the last visit in the follow-up phase, or date 
of disposition in the double-blind phase (Trial Disposition for Double-blind Phase case report 
form [CRF] page), or date of disposition in the follow-up phase (Disposition at Follow-up CRF 
page).
2.2.
Analysis Phases
There are 3 analysis phases defined in this study: Screening, Double-blind, and Follow-up (post 
double-blind). Each analysis phase has its own analysis reference start date.
Screening
The screening phase begins on the date informed consent is obtained and ends 1 day prior to the 
date of the first dose of study drug in the double-blind treatment phase.  The screening phase end 
date is left missing for those subjects who did not receive study drug.
Double-blind Phase
The analysis reference start date of the double-blind analysis phase is the date of the first dose of 
double-blind medication. The analysis reference end date of the double-blind analysis phase
(except for Adverse Events) is the maximum of the date of the last visit in the double-blind phase
and date of completion or early withdrawal from the double-blind phase (Trial Disposition for 
Double-blind Phase CRF page). For Adverse Events, the analysis reference end date of the 
double-blind analysis phase is the date of the last dose of study drug plus 2 days. For randomized 
subjects who did not receive any medication in the double-blind phase, both analysis reference
start and end dates are missing for the double-blind analysis phase.
Follow-up Phase
Start and end dates for the follow-up phase are only defined for subjects who continued into the 
follow-up phase. The analysis reference start date of the follow-up analysis phase is the day after 
the reference end date for the double-blind analysis phase. The analysis reference end date of the 
follow-up analysis phase is the maximum of the last follow-up visit date or the disposition date at 
follow-up (Disposition at Follow-up CRF page).
2.3.
Study Day
Study Day 1 or Day 1 refers to the start of the first study drug administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date.


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Study day for a visit is defined as:
a.
Visit date - (date of Study Day 1) +1, if visit date is >= date of Day 1
b.
Visit date - Date of Day 1, if visit date < date of Day 1 
There is no ‘Day 0’.
2.4.
Baseline and End Point (DB)
The baseline measurement is defined as the closest measurement taken prior to or at the time of 
the first dose of study drug, with the exception of the average predose ECG measurement, which 
is defined as the average of all ECG results collected up to and including the day of the first dose 
of study drug.  
End point (DB) is defined as the last available postbaseline result within the double-blind phase. 
Unscheduled visit results are included in this definition and will be considered as the end point 
(DB) value if the unscheduled visit result is the last postbaseline result available within the 
double-blind phase.
2.5.
Visit Windows
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. Listed below 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). 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 but they can be used for 
determination of clinically important end points. If 2 actual visits are equidistant from the target 
day within a visit window, the later visit is used.
All assignments will be made in chronological order. Once a visit date is assigned to a visit 
window, it will no longer be used for a later time point except for the end point (DB). Listed 
below (Table 1) are the visit windows and the target days for each visit defined in the protocol.
Assessments prior to Day 1 of the double-blind phase that are not considered a baseline 
assessment will be labeled as ‘Screening’.
Table 1: Visit Windows
Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time 
Interval
(label on 
output)
Time 
Interval
(Day)*
Target Time 
Point
(Day/Time)
MADRS
Screening
1
Screening
< 1
-28 to -3
DB
2
Baseline
≤1
1
3
Day 8
2 to 15
8
4
Day 22
16 to 32
22


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Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time 
Interval
(label on 
output)
Time 
Interval
(Day)*
Target Time 
Point
(Day/Time)
5
Day 42
33 to end of 
DB
42
DB last visit
End point
(DB)
2 to end of 
DB
HAM-A,
CGI-S,
SDS,
PGI-S,
SHAPS,
PROMIS-
Fatigue,
PROMIS-SD,
WLQ,
EQ-5D-5L,
PHQ-9
DB
2
Baseline
≤1
1
3
Day 8
2 to 15
8
4
Day 22
16 to 32
22
5
Day 42
33 to end of 
DB
42
DB last visit
End point
(DB)
2 to end of 
DB
Weight,
BMI,
Waist 
Circumference, 
ISI
Screening
1
Screening
<1
-28 to -3
DB
2
Baseline
≤1
1
5
Day 42
2 to end of 
DB
42
DB last visit
End point
(DB)
2 to end of 
DB
ECG
DB
1, 2 
Predose
≤1
-28 to 1
1, 2
Average 
Predose
≤1
-28 to 1
5
Day 42
2 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
Physical Exam
Screening
1
Screening
<1
-28 to -3
DB
2
Baseline
≤1
1
5
Day 42
2 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
Vital signs
Screening
1
Screening
<1
-28 to -3
DB
2
Baseline
≤1
1
3
Day 8
2 to 15
8
4
Day 22
16 to 32
22
5
Day 42
33 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB


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Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time 
Interval
(label on 
output)
Time 
Interval
(Day)*
Target Time 
Point
(Day/Time)
Follow-up
6
Follow-up
End of DB + 
1 to end of 
FU
49-56
Serum 
Chemistry, 
Urinalysis
Screening
1
Screening
≤1
-28 to -3
DB
2
Baseline
≤1
1
3
Day 8
2 to 25
8
5
Day 42
26 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
Hematology
Screening
1
Screening
<1
-28 to -3
DB
2
Baseline
≤1
1
3
Day 8
2 to 15
8
4
Day 22
16 to 32
22
5
Day 42
33 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
Lipid Panel, 
ASEX
DB
2
Baseline
≤1
1
5
Day 42
2 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
HbA1c
DB
1
Baseline
≤1
-28 to -3
5
Day 42
2 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
PWC
DB
5
Day 42
2 to end of 
DB
42
DB last visit
End point 
(DB)
2 to end of 
DB
Follow-up
TC
Telephone 
Contact
use Day 43 
visit
43
6
Follow-up
use Day 49 
to 56 visit
49-56
C-SSRS
Screening
1
Screening
<1
-28 to -3
DB
2
Baseline
≤1
1
3
Day 8
2 to 15
8
4
Day 22
16 to 32
22
5
Day 42
33 to end of 
DB
42


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Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time 
Interval
(label on 
output)
Time 
Interval
(Day)*
Target Time 
Point
(Day/Time)
DB last visit
End point 
(DB)
2 to end of 
DB
Follow-up
6
Follow-up
End of DB + 
2 to end of 
FU
49-56
*Relative to Study Day 1; DB=double-blind; FU=follow-up, TC=telephone contact
2.6.
Pooling Algorithm for Analysis Centers
Subjects will be enrolled at sites in Europe (Bulgaria, Finland, Germany, Russia, Ukraine), the 
US, and Japan.  Actual site enrollment rates will be monitored to avoid gross imbalances across 
centers. To account for region variability, region (US, Japan, Europe) will be used as a factor in 
the statistical models to analyze efficacy. 
2.7.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full analysis set, and 
safety analysis set.
2.7.1.
All Randomized Analysis Set
The all randomized analysis set includes all subjects who were randomized in the study (i.e.,
subjects who reported a randomization date, or were assigned a randomization number) 
regardless of whether or not treatment was received. This analysis set will be used for 
summarizing the overall study completion/withdrawal information.
2.7.2.
Efficacy Analysis Set
2.7.2.1.
Full Analysis Set
The efficacy analyses will be based on the full analysis set, which consists of all subjects who 
were randomly assigned to study drug and received at least 1 dose of study drug.
2.7.3.
Safety Analysis Set
Safety analyses will be based on the safety analysis set, which consists of all subjects who were 
randomly assigned to study drug and received at least 1 dose of study drug.  The safety analysis 
set is the same as the full analysis set.
2.8.
Definition of Subgroups
Descriptive statistics will be provided for the primary efficacy endpoint (change from baseline to 
the end of Week 6 in MADRS total score) by the following subgroups:

Baseline ISI score (≥15 versus <15, using the randomization stratification factor as 
entered into IWRS); this will also be used in the analyses as the baseline insomnia status


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
MDD subtype based on SCID-CT (with or without anxious distress based on the 
Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-
Fifth Edition [DSM-5] Axis I Disorders – Clinical Trials Version [SCID-CT])

Baseline Ruminative Response Scale (RRS) score (≥median score versus <median score
in the full analysis set)

Sex (male, female, undifferentiated)

Age group (18-34, 35-54, 55-64, 65-70 years)

Women of Childbearing Potential (WOCBP) (as determined by Reproductive Tracking
CRF page) vs. Men and Women of Non-Childbearing Potential (WONCBP)

Women of Childbearing Potential vs. Women of Non-Childbearing Potential

Adults (18-64) male, Elderly (≥65) male, Adults (18-64) female, Elderly (≥65) female

Region (US, Europe, Japan, as defined in Section 2.6)

Race

Ethnicity

MDD with anxiety based on HAM-A (No/Yes, defined as baseline HAM-A total score 
<18 versus ≥18)

Number of antidepressants used in the current episode based on the Massachusetts 
General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ; 1, 2, 
3 or more)

Number of major depressive episodes in lifetime, including current episode (<3, ≥3)

Prior medication use of adjunctive antipsychotics based on concomitant medication 
(Yes/No)

Prior medication use of adjunctive antipsychotics based on concomitant medication and 
MGH (Yes/No)

Prior medication use of benzodiazepines (Yes/No)

Baseline body mass index (BMI; underweight: <18.5 kg/m2, normal: 18.5 kg/m2 to <25 
kg/m2, overweight: 25 kg/m2 to <30 kg/m2, obese: ≥30 kg/m2)

Functional impairment based on baseline SDS category (not impaired [0-3], mild [4-11], 
moderate [12-19], marked [20-26] or extreme [27-30]).


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Additional subgroup analyses of the primary efficacy endpoint are described in Section 5.2.3.5.
2.9.
Imputation Rules for Missing Adverse Event (AE) Dates
Partial AE onset dates will be imputed as follows:

If the onset date of an AE is missing day only, it will be set to:
o
First day of the month that the AE occurred, if month/year of the onset of AE is 
different than the month/year of the study drug start
o
The day of study drug start, if the month/year of the onset of AE is the same as 
month/year of the study drug start date and month/year of the AE resolution date 
is different
o
The day of study drug start or day of AE resolution date, whichever is earlier, if 
month/year of the onset of AE and month/year of the study drug start date and 
month/year of the AE resolution date are the same.

If the onset date of an AE is missing both day and month, it will be set to the earliest of:
o
December 31 of the year of onset, if the year of onset is prior to the year of the 
study drug start date
o
January 1 of the year of onset, as long as this date is on or after the study drug 
start date
o
Month and day of the study drug start date, if this date has the same year as the 
year that the AE occurred
o
The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates will be imputed as follows:

If the resolution date of an AE is missing day only, it will be set to the earlier of the last 
day of the month of occurrence of resolution or the day of the date of death, if the death 
occurred in that month.

If the resolution date of an AE is missing both day and month, it will be set to the earlier
of December 31 of the year or the day and month of the date of death, if the death 
occurred in that year.

Completely missing resolution dates will not be imputed.
AE onset/resolution dates with missing times will be imputed as follows:


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
A missing time of onset of an AE will be set to the earlier of:
o
00:01 as long as the onset date is different from the study drug start date
o
The time of the study drug start if this is the same day the AE occurred.

The missing time of resolution of an AE will be set to 23:59.
If a missing time is associated with a partial date, the date will be imputed first prior to imputing 
the time.
2.10.
Imputation Rules for Missing Prior/Concomitant Medication Dates
2.10.1.
Prior Medications
Prior medications or therapy are those taken by subjects before the start of dosing of first study 
drug. Medications will be classified as prior if the medication start date is complete and prior to 
the date of first dose of study drug or the medication end date is complete and prior to the date of 
first dose of study drug.
If the medication start day is missing, and the month and year of the start date are not missing, 
then if:

The month and year of the start date of medication is earlier than the month and year of 
the initial study drug administration; or

The CRF indicates the medication was taken prior (prior medication flag=Yes) and the 
month and year of the start date of medication is the same as the month and year of the 
initial study drug administration
then the medication will be considered prior. 
If the medication start month and day are missing, and the year of the start date is not missing, 
then if:

The year of the start date of medication is earlier than the year of the initial study drug 
administration; or 

The CRF indicates the medication was taken prior when the year of the start date of 
medication is the same as the year of the initial study drug administration
then it will also be considered prior.
If the medication start date is completely missing, and the CRF indicates it was taken prior, it 
will also be considered prior.


