Conditions: Depressive Disorder, Major
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 107
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of flexibly dosed JNJ-42847922 (20 milligram \[mg\] or 40 mg) compared to flexibly dosed quetiapine extended-release (XR) (150 mg or 300 mg) as adjunctive therapy to an antidepressant drug in delaying time to all-cause discontinuation of study drug over a 6-months (24 weeks) treatment period, 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).

Detailed description:

Arms:
arm 1: Participants will receive 20 mg of JNJ-42847922 as a starting dose and matching placebo (1 capsule of 20 mg JNJ-42847922 and 1 capsule of matching placebo) once daily for 14 days. After Day 14, if needed, JNJ-42847922 dose can be increased to 40 mg (2\*20 mg capsules) and flexible dose of JNJ-42847922 (20 or 40 mg) will be taken once daily until Day 167. Dose of JNJ-42847922 (20 or 40 mg) will be adjusted by investigator based on the participant's clinical response and tolerability. Participants will continue to take their baseline selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases. arm 2: Participants will receive 1 capsule of quetiapine XR 50 mg along with 1 capsule of matching placebo once daily for 2 days, followed by 1 capsule of quetiapine XR 150 mg along with 1 capsule of matching placebo once daily from Day 3 to Day 14. After Day 14, if needed, quetiapine XR dose can be increased to 300 mg (2\*150 mg capsules) and flexible dose of quetiapine (150 or 300 mg) will be taken once daily until Day 167. Dose of quetiapine XR (150 or 300 mg) will be adjusted by investigator based on the participant's clinical response and tolerability. Participants will continue to take their baseline SSRI/SNRI antidepressant as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases.

Interventions: intervention 1: JNJ-42847922 intervention 2: Placebo Matching to JNJ-42847922 intervention 3: Quetiapine XR intervention 4: Placebo Matching to Quetiapine XR intervention 5: Selective Serotonin Reuptake Inhibitor (SSRI) intervention 6: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
Intervention descriptions: intervention 1: Participants will receive JNJ-42847922 capsule orally. intervention 2: Participants will receive placebo capsule matching to JNJ-42847922 orally. intervention 3: Participants will receive quetiapine XR capsule orally. intervention 4: Participants will receive placebo capsule matching to quetiapine XR orally. intervention 5: Participants will receive SSRI antidepressant (such as, citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, vilazodone or vortioxetine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26). intervention 6: Participants will receive SNRI antidepressant (such as duloxetine, milnacipran, levomilnacipran, venlafaxine, desvenlafaxine) as a part of background therapy (at the same dose, without change, every day and at approximately the same time as prior to entering the study) throughout the screening, double-blind, and follow-up phases (approximately up to Week 26).

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 26 April 2018
Janssen Research & Development *
Clinical Protocol
A 6-Month, Multicenter, Double-Blind, Randomized, Flexible-Dose, Parallel-Group Study 
to Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 versus Quetiapine 
Extended-Release as Adjunctive Therapy to Antidepressants in Adult Subjects With Major 
Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy 
Protocol 42847922MDD2002; Phase 2
AMENDMENT 2
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).
Status:
Approved  
Date:
26 April 2018
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-137631442, 4.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03321526