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2.10.2.
Concomitant Medications Taken During the Double-blind Phase
Concomitant medications taken during the double-blind phase are those that started on the same 
day as the first dose or after the start of dosing or those continuing from predose (prior 
medication flag=Yes) and the CRF indicates the medication is ongoing or the medication stop 
date is on or after the first dose of study drug. Medications that start after the analysis reference 
end date of the double-blind phase are not considered concomitant medications taken during the 
double-blind phase. 
If the medication start date is missing the day, but the month and year are complete, then if the 
month and year of the start date are on or prior to the month and year of the analysis reference 
end date of the double-blind phase and: 

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration 
then the medication is classified as concomitant during the double-blind phase.
If the medication start date is missing the month and day, but the year is complete, then if the 
year of the start date is the same as or prior to the year of the analysis reference end date of the 
double-blind phase and:

The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration 
then the medication is classified as concomitant during the double-blind phase.
If the medication start date is completely missing then if:


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
The CRF indicates that the medication is ongoing, or

The stop date of the medication is missing, or

The stop date of the medication is on or after the initial study drug administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study drug administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study drug administration
then the medication is classified as concomitant during the double-blind phase.
For concomitant medications categorized as “taken during DB” based on the rules above, the 
duration during the DB phase will be calculated as: Minimum of medication end date and the DB 
End date - Maximum of the medication start date and the DB start date + 1.  If there are partial 
start/end dates, the imputation rules for the duration during the DB phase are as follows: 
If the month of the start date is not missing but the day is, then the duration is imputed as: 
Minimum of the medication end date and the DB End Date - Maximum of the first day of 
the month and the DB Start Date + 1;
If the year of the start date is not missing but the month is, then the duration is imputed as: 
Minimum of the medication end date and the DB End Date - Maximum of the first day of 
the year and the DB Start Date + 1;
If the month of the end date is not missing but the day is, then the duration is imputed as:
Minimum of the last day of the month and the DB End Date - Maximum of the 
medication start date and the DB Start date + 1;
If the year of the end date is not missing but the month is, then the duration is imputed as:
Minimum of the last day of the year and the DB End Date - Maximum of the medication 
start date and the DB Start date + 1.
2.10.3.
Concomitant Medications Taken During the Follow-up Phase
Follow-up medications are those that started after the analysis reference end date of the double-
blind phase.


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3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
The data cutoff for the interim analysis will be 6 weeks after randomization of 160 subjects, 
which corresponds to approximately 57% of the sample size of the study. The primary purpose 
of the interim analysis will be to examine the dose-response relationship, to determine the doses 
of JNJ-42847922 and their allocation ratio to be used in subjects randomized after the interim 
analysis. The IAC will review the outputs from statistical analysis, exposure, exposure-response 
analysis, and safety for this determination.
The interim analysis will use the generalized MCP-Mod approach to establish a dose-response 
signal with respect to the primary efficacy endpoint. A 1-sided 0.30 significance level will be 
used to test for dose-response using the MCP-Mod approach on the change in MADRS total 
score to the end of Week 6. 
Unblinded exposure-response analyses will be performed by an independent internal 
pharmacometrician using data available at the interim analysis, with adequate firewalls so the 
study team will remain blinded. At the time of interim analysis, the IAC will review the exposure 
and exposure-response analyses to assist in selection of doses and the allocation ratio to be used 
in after the interim analysis.
No adjustment to the final significance level will be performed as a result of the interim analysis.
Further details regarding the interim analysis will be specified in a separate charter and interim 
analysis SAP.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be provided.  In addition, the number of subjects 
by region (as defined in Section 2.6), country, and site in the full analysis set will be provided.
4.1.
Demographics and Baseline Characteristics
Demographic and baseline characteristics (Table 2) and psychiatric history at baseline (Table 3) 
will be summarized by treatment group and overall for the full analysis set. The continuous 
variables will be summarized using descriptive statistics (N, mean, standard deviation [SD], 
median, minimum, and maximum). The categorical variables will be summarized using a 
frequency distribution with the number and percentage of subjects in each category.
Table 2: Demographic Variables and Baseline Characteristics
Continuous Variables:

Age (years), calculated based on date of informed consent date

Baseline weight (kg)

Baseline height (cm)

Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2

Baseline waist circumference (cm)
Categorical Variables:

Age (18-34, 35-54, 55-64, 65-70 years)


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
Sex (male, female, undifferentiated)

WOCBP vs. WONCBP vs. Men

Race (White, Black or African American, Asian, American Indian or Alaskan native, Native 
Hawaiian or other Pacific islander, Not reported); If multiple race categories are indicated, then 
Race is recorded as “Multiple”.

Ethnicity (Hispanic or Latino, not Hispanic or Latino)

Baseline BMI (underweight: <18.5 kg/m2, normal: 18.5 kg/m2 to <25 kg/m2, overweight: 25 
kg/m2 to <30 kg/m2, obese: ≥30 kg/m2)
Table 3: Psychiatric History at Baseline Variables
Continuous Variables:

Age (years) when diagnosed with MDD

Duration (weeks) of current depressive episode

Baseline MADRS total score

Baseline CGI-S score

Baseline PHQ-9 total score
Categorical Variables:

Current antidepressant type (SSRI, SNRI)

Antidepressant treatment history (number of medications with inadequate response taken for at 
least 4 weeks during the current episode as obtained in the MGH-ATRQ)

SCID-CT DSM-5 specifiers for MDD (anxious distress, mixed features, melancholic features, 
atypical features, peripartum onset, seasonal pattern)

Baseline CGI-S score (1=normal [not at all ill]; 2=borderline ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; 7=among the most extremely ill patients)

Functional impairment based on baseline SDS total score: not impaired (0-3), mild (4-11),
moderate (12-19), marked (20-26), or extreme (27-30)

Baseline ISI per IWRS (≥15 versus <15, using the randomization stratification factor as entered 
into IWRS); this will also be used in the analyses as the baseline insomnia status

Baseline ISI score per eDC (≥15 versus <15, using the eDC data)

Number of major depressive episodes in lifetime, including current episode (1, 2, ≥3)

Family history of alcohol abuse (yes, no)

Family history of anxiety disorder (yes, no)

Family history of bipolar disorder (yes, no)

Family history of depression (yes, no)

Family history of schizophrenia (yes, no)

Family history of substance abuse (yes, no)
By-subject listings of the demographic and baseline characteristics, as well as medical history
and tobacco use history, will be provided.
4.2.
Disposition Information
The number of screen failures will be summarized.
The number of subjects in the following disposition categories will be summarized throughout 
the study by treatment group and overall:


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
Subjects randomized 

Subjects receiving study drug

Subjects completing the double-blind phase

Subjects who discontinued from the double-blind phase 

Reasons for discontinuation from the double-blind phase 

Subjects completing the follow-up phase

Subjects who discontinued from the follow-up phase 
Listings of subjects will be provided for the following categories:

All randomized subjects 

Subjects who discontinued from the double-blind phase

Subjects who discontinued from the follow-up phase

Subjects who were unblinded during the study period

Subjects who were randomized yet did not receive study drug.
These summaries and listings will be provided for the all randomized analysis set.
For the safety analysis set, a Kaplan-Meier plot of the time to discontinuation of study drug will 
be provided.
4.3.
Treatment Compliance
4.3.1.
Treatment Compliance With Study Drug
Compliance for each subject will be calculated based on the percent of the scheduled number of 
capsules of study drug actually taken within the double-blind phase. It is defined as:
%compliance = (number of capsules taken / number of capsules supposed to have been 
taken)*100%.
The number of capsules supposed to have been taken will be calculated as the duration of 
treatment within the phase (i.e., date of last dose of study drug – date of first dose of study drug 
+ 1) multiplied by 2 (since each “dose” of study drug consists of 2 capsules). 
Descriptive statistics on the percent (%) compliance will be summarized by treatment group for 
the safety analysis set.  In addition, percent compliance will be categorized as <60%, 60%-
<80%, 80%-100%, >100% and the number and percentage of subjects in each category will be 
summarized.
4.3.2.
Treatment Compliance With Baseline SSRI/SNRI Antidepressant
Compliance for each subject will be calculated based on the percent of the scheduled number of 
days that the baseline SSRI/SNRI antidepressant was actually taken within the double-blind 
phase. It is defined as:
%compliance = (number of days baseline SSRI/SNRI antidepressant taken / number of days in 
double-blind phase)*100%.


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The number of days in the double-blind phase will be calculated as the duration of double-blind 
treatment phase (i.e., completion or discontinuation date of the double-blind phase – date of first 
dose of study drug + 1). 
Descriptive statistics on the percent compliance will be summarized by treatment group for the 
safety analysis set.  In addition, percent compliance will be categorized as <60%, 60%-<80%, 
80%-100%, >100% and the number and percentage of subjects in each category will be 
summarized.
4.4.
Extent of Exposure
Total duration of exposure (including days off drug) is defined as (date of last dose of study drug
– date of first dose of study drug) + 1.  Number of doses is defined as the total number of drug 
administrations. Taking more than 2 tablets within 4 hours is considered as overdose.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for total duration of 
exposure (including days off drug) and for number of doses will be presented by treatment group 
for the safety analysis set.  
A by-subject listing of study drug administration will be provided.
4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical trial. Subjects 
with major protocol deviations will be identified prior to database lock and the number and 
percentage of subjects with major protocol deviations will be summarized by category for the 
safety analysis set.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
More categories may be included depending on the nature of the protocol deviation.  A subject 
may be counted in more than one deviation category.
A by-subject listing showing the specific major protocol deviations will also be provided.
A summary of the number of subjects in the safety analysis set not meeting each 
inclusion/exclusion criterion will be presented.
4.6.
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study drug. Concomitant medications are defined as any therapy 


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used on or after the same day as the first dose of study drug, including those that started before 
and continue after the first dose of study drug.
If the medication start date is recorded as partial or completely missing, then the medication will 
be considered to be concomitant unless it is known to be prior to the first administration of study 
drug based on partial start date or stop date or the CRF indicates that the medication was taken 
prior (prior medication flag=Yes) (see Section 2.10 for detailed classification of prior and 
concomitant medications).
Prior medications will be summarized by treatment group and base preferred term for the safety 
analysis set.  The proportion of subjects who receive each prior medication will be summarized
as well as the proportion of subjects who receive at least one prior medication. In addition, the 
number and percent of subjects who receive antidepressant medications prior to the study will be 
summarized.  
Summaries of concomitant medications (other than antidepressant medications) will be presented 
by treatment group and base preferred term for the safety analysis set, for those medications used 
during the double-blind phase and for those used during the follow-up phase separately.  
Definitions for concomitant medications used during the double-blind phase and those used 
during the follow-up phase are provided in Section 2.10.2 and 2.10.3, respectively. 
The 
proportion of subjects who receive each concomitant medication will be summarized as well as 
the proportion of subjects who receive at least one concomitant medication.  
In addition, summary tables of the antidepressant concomitant medications received during the 
study will be presented by treatment group, for those medications used during the double-blind 
phase and for those used during the follow-up phase separately.  
A by-subject listing of all prior and concomitant medication will also be provided.
5.
EFFICACY
All efficacy analyses will be based on the full analysis set.
The efficacy variables for this study are listed in Table 4.
Table 4: Efficacy Variables
Efficacy Variable
Endpoint
MADRS

Change from baseline to the end of Week 6 in the 
MADRS total score
Primary

Correlation between baseline ISI score as a 
continuous variable and change from baseline to the 
end of Week 6 in the MADRS total score.
Secondary

Change from baseline to the end of Week 6 in the 
MADRS total score in subjects with baseline ISI 
score >15 versus subjects with baseline ISI score 
Secondary


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Efficacy Variable
Endpoint
<15.

Proportion of responders on depressive symptoms 
scale (>50% improvement in the MADRS total 
score from baseline to the end of Week 6)
Secondary

Proportion of subjects with remission on depressive 
symptoms scale (MADRS total score <8, <10, <12 
at the end of Week 6)
Secondary

Change from baseline to the end of Week 6 in the 
MADRS total score in subjects with MDD with 
anxious distress versus subjects with MDD without 
anxious distress.
Secondary

Change from baseline to the end of Week 6 in the 
MADRS-6 total score
Secondary
ISI

Shift in ISI score category from baseline to the end 
of Week 6.
Secondary
HAM-A

Change from baseline to the end of Week 6 in the 
HAM-A total score
Secondary

Proportion of responders on anxiety symptoms scale
(>50% improvement in the HAM-A total score from 
baseline to the end of Week 6)
Secondary
CGI-S

Change from baseline to the end of Week 6
Secondary
SDS

Change from baseline to the end of Week 6
Secondary
PHQ-9

Change from baseline to the end of Week 6
Secondary
SHAPS

Change from baseline to the end of Week 6
Secondary
PROMIS-SD

Change from baseline to the end of Week 6
Secondary
PROMIS-Fatigue

Change from baseline to the end of Week 6
Secondary
PGI-S

Change from baseline to the end of Week 6
Secondary
EQ-5D-5L, VAS 
and health status 
index

Change from baseline to the end of Week 6
Secondary
WLQ

Change from baseline to the end of Week 6
Secondary
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary efficacy endpoint will be evaluated at a 1-sided significance level of 0.05 using the 
MCP-Mod approach to test for dose-response. For all other analyses of the primary efficacy 


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endpoint and for all other efficacy endpoints, no multiplicity adjustment will be done will be 
presented.
For the interim analysis, a 1-sided 0.30 significance level will be used to test for dose-response 
using the MCP-Mod approach on the change in MADRS total score to the end of Week 6. No 
adjustment to the final significance level will be performed due to the interim analysis.
5.1.2.
Data Handling Rules
As sensitivity analyses, the change in MADRS total score, MADRS-6 total score, HAM-A total 
score, and PHQ-9 total score will be analyzed using an analysis of covariance (ANCOVA) 
model, using last observation carried forward (LOCF) data.  These analyses are further described 
in Sections 5.2.3.3, 5.3.4.2, and 5.3.8.2. 
For the analyses of response of depressive symptoms based on MADRS total score (Section 
5.3.1), remission of depressive symptoms based on MADRS total score (Section 5.3.2), response 
of anxiety symptoms based on HAM-A total score (Section 5.3.5), and response and remission of 
depressive symptoms based on PHQ-9 total score (Section 5.3.8.2), both observed case and 
imputed case where subjects with missing values will be imputed as non-responders/non-
remitters will be presented.
For the graphical presentations of the cumulative response rates, defined as the percentage of 
subjects experiencing at least a given value of percent reduction from baseline to the end of 
Week 6 for MADRS total score (Section 5.3.1), HAM-A total score (Section 5.3.5), and PHQ-9 
total score (Section 5.3.8.2), both observed and LOCF data will be presented. Since ISI is 
collected at only 1 postbaseline time point, the cumulative response curve for ISI (Section 
5.3.3.2) will be presented using observed data.
5.1.3.
Imputation Methods for Missing Items
For MADRS, imputation of the total score when there are missing items is described in Section 
5.2.1.  Likewise, for PROMIS-SD, PROMIS-Fatigue, WLQ and MADRS-6, imputation of the 
total score when there are missing items is described in Sections 5.3.10.1, 5.3.11.1, 5.3.14.1 and 
5.3.15.1, respectively.  For all other scales where multiple items are summed to create a total, if 
any item of the scale is missing at a visit, the total score for that scale at that visit will be left 
blank.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary efficacy endpoint is the change in MADRS total score from baseline to the end of 
Week 6.  The MADRS will be performed by independent, centralized remote raters during the 
study. The MADRS is a clinician-administered scale designed to measure depression severity 
and consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe 
or continuous presence of the symptoms).  The MADRS evaluates apparent sadness, reported 
sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, 


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inability to feel, pessimistic thoughts, and suicidal thoughts. The recall period for the MADRS is 
7 days.
A total score (0 to 60) is calculated by adding the scores of all 10 items. Higher scores represent 
a more severe condition.  Imputation of the total score will be performed only when 1 item score 
is missing. If 2 or more items are missing, the total score will be left missing. The total score 
will be imputed by calculating the sum of the scores of the non-missing items and multiplying it
by the ratio of the maximum possible number of items (i.e., 10) to the number of non-missing 
items (i.e., 9).
The MADRS change from baseline at Week 6 is calculated as (MADRS total score at Week 6 –
Baseline MADRS total score).  Negative changes in MADRS total score indicate improvement.
5.2.2.
Primary Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:
Population: subjects with MDD who have had an inadequate response to current antidepressant 
therapy with an SSRI/SNRI, as defined through appropriate inclusion/exclusion criteria to reflect 
the targeted patient population;
Variable: change in MADRS total score from baseline to the end of Week 6 (see Section 5.2.1);
Intervention Effect: the effect of the initially randomized treatment together with the oral 
SSRI/SNRI antidepressant that would have been observed had all subjects remained on their 
treatment throughout the double-blind phase;
Summary Measure: the difference in variable means.
The primary analysis will be based on the full analysis set and the MADRS total scores collected 
during the double-blind phase.
5.2.3.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for MADRS total score by treatment group.  
A frequency distribution of the MADRS individual item scores at each time point will be 
provided by treatment group.    
5.2.3.1.
MCP-Mod Analysis
The primary efficacy endpoint will be evaluated using the generalized MCP-Mod approach. The 
MCP-Mod approach provides a method for dose-finding using model-based estimation rather 
than hypothesis testing via pairwise comparisons.  The analysis will be done in two steps.
First, a mixed model for repeated measures (MMRM) analysis of the observed data from the 
placebo and JNJ-42847922 groups will be used as the method of addressing missing data and to 


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adjust for important covariates. The MMRM will include region (as defined in Section 2.6), time
(scheduled Week), treatment (placebo and JNJ-42847922 dose groups), baseline insomnia status 
(present/absent), and treatment-by-time interaction as factors and baseline MADRS total score as 
a covariate. An unstructured variance-covariance matrix will be used for observations clustered 
by subject.  In case of convergence problems, alternative variance-covariance structures will be 
tried in the following order, with the first structure that converges being used in the analysis: 
heterogeneous Toeplitz, standard Toeplitz, and AR(1) with separate subject random effect.  
Subjects in the full analysis set who do not have complete data will still contribute to the 
estimates at the end of Week 6, but will have less weight in the analysis than those subjects with 
complete data.  The Kenward-Roger method will be used for approximating the denominator 
degrees of freedom. Based on the MMRM, the least-squares (LS) mean estimates for each JNJ-
42847922 dose group and placebo at Week 6 and the corresponding variances will be obtained.
Subsequently, the generalized MCP-Mod approach will be applied towards the estimates 
obtained from the MMRM to analyze the dose-response relationship. This approach requires pre-
specification of a candidate model set. The actual candidate model set will depend on an interim 
analysis decision with two possible scenarios. The first scenario is when the 10 mg dose is not 
added after the interim analysis (i.e., subjects have been randomized to placebo, JNJ-42847922
20 mg and 40 mg dose groups only). For that scenario, using notation as in Bornkamp et al 
(2009)1, the candidate set consists of the following 3 standardized model profiles (with the 
corresponding parameters): “linear” (no parameters), “emax” (ED50=1.053), and “exponential”
(δ=18.20).  The second scenario is realized when the 10 mg dose is added after the interim 
analysis. For the second scenario, the candidate set is extended to the total of 4 standardized 
model profiles: “linear” (no parameters), “emax” (ED50=1.053), “exponential” (δ=18.20), and 
“sigEmax” (ED50=14.14, h=8.496). Figure 2 below shows the extended set (of note, the 
maximum response is scaled to 1).  Also, for the second scenario, the MCP-Mod model selection 
criteria will be based on the Akaike Information Criterion (AIC) with the k parameter equal to 
0.5. As a sensitivity analysis, the maximum of the candidate model trend test statistics will be 
used as MCP-MOD model selection criterion.
Figure 2:
MCP-Mod Candidate Model Set


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The significance of the dose-response signal associated with each candidate model will be 
determined using trend tests with model-specific optimal contrast coefficients. The maximum of 
the candidate model trend test statistics will be used to evaluate the presence of a dose-response 
signal, properly accounting for multiplicity at an overall level of 5% (1-sided) using MCP-Mod 
methodology. If the maximum test statistic is not significant, no dose-response relationship will 
be further explored. Otherwise, the model family corresponding to the candidate model with 
maximum trend test statistic will be used to fit to the observed data to represent the dose-
response relationship.  The corresponding confidence interval (CI) for the response at each dose 
and placebo will be computed. A bootstrap method may be used for obtaining CI as sensitivity 
analysis.
As a secondary analysis, age and gender will be added to the MMRM model for the MCP-MOD 
analyses.


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5.2.3.2.
MMRM Pairwise Comparisons
In conjunction with the MCP-Mod analysis, the pairwise comparison between JNJ-42847922 
doses and placebo will also be performed using the appropriate contrasts directly from the 
MMRM analysis described in Section 5.2.3.1, using estimates at the end of Week 6.  A 90% CI
for the difference in LS Means and p-value will be calculated based on the contrast test statistic
for each JNJ-42847922 dose level.
As a secondary analysis, age and gender will be added to the MMRM model described in Section 
5.2.3.1 for the pairwise comparison between JNJ-42847922 doses and placebo.
As a sensitivity analysis, the change in MADRS total score from baseline to the end of Week 6 
will be analyzed in an MMRM analysis with the exclusion of subjects with major protocol 
deviations that may affect efficacy (e.g., developed withdrawal criteria but not withdrawn, 
entered but did not satisfy criteria, received a disallowed concomitant treatment, received wrong 
treatment or incorrect dose and others that may affect efficacy). 
5.2.3.3.
Sensitivity Analysis – ANCOVA with LOCF
As a sensitivity analysis, the change in MADRS total score from baseline to the end of Week 6 
will be analyzed using an ANCOVA model of LOCF data.  The ANCOVA model will include
factors for treatment, region, baseline insomnia status (present/absent), and baseline MADRS 
total score as a continuous covariate.  A 90% CI for the difference in LS Means and p-value will 
be calculated based on the contrast test statistic for each JNJ-42847922 dose level.  
The last postbaseline observation during the double-blind phase will be carried forward as the
“End Point (DB)”.  Besides the end point (DB) assessment, the LOCF values will be created for 
intermediate postbaseline time points as well.  These imputed time points will be labeled ‘Day X 
LOCF’.
For example, if a subject has a visit on Day 7 for the “Day 8 visit” and then a final visit on Day 
10, the visit on Day 7 will be slotted to “Day 8” because Day 7 is closer to the target Day 8 than 
Day 10. The Day 10 visit will be used as “Day 22 LOCF”, “Day 42 LOCF” and “End Point
(DB)”. 
5.2.3.4.
Mediation Analysis
In the mediation analysis framework, natural direct effect can be conceived of as the independent 
treatment effect on the outcome (i.e., change in MADRS total score) that is above and beyond its 
effect on the mediator (i.e., change in ISI score); controlled direct effect can be conceived of as 
the independent treatment effect on the outcome controlling the mediator at a fixed level; and 
natural indirect effect can be conceived of as a treatment effect on the outcome that is accounted 
for by its effect on the mediator.
A mediation analysis will be performed to examine the mediating role of improvement in sleep
assessed by change from baseline in ISI score on change from baseline in MADRS total score
provided that both endpoints demonstrate a statistically difference between at least one dose of 
JNJ-42847922 and placebo.  This analysis will assess the extent to which change in MADRS 


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total score may be mediated by or independent of change in ISI score based on observed data 
(i.e., data collected at each time point without carrying forward previous values) at the end of 
Week 6. The analysis will consider both change in MADRS total score and change in ISI score
as continuous variables. The calculation of the ISI score is described in Section 5.2.3.5.