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
2
Status: Approved, Date: 26 April 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 11
TIME AND EVENTS SCHEDULE .............................................................................................................. 19
ABBREVIATIONS ...................................................................................................................................... 23
1.
INTRODUCTION................................................................................................................................ 25
1.1.
Background .................................................................................................................................... 27
1.1.1.
Nonclinical Studies ..................................................................................................................... 27
1.1.2.
Clinical Studies ........................................................................................................................... 29
1.2.
Comparator Drug ........................................................................................................................... 35
1.3.
Overall Rationale for the Study...................................................................................................... 35
1.4.
Overall Risk and Benefit Assessment............................................................................................ 37
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 38
2.1.
Objectives and Endpoints .............................................................................................................. 38
2.2.
Hypothesis ..................................................................................................................................... 42
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 42
3.1.
Overview of Study Design.............................................................................................................. 42
3.2.
Study Design Rationale.................................................................................................................. 44
4.
SUBJECT POPULATION.................................................................................................................. 51
4.1.
Inclusion Criteria ............................................................................................................................ 51
4.2.
Exclusion Criteria ........................................................................................................................... 53
4.3.
Prohibitions and Restrictions ......................................................................................................... 57
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 58
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 59
7.
TREATMENT COMPLIANCE............................................................................................................ 60
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 61
9.
STUDY EVALUATIONS .................................................................................................................... 62
9.1.
Study Procedures........................................................................................................................... 62
9.1.1.
Overview..................................................................................................................................... 62
9.1.2.
Screening Phase ........................................................................................................................ 63
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 64
9.1.4.
End-of-Study Visit/Follow-Up Visit.............................................................................................. 65
9.2.
Efficacy Evaluations....................................................................................................................... 65
9.2.1.
Montgomery-Åsberg Depression Rating Scale (MADRS).......................................................... 65
9.2.2.
Clinical Global Impression-Severity (CGI-S) .............................................................................. 65
9.2.3.
Patient Global Impression-Severity (PGI-S)............................................................................... 66
9.2.4.
Structured Interview Guide Version (SIGH-A) Hamilton Anxiety Rating Scale (HAM-A) ........... 66
9.2.5.
Patient Reported Outcomes Measurement Information System-Sleep Disturbance 
(PROMIS-SD) and Sleep-Related Impairment (PROMIS-SRI) Short Forms............................. 66


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
9.2.6.
Quality of Life in Depression Scale (QLDS) ............................................................................... 67
9.2.7.
Symptoms of Major Depressive Disorder Scale (SMDDS) ........................................................ 67
9.2.8.
Subjective Sleep Parameters (Consensus Sleep Diary-Morning Administration [CSD-
M])............................................................................................................................................... 67
9.2.9.
Symbol Digit Modalities Test (SDMT)......................................................................................... 67
9.2.10.
Trail Making Test Part B (TMT-Part B)....................................................................................... 68
9.2.11.
Hopkins Verbal Learning Test-Revised (HVLT-R) ..................................................................... 68
9.3.
Pharmacokinetics........................................................................................................................... 68
9.3.1.
Analytical Procedures................................................................................................................. 69
9.3.2.
Pharmacokinetic Parameters ..................................................................................................... 69
9.4.
Biomarkers ..................................................................................................................................... 69
9.5.
Pharmacogenomic (DNA) Evaluations .......................................................................................... 70
9.6.
Medical Resource Utilization and Health Economics .................................................................... 70
9.7.
Safety Evaluations ......................................................................................................................... 70
9.8.
Sample Collection and Handling.................................................................................................... 74
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 75
10.1.
Completion ..................................................................................................................................... 75
10.2.
Withdrawal From the Study............................................................................................................ 75
10.3.
Withdrawal From the Use of Research Samples........................................................................... 76
11.
STATISTICAL METHODS................................................................................................................. 77
11.1.
Subject Information ........................................................................................................................ 77
11.2.
Sample Size Determination ........................................................................................................... 77
11.3.
Efficacy Analyses ........................................................................................................................... 77
11.4.
Biomarker Analyses ....................................................................................................................... 78
11.5.
Pharmacokinetic Analyses............................................................................................................. 78
11.6.
Pharmacogenomic Analyses ......................................................................................................... 78
11.7.
Medical Resource Utilization and Health Economics Analyses..................................................... 78
11.8.
Safety Analyses ............................................................................................................................. 78
12.
ADVERSE EVENT REPORTING ...................................................................................................... 80
12.1.
Definitions ...................................................................................................................................... 80
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 80
12.1.2.
Attribution Definitions.................................................................................................................. 81
12.1.3.
Severity Criteria .......................................................................................................................... 82
12.2.
Special Reporting Situations.......................................................................................................... 82
12.3.
Procedures..................................................................................................................................... 82
12.3.1.
All Adverse Events...................................................................................................................... 82
12.3.2.
Serious Adverse Events ............................................................................................................. 84
12.3.3.
Pregnancy................................................................................................................................... 84
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 85
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 85
13.1.
Procedures..................................................................................................................................... 85
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 85
14.
STUDY DRUG INFORMATION......................................................................................................... 86
14.1.
Physical Description of Study Drug(s) ........................................................................................... 86
14.2.
Packaging ...................................................................................................................................... 86
14.3.
Labeling.......................................................................................................................................... 86
14.4.
Preparation, Handling, and Storage............................................................................................... 86
14.5.
Drug Accountability ........................................................................................................................ 86
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 87
16.
ETHICAL ASPECTS ......................................................................................................................... 87