Simulation-based Counterfactual Approach: this analysis introduced by Imai et.al 2
obtains the natural direct effect and natural indirect effect using numerical simulations. 
The approach uses parametric bootstrapping to construct the point estimate and its 
uncertainty estimates for direct effect and indirect effect from the bootstrap sampling 
distribution. For each bootstrapped sample, change from baseline in MADRS total score 
and change from baseline in ISI score will be analyzed.  The ANCOVA analysis of 
change in MADRS total score from baseline will include factors for treatment (placebo 
and JNJ-42847922 dose groups), region, and baseline insomnia status (present/absent), 
change from baseline (Day 1, predose) in ISI score, treatment-by-change from baseline in 
ISI score interaction if the interaction is significant, and baseline MADRS total score as a 
covariate. The ANCOVA analysis of change in ISI score will include factors for 
treatment (placebo and JNJ-42847922 dose groups), region, and baseline insomnia status 
(present/absent), and baseline MADRS total score as a covariate. Estimate of the 
controlled direct effect will be obtained by plugging in the estimated coefficient values 
and the mean level of change in ISI score into the analytic expressions.
Since the relationship can be bi-directional, a mediation analysis similar to the above analysis 
will be performed, to assess the extent to which change in ISI score may be mediated by or 
independent of change in MADRS total score, based on observed data (i.e., data collected at each 
time point without carrying forward previous values) at the end of Week 6.
5.2.3.5.
Subgroup Analyses
In addition to the analyses described below, descriptive statistics will be provided for the primary 
efficacy endpoint (change from baseline to the end of Week 6 in MADRS total score) by the 
subgroups identified in Section 2.8.  
Baseline ISI Score
The ISI has 7 questions, each rated on a 5-point Likert scale ranging from 0 to 4.  The total score 
is calculated as the sum of the 7 items.
The correlation between baseline ISI score as a continuous variable and change from baseline to 
the end of Week 6 in the MADRS total score will be evaluated by means of a scatter plot and if 
appropriate, regression analysis. 
In addition, subjects will be dichotomized based on their baseline ISI score (≥15 versus <15) to 
evaluate whether there are differences in these subgroups (i.e., evaluating change from baseline 
to the end of Week 6 in the MADRS total score in subjects with ISI score ≥15 versus subjects 
with ISI score <15).  Descriptive statistics of the change from baseline to the end of Week 6 in 
the MADRS total score will be presented by treatment group for these subgroups.  


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MDD Subtype
Subjects will be dichotomized based on whether they have MDD with anxious distress or MDD 
without anxious distress (as determined by the SCID-CT) to evaluate whether there are 
differences in these subgroups (i.e., evaluating change from baseline to the end of Week 6 in the 
MADRS total score in subjects with and without anxious distress).  Descriptive statistics of the 
change from baseline to the end of Week 6 in the MADRS total score will be presented by 
treatment group for these subgroups.  
Baseline RRS Score
The RRS consists of 22 items which are rated on 4-point Likert scales ranging from “almost 
never” to “almost always”.  The total score is calculated as the sum of the 22 items.
Subjects will be dichotomized based on their baseline RRS score to evaluate whether there are 
differences in these subgroups (i.e., evaluating change from baseline to the end of Week 6 in the 
MADRS total score in subjects with RSS score ≥the median versus subjects with RRS score 
<median).  Descriptive statistics of the change from baseline to the end of Week 6 in the 
MADRS total score will be presented by treatment group for these subgroups.  
In addition, the correlation between baseline RRS score as a continuous variable and change 
from baseline to the end of Week 6 in the MADRS total score will be evaluated by means of a 
scatter plot and if appropriate, regression analysis.
5.3.
Secondary Efficacy Endpoints
5.3.1.
Response of Depressive Symptoms
5.3.1.1.
Definition
A secondary efficacy endpoint is the proportion of responders on depressive symptoms scale at 
the end of Week 6, defined as a ≥50% improvement in MADRS total score from baseline to the 
end of Week 6.  The calculation of the MADRS total score is described in Section 5.2.1. The 
percentage change from baseline for MADRS total score is calculated as 100*(MADRS total 
score at Day X – Baseline MADRS total score)/(Baseline MADRS total score). Negative percent 
changes in MADRS total score indicate improvement (eg, percent change < -50% indicates 
improvement >50%).
A subject is defined a responder (yes=1) at a given time point if the percent reduction in 
MADRS total score is ≥50%. Subjects who do not meet such criterion will be considered as non-
responders and will be assigned a value of 0 (i.e., no).  Observed case analysis, i.e., no 
imputation for subjects with missing values, will be explored. 


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5.3.1.2.
Utility Estimand
The secondary endpoint of proportion of responders on depressive symptoms scale at the end of 
Week 6 can also be considered a “utility estimand”, as it considers efficacy and tolerability data 
together.  It is defined by the following 4 components:
Population: subjects with MDD who have had an inadequate response to current antidepressant 
therapy with an SSRI/SNRI, as defined through appropriate inclusion/exclusion criteria to reflect
the targeted patient population;
Variable: is binary (responder or non-responder), as defined in Section 5.3.1.1; subjects who do 
not have a MADRS total score at the end of Week 6 (eg, subjects who have early discontinuation
of study drug) will be considered non-responders;
Intervention Effect: is not applicable as the intercurrent event (discontinuation of study drug) is 
captured in the variable definition;
Summary Measure:  the difference in response proportions.
The analysis will be based on the full analysis set and the MADRS total scores collected during 
the double-blind phase.
5.3.1.3.
Analysis Methods
The number and percentage of subjects who achieve a response will be summarized at each time 
point during the double-blind phase by treatment group. The point estimate and 2-sided 90% 
confidence interval will be provided for the relative response using a Mantel-Haenszel test 
controlling for region and baseline insomnia status (present/absent).
The cumulative response rate, defined as the percentage of subjects experiencing at least a given 
value of percent reduction from baseline to the end of Week 6 in MADRS total score, will be 
presented graphically, for both observed and LOCF data.
The cumulative distribution function of the time to sustained response will be estimated by the 
Kaplan-Meier method. Time to sustained response will be summarized (number of sustained 
responders, number of censored subjects, median, 25th and 75th percentile, if estimable) by 
treatment group. Sustained response is defined as the first occurrence of response on Day 8 or 
Day 22 that is maintained through the end of Week 6 assessment. Subjects are allowed one 
excursion (non-response) on a subsequent visit prior to Day 42, however the score must show at 
least 25% improvement. Subjects who discontinue early are not considered to have sustained 
response. A stratified log rank test (stratified for region and baseline insomnia status) will be 
used to test the hypothesis that there is no difference between the JNJ-42847922 dose groups and 
placebo in the probability of achieving sustained response.
A variation of definition for sustained response will be explored, for which no excursion is 
allowed. The analyses mentioned above will be repeated for this variation.    


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5.3.2.
Remission of Depressive Symptoms
5.3.2.1.
Definition
A secondary efficacy endpoint is the proportion of subjects with remission of depressive 
symptoms at the end of Week 6, defined as a MADRS total score ≤8, ≤10, or ≤12 at the end of 
Week 6.  Subjects who do not meet such criterion will be considered as non-remitters.   
Observed case analysis, i.e., no imputation for subjects with missing values, will be explored. 
The calculation of the MADRS total score is described in Section 5.2.1.
5.3.2.2.
Analysis Methods
The number and percentage of subjects who achieve remission (based on each of the 3 
definitions) will be summarized at each time point during the double-blind phase by treatment 
group.
The point estimate and 2-sided 90% confidence interval will be provided for the relative risk of
remission using a Mantel-Haenszel test controlling for region and baseline insomnia status 
(present/absent).
5.3.3.
Shift in Insomnia Severity Index (ISI) Score Category
5.3.3.1.
Definition
A secondary efficacy endpoint is the shift in ISI score category from baseline to the end of Week 
6.  The calculation of the ISI score is described in Section 5.2.3.5.  The scores are categorized as 
follows: score 0-7=no clinically significant insomnia; score 8-14=sub-threshold insomnia; score 
15-21=moderate insomnia, and score 22-28=clinically severe insomnia.
5.3.3.2.
Analysis Methods
The shift in ISI score category from baseline to the end of Week 6 will be presented.  A 
frequency distribution of the ISI individual item scores at each time point will be provided by 
treatment group.  In addition, descriptive statistics of the ISI score at Baseline and Week 6, as 
well as the change from baseline to Week 6, will be presented by treatment group.  Descriptive 
statistics will also be provided for change from baseline to the end of Week 6 in ISI total score 
by baseline ISI score (≥15 versus <15, using the randomization stratification factor as entered 
into IWRS)
The change in ISI score from baseline to the end of Week 6 will be analyzed using an ANCOVA 
model.  The ANCOVA model will include factors for treatment and region, and baseline ISI 
score as a continuous covariate.  A 90% CI for the difference in LSMeans and p-value will be 
calculated based on the contrast test statistic for each JNJ-42847922 dose level.
The cumulative response rate, defined as the percentage of subjects experiencing at least a given 
value of percent reduction from baseline to the end of Week 6 in ISI score, will be presented 
graphically, using observed data.


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5.3.4.
Change in Hamilton Anxiety Rating Scale (HAM-A)
5.3.4.1.
Definition
A secondary efficacy endpoint is the change from baseline to the end of Week 6 in the HAM-A
total score.  The original 14-item clinician-administered HAM-A scale assesses the severity of 
different anxiety-related symptoms. It is a commonly used, validated scale in clinical trials 
assessing anxiety. However, the original HAM-A lacks instructions for administration and clear 
anchor points for the assignment of severity ratings. For this reason, the structured interview 
guide version (SIGH-A) will be used in this study.  
Each of the 14-items in the scale is scored on a 5-point scale, ranging from 0 (not present) to 4 
(very severe, symptom is incapacitating).  A total score (0 to 56) is calculated by adding the 
scores of all 14 items, where 0-13 indicates normal range, 14-17 indicates mild severity, 18–24 
mild to moderate severity, 25–30 moderate to severe, and ≥31 severe. Higher scores represent a 
more severe condition. 
The HAM-A change from baseline at Week 6 is calculated as (HAM-A total score at Week 6 –
Baseline HAM-A total score).  Negative changes in HAM-A total score indicate improvement.
The somatic factor score of HAM-A is defined as the sum of items 7 to 13; and the psychic 
factor score of HAM-A is defined as the sum of items 1-6 and 14.
5.3.4.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for HAM-A total score, and HAM-A 
somatic and psychic factor scores by treatment group.  
The change from baseline to Day 8, 22, and 42 in HAM-A total score will be analyzed using the 
same MMRM as described in Section 5.2.3.1 for the primary efficacy endpoint, with the 
continuous covariate “baseline MADRS total score” changed to “baseline HAM-A total score”.
As a sensitivity analysis, the change in HAM-A total score from baseline to the end of Week 6 
will be analyzed using an ANCOVA model, using LOCF data.  The derivation of the LOCF 
values is described in Section 5.2.3.3.  The ANCOVA model will include factors for treatment, 
region, baseline insomnia status (present/absent), and baseline HAM-A total score as a 
continuous covariate.  A 90% CI for the difference in LSMeans and p-value will be calculated 
based on the contrast test statistic for each JNJ-42847922 dose level.  
In addition, a frequency distribution over time of the HAM-A total score categories and HAM-A
individual item scores at each time point will be provided by treatment group.    
The shift in HAM-A total score category from baseline to each time point will be presented by 
treatment group.


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The correlations between HAM-A total score and MADRS total score will be evaluated using 
Pearson and Spearman correlation coefficients.  These correlations will look at the correlations 
of the actual values at each time point, as well as the change from baseline.  Scatter plots will 
also be presented.    
5.3.5.
Response of Anxiety Symptoms
5.3.5.1.
Definition
A secondary efficacy endpoint is the proportion of responders on anxiety symptoms scale at the 
end of Week 6, defined as a ≥50% improvement in the HAM-A total score from baseline to the 
end of Week 6.  The calculation of the HAM-A total score is described in Section 5.3.4.1. The
percentage change from baseline for HAM-A total score is calculated as 100*(HAM-A total 
score at Day X – Baseline HAM-A total score)/(Baseline HAM-A total score). Negative percent 
changes in HAM-A total score indicate improvement (eg, percent change < -50% indicates 
improvement >50%).
A subject is defined a responder (yes=1) at a given time point if the percent reduction in HAM-A 
is ≥50%. Subjects who do not meet such criterion will be considered as non-responders and will 
be assigned a value of 0 (i.e., no). Observed case analysis, i.e., no imputation for subjects with 
missing values, will be explored.
5.3.5.2.
Analysis Methods
The number and percentage of subjects who achieve a response will be summarized at each time 
point during the double-blind phase by treatment group. 
The cumulative response rate, defined as the percentage of subjects experiencing at least a given 
value of percent reduction from baseline to the end of Week 6 in HAM-A total score, will be 
presented graphically, for both observed and LOCF data.
5.3.6.
Clinical Global Impression-Severity (CGI-S)
5.3.6.1.
Definition
A secondary efficacy endpoint is the change from baseline to the end of Week 6 in the CGI-S 
score.  The CGI-S provides an overall clinician-determined summary measure of the severity of 
the subject’s illness that takes into account all available information, including knowledge of the 
subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the subject’s ability to function. The CGI-S evaluates the severity of 
psychopathology on a scale of 1 to 7. Considering total clinical experience with the depression 
population, a subject is assessed on severity of illness at the time of rating according to: 
1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6=severely ill; 7=among the most extremely ill patients. The CGI-S permits a global evaluation 
of the subject's condition at a given time.
The CGI-S change from baseline at Week 6 is calculated as (CGI-S score at Week 6 – Baseline 
CGI-S score).  Negative changes in CGI-S score indicate improvement.


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5.3.6.2.
Analysis Methods
A frequency distribution over time of the CGI-S scores at Baseline, Day 8, Day 22, and Day 42
will be provided by treatment group.  In addition, descriptive statistics of the actual values and 
the change from baseline will be presented by treatment group for observed case data.
The analysis of the change in CGI-S score from baseline to Day 8, 22, and 42 will be performed 
using an ANCOVA model on the ranks of the change in score with treatment, region, and 
baseline insomnia status as factors, and unranked baseline CGI-S score as a covariate.
In addition, the correlation between CGI-S score and HAM-A total score and MADRS total 
score will be evaluated using Spearman correlation coefficients.  These correlations will look at 
the correlations of the actual values at each time point, as well as the change from baseline.  
Scatter plots will also be presented.    
5.3.7.
Sheehan Disability Scale (SDS)
5.3.7.1.
Definition
A secondary efficacy endpoint is the change from baseline to the end of Week 6 in the SDS.  The 
SDS is a subject-reported, 5-item questionnaire which has been widely used and accepted for 
assessment of functional impairment and associated disability. The first 3 items assess disruption 
of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating 
scale. The scores for the first 3 items are summed to create a total score of 0-30 where a higher 
score indicates greater impairment. It also has 1 item on days lost from school or work and 1 
item on days when underproductive. The recall period for this study is 7 days. 
The SDS change from baseline at Week 6 is calculated as (SDS total score at Week 6 – Baseline 
SDS total score).  Negative changes in SDS total score indicate improvement.
5.3.7.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for SDS total score by treatment group.  In 
addition, descriptive statistics of the actual values and the change from baseline, as well as a 
frequency distribution, will be presented by treatment group for each of the 5 SDS individual 
item scores at each time point.    
The change from baseline to Day 8, 22, and 42 in SDS total score will be analyzed using the 
same MMRM as described in Section 5.2.3.1 for the primary efficacy endpoint, with the 
covariate “baseline MADRS total score” changed to “baseline SDS total score”.
In addition, the percentage of subjects who have not worked/studied at all during the past 7 days 
will be summarized at each time point during the double-blind phase by treatment group.


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5.3.8.
Patient Health Questionnaire 9-item (PHQ-9)
5.3.8.1.
Definition
A secondary efficacy endpoint is the change from baseline to the end of Week 6 in PHQ-9.  The 
PHQ-9 is a 9-item, patient-reported outcome (PRO) measure to assess depressive symptoms. The 
scale scores each of the 9 symptom domains of the DSM-5 MDD criteria and it has been used 
both as a screening tool and a measure of response to treatment for depression. Each item is rated 
on a 4 point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every 
day). The subject’s item responses are summed to provide a total score (range of 0 to 27), with 
higher scores indicating greater severity of depressive symptoms. The recall period is 2 weeks.  
The severity of the PHQ-9 is categorized as follows: None-minimal (0-4), Mild (5-9), Moderate 
(10-14), Moderately Severe (15-19) and Severe (20-27).
The PHQ-9 change from baseline at Week 6 is calculated as (PHQ-9 total score at Week 6 –
Baseline PHQ-9 total score).  Negative changes in PHQ-9 total score indicate improvement.
5.3.8.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for PHQ-9 total score by treatment group.  
The change from baseline to Day 8, 22, and 42 in PHQ-9 total score will be analyzed using the 
same MMRM as described in Section 5.2.3.1 for the primary efficacy endpoint, with the 
covariate “baseline total MADRS score” changed to “baseline PHQ-9 total score”.
As a sensitivity analysis, the change in PHQ-9 total score from baseline to the end of Week 6 
will be analyzed using an ANCOVA model, using LOCF data.  The derivation of the LOCF 
values is described in Section 5.2.3.3.  The ANCOVA model will include factors for treatment, 
region, baseline insomnia status (present/absent), and baseline PHQ-9 total score as a continuous 
covariate.  A 90% CI for the difference in LS Means and p-value will be calculated based on the 
contrast test statistic for each JNJ-42847922 dose level.  
Frequency distributions of the PHQ-9 severity categories, of the 9 individual items, and of the 
responses to the question “How difficult have these problems made it for you to do your work, 
take care of things at home, or get along with other people” will be provided at each assessment 
time point.
In addition, the number and percentage of subjects who achieve remission of depressive 
symptoms (defined as a PHQ-9 total score <5) will be summarized at each time point during the 
double-blind phase by treatment group.  Subjects who do not meet such criterion will be 
considered as non-remitters.
The number of subjects who are responders on depressive symptoms based on the PHQ-9 will 
also be evaluated.  The first definition of a responder on PHQ-9 will be based on an 
improvement in PHQ-9 total score of ≥6 points.  Based on this definition, a subject is defined a 
responder (yes=1) at a given time point if the improvement in PHQ-9 total score is ≥6 points. 


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Subjects who do not meet such criterion will be considered as non-responders and will be 
assigned a value of 0 (i.e., no).
The second definition of a responder on PHQ-9 will be based on a ≥50% improvement in PHQ-9 
total score from baseline.  The percentage change from baseline for PHQ-9 total score is 
calculated as 100*(PHQ-9 total score at Day X – Baseline PHQ-9 total score)/(Baseline PHQ-9 
total score). Negative percent changes in PHQ-9 total score indicate improvement (eg, percent 
change < -50% indicates improvement >50%).  Based on this definition, a subject is defined a 
responder (yes=1) at a given time point if the percent reduction in PHQ-9 total score is ≥50%. 
Subjects who do not meet such criterion will be considered as non-responders and will be 
assigned a value of 0 (i.e., no).
For both definitions, the number and percentage of subjects who achieve a response will be 
summarized at each time point during the double-blind phase by treatment group. Observed case 
analysis, i.e., no imputation for subjects with missing values, will be explored.
The cumulative response rate, defined as the percentage of subjects experiencing at least a given 
value of percent reduction from baseline to the end of Week 6 in PHQ-9 total score, will be 
presented graphically, for both observed and LOCF data.
5.3.9.
Snaith-Hamilton Pleasure Scale (SHAPS)
5.3.9.1.
Definition
A secondary efficacy endpoint is the change from baseline to the end of Week 6 in SHAPS.  The 
SHAPS is a reliable, valid, and unidimensional instrument to assess hedonic capacity in adults 
with MDD. It is a 14-item, self-report tool. Each of the items has a set of 4 response categories-
Definitely Agree/Strongly Agree, Agree, Disagree, and Strongly Disagree, with either of the 
Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 
0. The subject’s item responses are summed to provide a total range (range of 0 to 14).  A higher 
total SHAPS score indicates higher levels of present state of anhedonia.
The SHAPS change from baseline at Week 6 is calculated as (SHAPS total score at Week 6 –
Baseline SHAPS total score).  Negative changes in SHAPS total score indicate improvement.
5.3.9.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for SHAPS total score by treatment group.  
The change from baseline to Day 8, 22, and 42 in SHAPS total score will be analyzed using the 
same MMRM as described in Section 5.2.3.1 for the primary efficacy endpoint, with the 
covariate “baseline total MADRS score” changed to “baseline SHAPS total score”.
Frequency distributions of the SHAPS individual items will be provided at each assessment time 
point.


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5.3.10.
Patient Reported Outcome Measurement Information System-Sleep 
Disturbance (PROMIS-SD)
5.3.10.1.
Definition
The PROMIS-SD Short Form subscale consists of a static 8-item questionnaire. Using a recall 
period of the past 7 days, it assesses the concepts of sleep initiation (2 items), quality of sleep (3 
items), early morning feelings (2 items) and worrying about sleep (1 item). 
Each question has five response options ranging in value from one to five. To find the total raw 
score for a short form with all questions answered, sum the values of the response to each 
question. For the 8-item form, the lowest possible raw score is 8; the highest possible raw score 
is 40.  Lower scores indicate less sleep disturbance.  Note that the “direction” of the responses is 
not the same for all questions, i.e., sometimes a response of “not at all” indicates more sleep 
disturbance and sometimes a response of “not at all” indicates less sleep disturbance.  
“My sleep quality was” ranges from 5=very poor to 1=very good
“My sleep was refreshing” ranges from 5=not at all to 1=very much
“I had a problem with my sleep” ranges from 1=not at all to 5=very much
“I had difficulty falling asleep” ranges from 1=not at all to 5=very much
“My sleep was restless” ranges from 1=not at all to 5=very much
“I tried hard to get to sleep” ranges from 1=not at all to 5=very much
“I worried about not being able to fall asleep” ranges from 1=not at all to 5=very much
“I was satisfied with my sleep” ranges from 5=not at all to 1=very much
A score can be approximated if a participant skips a question.  However, for the 8-item form, at 
least 4 items must have been answered in order to calculate a score.  After confirming that 
enough responses were provided, sum the response scores from the items that were answered. 
Multiply this sum by the total number of items in the short form. Finally, divide by the number 
of items that were answered. For example, if a respondent answered 5 of 8 questions and 
answered all items with the second lowest response option (2), you would sum all responses 
(10), multiply by the number of items in the short form (8) and divide by the number of items 
that were answered (5). Here (10x8)/5=16. If the result is a fraction, round up to the nearest 
whole number. 
The formula is:  
(Raw sum x number of items on the short form) / Number of items that were actually answered
This is a pro-rated raw score.
The raw score (i.e., the total raw score or pro-rated raw score) can be converted into a T-score 
for each participant based on the table in Attachment 1.  The T-score rescales the raw score into 
a standardized score with a mean of 50 and an SD of 10.