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
16.1.
Study-Specific Design Considerations........................................................................................... 87
16.2.
Regulatory Ethics Compliance....................................................................................................... 89
16.2.1.
Investigator Responsibilities ....................................................................................................... 89
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 90
16.2.3.
Informed Consent ....................................................................................................................... 91
16.2.4.
Privacy of Personal Data ............................................................................................................ 92
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 93
16.2.6.
Country Selection ....................................................................................................................... 93
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 93
17.1.
Protocol Amendments.................................................................................................................... 93
17.2.
Regulatory Documentation ............................................................................................................ 94
17.2.1.
Regulatory Approval/Notification ................................................................................................ 94
17.2.2.
Required Prestudy Documentation............................................................................................. 94
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 95
17.4.
Source Documentation................................................................................................................... 95
17.5.
Case Report Form Completion ...................................................................................................... 96
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 97
17.7.
Record Retention ........................................................................................................................... 97
17.8.
Monitoring ...................................................................................................................................... 98
17.9.
Study Completion/Termination....................................................................................................... 98
17.9.1.
Study Completion/End-of-Study ................................................................................................. 98
17.9.2.
Study Termination....................................................................................................................... 98
17.10.
On-Site Audits ................................................................................................................................ 99
17.11.
Use of Information and Publication................................................................................................ 99
REFERENCES.......................................................................................................................................... 101
INVESTIGATOR AGREEMENT ............................................................................................................... 108
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) ........................................................................................................... 105
Attachment 2:
Anticipated Events.................................................................................................... 106
Attachment 3:
Standard Blood Volumes Collected.......................................................................... 107
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
List of Completed Studies......................................................................................................... 30
Table 2:
Dose Description....................................................................................................................... 59
Table 3:
Description of Interventions ...................................................................................................... 60
FIGURES
Figure 1: Study Design Schematic.............................................................................................................. 42


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
5
Status: Approved, Date: 26 April 2018
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
6 April 2017
Amendment 1
10 November 2017
Amendment 2
26 April 2018
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (26 April 2018)
The overall reason for the amendment: To add results of the male and female rat fertility studies. To exclude 
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 Considerations; 
References (68-72)
Added results from the male and female rat fertility studies and relevant literature 
references.
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, WOCBP will be excluded from this study until more is learned about the effect of 
JNJ-42847922 on female reproduction.
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 the 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)”.
Subject 4.1. Inclusion 
Criteria
Deleted Inclusion Criteria #11 and #12. (these criteria are no longer required now 
that the female population is restricted to WONCBP. Relevant information on 
WONCBP from Inclusion Criterion #11 was moved to Inclusion criterion #1)
Subject 4.2. Exclusion 
Criteria
Revised Exclusion Criterion #28 as follows:

Is pregnant, or breastfeeding, or planning to become pregnant while enrolled in 
this study or within 1 month after the last dose of study drug.
Section 1.4. Overall Risk 
and Benefit Assessment; 
Section 3.2. Study Design 
Rationale; 
Section 16.1. Study-Specific 
Design Considerations
Added text to clarify that WOCBP will be excluded from the study and to explain the 
rationale for excluding these subjects based on the nonclinical fertility findings.
Deleted text related to inclusion of WOCBP. 
Deleted following sentences: “It is expected that this population will be 
representative for the targeted subject population for future clinical trials.” 
and: “The study population in this protocol is intentionally broad”