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The change in the PROMIS-SD score from baseline to each time point in the double-blind phase
will be calculated, for both the raw score and the T-score.
5.3.10.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Weeks 2, 4, and 6 will be presented for PROMIS-SD raw score and the T-score 
by treatment group.  
The change from baseline to Day 8, 22, and 42 in the PROMIS-SD raw score and the T-score 
will be analyzed using the same MMRM as described in Section 5.2.3.1 for the primary efficacy 
endpoint, with the covariate “baseline MADRS total score” changed to “baseline PROMIS-SD 
raw score” or “baseline PROMIS-SD T-score”, respectively.
Frequency distributions of the PROMIS-SD individual items will be provided at each assessment 
time point.
In addition, the correlations between baseline ISI score as a continuous variable and change from 
baseline to the end of Week 6 in the PROMIS-SD raw score and T-score will be evaluated by 
means of scatter plots and if appropriate, regression analysis.
5.3.11.
Patient Reported Outcome Measurement Information System- Fatigue
(PROMIS-Fatigue)
5.3.11.1.
Definition
The PROMIS-Fatigue Short Form subscale consists of a static 8-item questionnaire. Using a 
recall period of the past 7 days, it assesses a range of symptoms from mild subjective feelings of 
tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely 
decreases one’s ability to execute daily activities and function normally in family or social roles. 
Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the 
impact of fatigue on physical, mental, and social activities. The fatigue short form is generic 
rather than disease-specific.
Each question has five response options ranging in value from one to five. To find the total raw 
score for a short form with all questions answered, sum the values of the response to each 
question. For the 8-item form, the lowest possible raw score is 8; the highest possible raw score 
is 40.  Lower scores indicate less fatigue.    
“I feel fatigued” ranges from 1=not at all to 5=very much
“I have trouble starting things because I am tired” ranges from 1=not at all to 5=very 
much
“How run-down did you feel on average” ranges from 1=not at all to 5=very much
“How fatigued were you on average” ranges from 1=not at all to 5=very much
“How much were you bothered by your fatigue on average” ranges from 1=not at all to 
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“To what degree did your fatigue interfere with your physical functioning” ranges from 
1=not at all to 5=very much
“How often did you have to push yourself to get things done because of your fatigue” 
ranges from 1=never to 5=always
“How often did you have trouble finishing things because of your fatigue” ranges from 
1=never to 5=always
A score can be approximated if a participant skips a question.  However, for the 8-item form, at 
least 4 items must have been answered in order to calculate a score.  After confirming that 
enough responses were provided, sum the response scores from the items that were answered. 
Multiply this sum by the total number of items in the short form. Finally, divide by the number 
of items that were answered. For example, if a respondent answered 5 of 8 questions and 
answered all items with the second lowest response option (2), you would sum all responses 
(10), multiply by the number of items in the short form (8) and divide by the number of items 
that were answered (5). Here (10x8)/5=16. If the result is a fraction, round up to the nearest 
whole number. 
The formula is:  
(Raw sum x number of items on the short form) / Number of items that were actually answered
This is a pro-rated raw score.
The raw score (i.e., the total raw score or pro-rated raw score) can be converted into a T-score 
for each participant based on the table in Attachment 2.  The T-score rescales the raw score into 
a standardized score with a mean of 50 and an SD of 10.
The change in the PROMIS-Fatigue score from baseline to each time point in the double-blind 
phase will be calculated, for both the raw score and the T-score.
5.3.11.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for PROMIS-Fatigue raw score and the T-
score by treatment group.  
The change from baseline to Day 8, 22, and 42 in the PROMIS-Fatigue raw score and the T-
score will be analyzed using the same MMRM as described in Section 5.2.3.1 for the primary 
efficacy endpoint, with the covariate “baseline MADRS total score” changed to “baseline 
PROMIS-Fatigue raw score” or “baseline PROMIS-Fatigue T-score”, respectively.
Frequency distributions of the PROMIS-Fatigue individual items will be provided at each 
assessment time point.


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5.3.12.
Patient Global Impression-Severity (PGI-S)
5.3.12.1.
Definition
The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 
4=severe). Considering all aspects of depression, subjects will rate their severity on the PGI-S.
5.3.12.2.
Analysis Methods
A frequency distribution over time of the PGI-S scores at Baseline, Day 8, Day 22, and Day 42
will be provided by treatment group.  In addition, descriptive statistics of the actual values and 
the change from baseline will be presented by treatment group for observed case data.
The analysis of the change in PGI-S score from baseline to Day 8, 22, and 42 will be performed 
using an ANCOVA model on the ranks of the change in score with treatment, region, and 
baseline insomnia status as factors, and unranked baseline PGI-S score as a covariate.
5.3.13.
European Quality of Life (EuroQol) Group, 5 Dimension, 5-Level 
questionnaire (EQ-5D-5L)
5.3.13.1.
Definition
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily 
designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the 
following 
5 
dimensions: 
Mobility, 
self-care, 
usual 
activities, 
pain/discomfort 
and 
anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems 
(Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate 
problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems).
The subject selects an answer for each of the 5 dimensions considering the response that best 
matches his or her health “today.” The descriptive system can be represented as a health state. 
The EQ-VAS self-rating records the respondent’s own assessment of his or her overall health 
status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the 
best health you can imagine.
Individual scores from the 5 dimensions will be used to obtain a weighted health status index as 
shown below: 
(i) Scores from each dimension will be combined to obtain a 5L profile score: eg, a 
score of 1 for each dimension will give a 5L profile score of 11111. Dimension 
scores will be combined in the following order: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort, Anxiety/Depression
(ii) The value set of the Health Status Index (HSI) for various values of 5L profile 
scores 
is 
published 
for 
Canada 
in 
the
following 
website: 
https://www.ncbi.nlm.nih.gov/pubmed/26492214


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(iii)The Canadian value set will be used to get the HSI values for all the countries 
participating in the study.
In addition, a sum score will be derived as follows: The scores of the five dimensions (values 1-
5) will be added (sums between 5 and 25). From this score, subtract 5 (range 0-20) and multiply 
by 5 (range 0-100).
5.3.13.2.
Analysis Methods
Descriptive statistics of actual values on Baseline, Day 8, Day 22, and Day 42 and changes from 
baseline to Day 8, 22, and 42 will be provided by treatment group for the weighted EQ-5D health 
status index, the EQ-VAS, and the sum score.
Individual dimension responses will also be summarized at each visit with frequency counts and 
percentage of subjects by treatment group.
5.3.14.
Work Limitations Questionnaire (WLQ)
5.3.14.1.
Definition
The objective of the WLQ is to assess the on-the-job impact of chronic health problems and/or 
treatment ("work limitations") in adults. It is a PRO tool, consisting of 8 items in the short form 
version. The subject’s impressions are captured using 5-point Likert scales. The recall period is 2 
weeks.  
Step 1: Assign Numerical Values to Each Response
There are 4 scales within the WLQ-Short Form, each consisting of 2 items, and each of the 8 
items is given a score as follows:
Scale/Items
Coding
WLQ Time Management
“Get going easily at the beginning of the 
workday”
“Start on your job as soon as you arrived at 
work”
5=difficult all of the time 
4=difficult most of the time 
3=difficult some of the time 
2=difficult a slight bit of the time 
1=difficult none of the time
[set to missing value]=does not apply to my 
job
WLQ Physical Tasks
“Sit, stand, or stay in one position for longer 
than 15 minutes while working”
“Repeat the same motions over and over again 
1= able all of the time
2= able most of the time
3= able some of the time
4=able a slight bit of the time
5=able none of the time


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while working”
[set to missing value]=does not apply to my 
job
WLQ Mental-Interpersonal Tasks
“Concentrate on your work”
“Speak with people in-person, in meetings or 
one the phone”
5=difficult all of the time 
4=difficult most of the time 
3=difficult some of the time 
2=difficult a slight bit of the time 
1=difficult none of the time
[set to missing value]=does not apply to my 
job
WLQ Output Tasks
“Handle the workload”
“Finish work on time”
5=difficult all of the time 
4=difficult most of the time 
3=difficult some of the time 
2=difficult a slight bit of the time 
1=difficult none of the time
[set to missing value]=does not apply to my 
job
Step 2: Score the Four WLQ Scales
After each of the 8 items is scored, the scores for the 4 WLQ scales are determined.  For each the 
of 4 WLQ scales, the following 2 steps will be performed:
(i) Compute the average item score for a scale, including addressing missing data.
(ii) Convert the average item score to a 0-100 range.
Average Item Score
The average item score within a scale is calculated by summing the non-missing item scores 
within a scale and then dividing by the number of items with non-missing answers within the 
scale (i.e., not including items coded as missing).  For example, if a respondent answers items in 
the Time Management scale as follows:
“Get going easily at the beginning of the workday” = 2
“Start on your job as soon as you arrived at work” = 4 
First, sum the item scores: 2+4.  Then divide by the number of items with valid answers, i.e.,
divide by 2.  Your answer is therefore 6/2=3.0.
A scale score can still be calculated even if one of the responses within a scale is missing (either 
left blank or a “does not apply to my job” response). The scale score is calculated based on the 


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one non-missing item’s score.  In this case, the average item score is the value of the non-
missing item score.  
If both of the items within a scale are missing, the scale cannot be scored and the scale score will 
be treated as missing data.
Converting the Average Item Score to the Scale Score
To obtain the final WLQ Scale Score, convert average item score to a 0-100 range using the 
following formula:
WLQ Scale Score = 25*(average item score-1)
For example, using the average item score from above, the WLQ Time Management Scale Score 
is: 25*(3-1) = 50.
Step 3: Checking and Fixing Physical Scale Score Errors
Although the response categories in the Physical Scale are different than the other 3 scales, some 
people may not notice the change in wording. They report on the amount of time they had 
difficulty while they should be reporting on the amount of time they did not have difficulty. 
If the answers to the Physical Scale items contradict the answers in the other 3 scales, it can be 
reasonably inferred that the respondent didn’t notice the direction change.  
For these cases, implement the Physical Scale score correction as follows.
If the Physical Scale score computed above is greater than or equal to 75 and the other three 
scale scores are less than or equal to 30, the Physical Scale needs to be reversed by subtracting 
the original physical scale score from 100.
For example, if the Physical Scale score is 80 and the other three scale scores are 30, 25, and 25 
respectively, the corrected Physical Scale score is 100-80=20.
Step 4: Compute the Summary Score of Productivity Loss
After the 4 WLQ scale scores are determined, then the WLQ Productivity Loss Score is 
computed.  The WLQ Productivity Loss Score indicates the percentage decrement in work 
output due to health problems.  This is important when comparing WLQ results to other 
published scales, which sometimes measure productivity using the metric of time (productivity 
hours lost) or effort (percent effectiveness). The WLQ Productivity Loss Score tells you the 
estimated percent difference in an employee’s at-work productivity compared to employees who 
do not have health-related work limitations (a healthy benchmark group).
To obtain the WLQ Productivity Loss Score, the following 2 steps are performed:
(i) Calculate the WLQ Index


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(ii) Convert the WLQ Index into the WLQ Productivity Loss Score
Calculate the WLQ Index
The WLQ Productivity Loss score is based on a weighted sum of the scores from the 4 WLQ 
scales (Time Management, Physical, Mental-Interpersonal, and Output).  The resulting score 
(known as the WLQ Index) is in the form of the natural log of work productivity.  If a scale score 
is missing (in other words, it could not be computed using the procedures described previously), 
then Step 4 cannot be completed.  
If there are scores for each of the WLQ’s four scales, the following formula is used:
WLQ Index = (1*WLQ Time Scale + 2*WLQ Physical Scale + 3*WLQ Mental-
Interpersonal Scale + 4*WLQ Output Scale), 
where 1 = 0.00048, 2 = 0.00036, 3 = 0.00096, and 4 = 0.00106
Convert the WLQ Index into the WLQ Summary Productivity Loss Score
The final step needed to generate the WLQ Productivity Loss Score is to convert the WLQ Index 
score to a percentage.  The formula is as follows:
WLQ Productivity Loss Score = (1- exp (-WLQ Index))
(‘exp’ stands for exponent.  Therefore, to obtain the Productivity Loss Score, take the exponent 
of the negative WLQ Index score and subtract the result from 1.)
This result is then multiplied by 100 to express the score as a % of at-work productivity loss.  
For example, if the four WLQ scale scores for the Time Management, Physical, Mental-
Interpersonal, and Output scales were 25, 35, 25, and 40, respectively, the WLQ Index score 
would be calculated as: 
(0.00048*25) + (0.00036*35) + (0.00096*25) + (0.00106*40) = 0.091.
Then the Productivity Loss score would be calculated as: 1-exp(-0.091)=0.08698.  This is then 
multiplied by 100 (i.e., 0.08698*100 = 8.698%) to get the % of at-work productivity loss.
The resulting WLQ Productivity Loss score is a relative measure.  It is interpreted as the 
percentage of productivity loss in the past two weeks due to presenteeism relative to a healthy 
benchmark sample. The benchmark sample consists of employees who had WLQ scale scores of 
zero (not limited by health).  It is not necessary to further adjust scores by age, gender, or other 
demographic characteristics.  The maximum attainable for WLQ index (with all scales at 100) is 
28.6% and the maximum attainable productivity loss is 24.9%.


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5.3.14.2.
Analysis Methods
Descriptive statistics of actual values on Baseline, Day 8, Day 22, and Day 42 and changes from 
baseline to Day 8, 22, and 42 will be provided by treatment group for each of the 8 items, the 4 
WLQ scales, and the WLQ Productivity Loss score.
Each of the 8 items will also be summarized at each visit with frequency counts and percentage 
of subjects by treatment group.
5.3.15.
MADRS-6
5.3.15.1.
Definition
MADRS-6 is the depression subscale of the full MADRS, including the following 6 items: 
Apparent Sadness, Reported Sadness, Inner tension, Lassitude, Inability to feel, Pessimistic 
thoughts.  
A total score (0 to 36) is calculated by adding the scores of all 6 items. Higher scores represent a 
more severe condition.  Imputation of the total score will be performed only when 1 item score is 
missing. If 2 or more items are missing, the total score will be left missing.  The total score will 
be imputed by calculating the sum of the scores of the non-missing items and multiplying it by 
the ratio of the maximum possible number of items (i.e., 6) to the number of non-missing items 
(i.e., 5).
The MADRS-6 change from baseline at Week 6 is calculated as (MADRS-6 total score at Week 
6 – Baseline MADRS-6 total score).  Negative changes in MADRS-6 total score indicate 
improvement.
5.3.15.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Day 8, Day 22, and Day 42 and the change 
from baseline to Day 8, 22, and 42 will be presented for MADRS-6 total score by treatment 
group.  
The change from baseline to Day 8, 22, and 42 in MADRS-6 total score will be analyzed using 
the same MMRM as described in Section 5.2.3.1 for the primary efficacy endpoint, with the 
continuous covariate “baseline MADRS total score” changed to “baseline MADRS-6 total 
score”.
As a sensitivity analysis, the change in MADRS-6 total score from baseline to the end of Week 6 
will be analyzed using an ANCOVA model, using LOCF data.  The derivation of the LOCF 
values is described in Section 5.2.3.3.  The ANCOVA model will include factors for treatment, 
region, baseline insomnia status (present/absent), and baseline MADRS-6 total score as a 
continuous covariate.  A 90% CI for the difference in LS Means and p-value will be calculated 
based on the contrast test statistic for each JNJ-42847922 dose level.
6.
SAFETY
All safety analyses will be based on the safety analysis set.


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6.1.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study drug through the day of last dose plus 2 days is considered to be 
treatment-emergent. If the AE occurs on the day of the initial administration of study drug, and 
either the AE time or time of administration are missing, then the AE will be assumed to be 
treatment-emergent. If the AE date is recorded as partial or completely missing, then the AE will 
be considered to be treatment-emergent unless it is known to be prior to the first administration 
of study drug based on partial onset date or resolution date.
All reported treatment-emergent adverse events (TEAEs) will be included in the analysis.  For 
each TEAE, the number and percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized by system organ class, preferred term, and treatment group.
Summary tables will be provided for:

TEAEs

TEAEs occurring in ≥5% of subjects in any treatment group

Treatment-emergent serious AEs (SAEs)

TEAEs leading to discontinuation of study drug

TEAEs by severity

TEAEs by relationship to study drug
For the summaries of TEAEs 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 the same TEAE for the subject.
In addition, a summary table will be generated showing the number and percentage of subjects 
who experience at least 1 occurrence of a given TEAE by system organ class, preferred term, 
lowest level term, and treatment group. 
A summary of all somnolence-related TEAEs (MedDRA preferred terms: somnolence, 
hypersomnia, and sedation; regardless of start time) will be presented. 
Adverse events of special interest are cataplexy, sleep paralysis, and complex, sleep-related 
behaviors (parasomnias). Subjects with TEAEs of special interest will be presented separately, 
by preferred term and treatment group.  The AEs to be included in the summary of TEAEs of 
special interest are marked as such on the AE CRF.
A summary table of non-TEAEs occurring on or after the date of last dose of study drug plus 3
days until the overall reference end date for the study will also be provided.
In addition to the summary tables, listings will be provided for subjects who:

Died

Had SAEs


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
Had AEs leading to discontinuation of study drug

Had somnolence-related TEAEs

Had TEAEs of special interest
6.2.
Clinical Laboratory Tests
Descriptive statistics will be presented for all chemistry (including the lipid panel), hematology
(including hemoglobin A1c [HbA1c]), and urinalysis (pH and specific gravity) laboratory 
parameters at each scheduled time point.  In addition, change from baseline to all postbaseline 
time points will be summarized for chemistry, hematology, and urinalysis (pH and specific 
gravity) parameters and displayed by treatment group. 
The number and percentage of subjects with treatment-emergent postbaseline markedly 
abnormal postbaseline values 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 listed in Attachment 3.  The identification of TEMA laboratory values is 
based on the postbaseline value being out of range while the baseline value is either missing or 
within the range given in Attachment 3. If postbaseline laboratory results are above the upper 
limit and the baseline value is below the lower limit, then the postbaseline abnormality will also 
be considered TEMA. The same applies to the postbaseline value being below the lower limit 
with the baseline value being above the upper limit. 
In addition, the number of subjects with the following shifts in chemistry laboratory values from 
baseline to the maximum postbaseline time point will be presented:

Glucose: 
o
from <100 mg/dL to ≥126 mg/dL (normal to high)
o
from <100 mg/dL to [≥100 mg/dL - <126 mg/dL] (normal to borderline high)
o
from [≥100 mg/dL - <126 mg/dL] to ≥126 mg/dL (borderline high to high)

Triglycerides: 
o
from <150 mg/dL to ≥200 mg/dL (normal to high/very high) 
o
from <150 mg/dL to ≥500 mg/dL (normal to very high)
o
from [≥150 mg/dL - <200 mg/dL] to ≥200 mg/dL (borderline high to high/very 
high)
o
from [≥150 mg/dL - <200 mg/dL] to ≥500 mg/dL (borderline high to very high)
o
from [≥200 mg/dL - <500 mg/dL] to ≥500 mg/dL (high to very high)

Total Cholesterol


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o
from <200 mg/dL to ≥200 mg/dL (normal to borderline high/high)
o
from <200 mg/dL to ≥240 mg/dL (normal to high)
o
from <200 mg/dL to [≥200 mg/dL - <240 mg/dL] (normal to borderline high)
o
from [≥200 mg/dL - <240 mg/dL] to ≥240 mg/dL (borderline high to high)

HDL Cholesterol: from ≥40 mg/dL to <40 mg/dL (normal to low).
The following conversion rules will be used: Glucose 1 mg/dL=0.05551 mmol/L; Triglycerides 1 
mg/dL=0.01129 mmol/L; Total Cholesterol, HDL Cholesterol 1 mg/dL=0.02586 mmol/L.
The incidence of subjects with treatment-emergent ALT values >3*upper normal limit (ULN) or 
AST > 3* ULN will be presented for the double-blind phase. Additionally, incidence of 
treatment-emergent hepatic toxicity (Hy’s Law5) defined as (ALT values >3*ULN or AST > 3* 
ULN) AND total bilirubin values >2*ULN will be presented for the double-blind phase. Similar 
to the markedly abnormal analysis, only subjects with baseline (ALT values ≤3*ULN or AST 
≤3*ULN) (AND baseline total bilirubin values ≤2*ULN for hepatic toxicity) (or if baseline 
value is missing) will be eligible for these analyses.
A listing of subjects with markedly abnormal laboratory values will be provided.
6.2.1.
Homeostatic Assessment (HOMA) Modeling
Insulin resistance and beta-cell function based upon fasting glucose and insulin using the 
homeostatic assessment (HOMA) 3 model will be assessed. Two variables, HOMA IR (insulin 
resistance) and HOMA-%B (beta-cell function) will be derived. The relationship between 
glucose and insulin secretion, mathematically approximated using a simple nonlinear solution, is 
given below:
 	
	 

	 () =

22.5
  	 	 () =
20 " 
[$ −3.5]
where FG = fasting glucose (mmol/L); FI = fasting insulin (mU/L); Insulin: 
1 µIU/mL = 6.945 pmol/L. HOMA IR and HOMA-%B will not be derived if FG is <=3.5.
The descriptive statistics for HOMA-IR and HOMA-%B at baseline and at end point (DB) for 
the safety analysis set will include the following:
  Geometric mean (GM) = exp(mean(logs));
  GM mean ± 1 SD = (exp(mean(logs) - 1 SD(logs)), exp(mean(logs) + 1 SD(logs)));
  where logs indicates the natural logarithm of the HOMA values.


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6.3.
Vital Signs and Physical Examination Findings
Continuous vital sign variables including weight, waist circumference, temperature, supine and 
standing pulse, supine and standing blood pressure (systolic and diastolic), and BMI will be 
summarized at each assessment time point by treatment group.  BMI will be calculated as weight 
(kg)/(height (m))2, at each time point that body weight is measured. The height measurement 
collected at screening will be used in the calculation. Changes from baseline to each postbaseline
time point will be summarized. Descriptive statistics (N, mean, SD, median, minimum and 
maximum) will be presented.   
Incidence of treatment-emergent clinically important abnormalities in vital signs during the 
double-blind phase, as defined in Table 5, will be summarized for subjects who had at least one 
postbaseline assessment for that vital sign.  If the baseline value is missing, the postbaseline 
value will be compared against the abnormally low/abnormally high criteria. Vital sign 
assessments collected during follow-up will not be used for this summary.
Table 5: Clinically Important Abnormalities in Vital Signs
Vital Sign Parameter Postbaseline value outside of normal limit if:
Abnormally low
Abnormally high
Pulse (bpm)
A decrease from baseline of 
15 to a value ≤50
An increase from baseline of 
15 to a value ≥100
Systolic BP (mmHg)
A decrease from baseline of 
20 to a value ≤90
An increase from baseline of 
20 to a value ≥180
Diastolic BP (mmHg)
A decrease from baseline of
15 to a value ≤50
An increase from baseline of
15 to a value ≥105
Body weight (kg)
A decrease from baseline of 7%  An increase from baseline of 
7%  
Body temperature (°C) <35.5°C
>37.5°C
BP = blood pressure
A listing of subjects with treatment-emergent clinically important abnormalities in vital signs 
will be presented.
Orthostatic hypotension is defined as an absolute decrease in systolic (>20 mm Hg) or diastolic 
(>10 mm Hg) blood pressure after standing for at least 1 minute relative to supine position with 
an increase in pulse rate of >15 beats per minute (Table 6). The number and percentage of 
subjects who experience treatment-emergent orthostatic hypotension outside of pre-defined 
limits at any time during the double-blind phase and for whom the orthostatic hypotension was 
not present at baseline will be tabulated. Vital sign assessments collected during follow-up will 
not be used for this summary.


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Table 6: Abnormal Limits for Orthostatic Hypotension Parameters (Changes in
Vital Signs in Standing Relative to Supine Position) 
Vital Sign 
Outside of normal limit if difference
(standing minus supine)
(1)    Pulse (bpm)
>15 bpm
(2a)  Systolic BP (mmHg) 
< -20 mmHg
(2b)  Diastolic BP (mmHg)
< -10 mmHg
BP = blood pressure
Note: 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 values will 
remain missing.  
A listing of subjects with treatment-emergent orthostatic hypotension will be presented.
In addition, a by-subject listing of the physical examination data will be presented.
6.4.
Electrocardiogram
Twelve-lead ECGs will be recorded in a supine position so that the different ECG intervals (RR, 
PR, QRS, QT) can be measured.  ECGs will be assessed at screening, Baseline, and Week 6.  
The ECGs will be read by a central reader.  The ECG variables that will be analyzed are heart 
rate, PR interval, RR interval, QRS interval, QT interval, and QTc using the following correction 
methods: Bazett’s formula (QTcB) and Fridericia’s formula (QTcF).
Bazett’s formula: 
QTcB (msec) = QT (msec) * (HR(bpm)/60)0.5;
Fridericia’s formula:
QTcF (msec) = QT (msec) * (HR(bpm)/60)0.33
Descriptive statistics for observed values and changes from average predose will be presented by 
treatment group for the above ECG variables at each scheduled time point.  Average predose 
ECG is defined as the average of all ECG results collected up to and including the day of the first 
dose of study drug.  
The identification of treatment-emergent abnormal ECG values is based on the post-baseline 
value (a value occurring after the first study drug administration) being out of range while the 
average predose value is either missing or within the limits given in Error! Reference source 
not found.. If post-baseline ECG results are above the upper limits (abnormally high) and the 
average predose value is below the lower limits (abnormally low), then the post-baseline 
abnormality will also be considered treatment-emergent. The same applies to the post-baseline 
value being below the lower limits (abnormally low) with the average predose value being above 
the upper limits (abnormally high).    The number and percentage of subjects with treatment-


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emergent ECG values outside the pre-defined normal limits defined below will be presented for 
the postbaseline value by treatment group.  
Table 7: Abnormal Limits for ECG Parameters 
ECG Parameter
Outside of normal limit if ...
Abnormally low
Abnormally high
Heart Rate (bpm)
50 bpm
100 bpm
PR interval (msec)
120 msec
200 msec
QRS interval (msec)
60 msec
120 msec
QT interval (msec)
200 msec
500 msec
In addition, the number and percentage of subjects within each of the categories defined below 
will be presented for the average predose and the maximum postbaseline value during the DB 
phase by treatment group. The maximum postbaseline value during the double-blind period will 
be computed for each ECG parameter using data from both scheduled and unscheduled visits.
Categories to assess QT prolongation:
QTc Interval:

Normal QTc (≤450 msec for male and ≤470 msec for female)

QTc (>450 to ≤480 msec for male and >470 to ≤480 msec for female)

QTc (>480 to ≤500 msec)

QTc (>500 msec)
Clinically significant QTc: 

No (≤500 msec)

Yes (>500 msec)
Change from baseline:

No concern: QTc ≤30 msec

Concern: QTc >30 – 60 msec

Clear concern: QTc >60 msec
The interpretation of the ECGs as determined by the central reader will be displayed by the 
number of subjects and percentages meeting the normality criteria. The interpretation will be 
summarized over time.
Listings of treatment-emergent abnormal ECG values, QTc intervals >450 msec for male and 
>470 msec for female, and QTc interval changes >30 msec will also be provided.


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6.5.
Other Safety Parameters
6.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
Emergence of suicidal ideation will be assessed using the C-SSRS.  The C-SSRS is a low-burden 
measure of the spectrum of suicidal ideation and behavior. It is a semi-structured clinician-
administered questionnaire designed to solicit the occurrence, severity, and frequency of suicide-
related ideation and behaviors during the assessment period.
Using the C-SSRS, potentially suicide-related events will be categorized using the following 
scores:
Suicidal Ideation (1-5)
1: Wish to be Dead
2: Non-specific Active Suicidal Thoughts
3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan
5: Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior (6-10)
6: Preparatory Acts or Behavior
7: Aborted Attempt
8: Interrupted Attempt
9: Actual Attempt (non-fatal)
10: Completed Suicide
If no events qualify for a score of 1 to 10, a score of 0 will be assigned (0=“no event that can be 
assessed on the basis of C-SSRS”).  Higher scores indicate greater severity.
A frequency distribution at each time point by treatment group will be provided. Shifts from 
baseline to the maximum postbaseline score during the double-blind phase will be summarized 
by treatment group. 
The maximum postbaseline score during the double-blind phase assigned for each subject will be 
summarized into one of three broad categories: No suicidal ideation or behavior (0), Suicidal 
ideation (1-5), Suicidal behavior (6-10).  Shifts from baseline to the maximum category during 
the double-blind phase will be summarized by treatment group. 
In addition, a frequency distribution at each time point for whether the “subject has engaged in 
non-suicidal self-injurious behavior” will be presented by treatment group.
A listing of C-SSRS items throughout the study for subjects with Suicidal Ideation or Behavior 
at any time point will be provided.


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6.5.2.
Physicians Withdrawal Checklist (PWC)
The Physician Withdrawal Checklist (20 items; PWC-20) is a simple and accurate method used 
to assess potential withdrawal symptoms following cessation of treatment and will be measured 
on Week 6, during the telephone contact, and at the follow-up visit. Each of the 20 items is rated 
on a 4-point Likert scale, with 0=not present, 1=mild, 2=moderate, 3=severe.  
For each of the 20 items, a frequency distribution will be provided by treatment group at each 
time point.  
In addition, symptoms at follow-up (telephone contact and the follow-up visit) will be compared 
to the Week 6/early withdrawal visit and will be summarized as follows: new or worsened 
symptoms, symptoms present and unchanged, improved symptoms, and no symptoms.  This 
analysis will be repeated including only subjects whose Week 6/early withdrawal visit is the day 
after their last dose of study drug.    
A total score (0 to 24) will be calculated by adding the scores of the following 8 items: Nausea-
Vomiting, Diarrhea, Poor Coordination, Diaphoresis, Tremor-Tremulousness, Dizziness-
Lightheadedness, Increased Acuity Sound Smell Touch, Paresthesias. If 1 or more items are 
missing, the total score will be left missing.
Higher scores represent a more severe 
condition. The total score will be summarized with descriptive statistics by treatment group.
A listing of subjects with withdrawal symptoms following abrupt cessation of treatment (i.e.,
those subjects with new or worsened symptoms compared to the Week 6/early withdrawal visit)
will be presented.
6.5.3.
Arizona Sexual Experiences Scale (ASEX)
Effect on sexual functioning will be assessed using the ASEX at Baseline and Week 6. The 
ASEX is a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile 
erection, ability to reach orgasm, and satisfaction from orgasm. Each of the 5 items is rated on a 
6-point Likert scale, ranging from 1 to 6.  The 5 items are summed to create a total score, ranging 
from 5 to 30, with the higher scores indicating more sexual dysfunction.  If any item of the scale 
is missing at a visit, the total score for that scale at that visit will be left blank.
For each of the 5 items, a frequency distribution will be provided by treatment group and gender 
at each time point.  In addition, for each of the 5 items, a frequency distribution will be provided 
by treatment group, combining the responses for the genders.  For this analysis, “vaginal 
lubrication/penile erection” will be summarized as 1 question.  The ASEX total score at each 
time point and the change from baseline will be summarized with descriptive statistics by 
treatment group.
The number and percentage of subjects who have ASEX total score 19 or greater, or a score of 5 
or greater on any item, or a score of 4 or greater on any 3 items, reflecting sexual dysfunction,
will be summarized at each time point by treatment group.


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7.
SUMMARY OF PLASMA CONCENTRATIONS FOR JNJ-42847922, M12, AND 
M16
Plasma concentrations for JNJ-42847922 and metabolites (M12 and M16) will be summarized 
by dose, day and time point, using descriptive statistics.
8.
BIOMARKERS
Details of the biomarker analyses are provided in a separate document.


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REFERENCES
1.
Bornkamp B, Pinheiro JC, and Bretz, F. MCPMod: An R Package for the Design and Analysis of Dose-
Finding Studies. Journal of Statistical Software; 2009; 29(7):1-23.
2.
Imai K, Keele L, Tingley D (2010). A general approach to causal mediation analysis. Psychological Methods, 
Vol. 15, No. 4, pp. 309–334.
3.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: 
insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, 
Diabetologia 28:412–419, 1985.
4.
Pinheiro J, Bornkamp B, Glimm E, Bretz, F. Model-based dose finding under model uncertainty using general 
parametric models. Stat Med. 2014;33(10):1646-1661.
5.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER), Center for Biologics Evaluation and Research (CBER). [2009] Guidance for industry 
drug induced liver injury: premarketing clinical evaluation. Available: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf


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ATTACHMENTS
Attachment 1: Conversion of Raw Score to T-Score for PROMIS-SD


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Attachment 2: Conversion of Raw Score to T-Score for PROMIS-Fatigue


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Attachment 3: Criteria for Treatment-emergent Markedly Abnormal Laboratory Values
Markedly Abnormal Limits
Laboratory Parameter (unit)
Low
High
Clinical Chemistry
Albumin (g/dL) but SI unit = g/L
2.424
6.0 60
Alkaline phosphatase (U/L)
N/A
250
Alanine transaminase (SGPT) (U/L)
N/A
200
Aspartate transaminase (SGOT) (U/L)
N/A
250
Bicarbonate (mEq/L) but SI unit=mmol/L
15.115.1
34.934.9
Bilirubin (direct) (mg/dL) but SI unit =mol/L
N/A
3.0 mg/dL51.3 umol/L
Bilirubin (total) (mg/dL) but SI unit =mol/L
N/A
3.0 mg/dL51.3 umol/L
Blood urea nitrogen (mg/dL) but SI unit=mmol/L
N/A
50 mg/dL17.9 mmol/L 
Calcium (mg/dL) but SI unit=mmol/L
61.497 mmol/L
122.994 mmol/L
Chloride (mEq/L or mmol/L)
94
112
Cholesterol (mg/dL) but SI unit=mmol/L
N/A
3007.758 mmol/L
Creatine kinase (U/L)
N/A
990
Creatinine (mg/dL)   SI unit=mol/L
N/A
3265.2 mol/L
Gamma glutamyl transferase (U/L) 
N/A
300 U/L
Glucose Plasma (mg/dL) but SI unit=mmol/L
402.204 mmol/L
30016.653 mmol/L
High-density lipoprotein cholesterol (HDL) (mg/dL) 
but SI unit=mmol/L
350.905
N/A
Lactic acid dehydrogenase (LDH) (U/L)
N/A
500
Low-density lipoprotein cholesterol (LDL) (mg/dL) 
but SI unit=mmol/L
892.3015
1604.1376 mmol/L
Phosphate (mg/dL) but SI unit=mmol/L
2.20.71038 mmol/L
8.12.61549 mmol/L
Potassium (mmol/L)
3.0
5.8
Sodium (mEq/L) but SI unit = mmol/L
125125
155155
Total protein (g/L)
50
N/A
Triglycerides (mg/dL) but SI unit=mmol/L
N/A
5005.645 mmol/L
Uric acid (mg/dL) but SI unit=mol/L
1.589.22
10594.8 mol/L
Hematology
Hematocrit (%) – female
0.28
0.50
  - male
0.24
0.55
Hemoglobin (g/dL) but SI unit=g/L
880
19190
Hemoglobin A1c (%)
4
8
Neutrophils (%)
30
90
Monocytes (%)
N/A
20
Eosinophils (%)
N/A
10
Basophils (%)
N/A
6
Lymphocytes (%)
10
60
Reticulocytes (%)
0.5
1.5
Platelet count (109/L; giga/L)
100
600
Red blood cell (RBC) count (1012/L; tera/L) - female
3.0
5.5
                                                                      - male
3.0
6.4
White blood cell (WBC) count (109/L; giga/L)
2.5
15.0
Urinalysis
Urine pH
N/A
6.5
Urine specific gravity
< 1.001
> 1.035
Note: Values should be flagged as markedly abnormally low if the value is less than the value indicated in 
the “Low” column.  Likewise, values should be flagged as markedly abnormally high if the value is greater 
than the value indicated in the “High” column. 
Note:  The same limits apply to both males and females unless gender is indicated.
N/A = Not applicable.