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
6
Status: Approved, Date: 26 April 2018
Applicable Section(s)
Description of Change(s)
Synopsis (Safety 
Evaluations); 
Time and Events Schedule; 
Section 9.1.1. Overview; 
Section 9.1.2. Screening; 
Section 9.7. Safety 
Evaluations
The specific serum and urine pregnancy tests were removed from the Time and 
Events schedule, and the wording was updated to clarify that pregnancy tests can be 
performed if determined necessary by the investigator. 
Footnotes in the Time and Events Schedule were updated as follows:

Footnote h: Women of childbearing potential only. “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. A FSH test may also be performed at investigator judgment to assist in 
determining if a woman is of non-childbearing potential.”
(also added FSH to the abbreviations)

Footnote ‘i’ was deleted (and the subsequent footnote numbering updated 
accordingly)

Footnote ‘p’ was updated to indicate that menstrual tracking will be performed in
“premenopausal women”.
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

Inclusion Criterion #1: Changed the maximum age of the study population from 
64 years to “70 years”, inclusive.
Corresponding edits were also made in other relevant sections.
Rationale:  To make the evening dosing window less restrictive and to add further instructions on dosing. 
Synopsis (Description of 
interventions); 
Time and Events Schedule 
(footnote g); 
Table 3
Changed the dosing time from “at least” 3 hours after the last meal to 
“approximately” 3 hours after the last meal.
Added that the study drug should be taken with “approximately” 100 mL of water
Section 6. Dosage and 
Administration. 
Added the following text: “Subjects will administer the assigned study drug once 
daily at bedtime, approximately 3 hours after the last meal, from Day 1 to Day 167. 
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 42847922MDD2002 Amendment 2
7
Status: Approved, Date: 26 April 2018
Applicable Section(s)
Description of Change(s)
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. 

Inclusion Criterion #14: 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 #8: 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. 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: “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.”
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
Revised the final table column to make it clear that the End-of-Study/Follow-up visit 
will be conducted 7 to 14 days after the last dose. 

Changed the Visit window for the End-of-Study/Follow-up visit from “±7 days” 
to “7 to 14 days after the last dose”

Changed the Study Week for the End-of-Study/Follow-up visit from “26” to 
“25-26”
Time and Events Schedule 
Changed window for Visit 6 from “±5 days” to “±4 days”. 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
8
Status: Approved, Date: 26 April 2018
Applicable Section(s)
Description of Change(s)
Time and Events Schedule 
(footnote 1); Section 9.1.1. 
Overview 
The wording pertaining to the order of study assessments was revised to indicate that 
the proposed order (ECGs, vital signs, blood draws, PRO assessments and then other 
procedures) is a recommendation, not a requirement. 
Section 9.7. Safety 
Evaluations (Vital signs)
Deleted the text stating that vital signs should be measured in non-fasting conditions 
whenever possible.
Rationale: To clarify that the 6-month treatment period is equivalent to a 24-week treatment period (ie, 1 month = 
4 weeks). 
Synopsis; 
Section 1. Introduction; 
Section 2.1. Objectives and 
Endpoints; 
Section 3.1. Overview of 
Study Design
Where the study is described as a “6-month” study, the qualifier “(24-week)” was
added.
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 9.7. 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 42847922MDD2002 Amendment 2
9
Status: Approved, Date: 26 April 2018
Amendment 1 (10 November 2017)
The overall reason for the amendment: Safety results from 2 nonclinical toxicology studies were added as well 
as scheduling of an ongoing rat fertility study that is applicable to long-term treatment with JNJ-42847922.
Applicable 
Section(s)
Description of Change(s)
Rationale: Update nonclinical toxicology data and related study conduct.
Section 1.1.1 
(Toxicology), 3.2, 
16.1, References
(65, 66)
Added toxicology results from a 6-month rat and a 9-month dog study.
Section 1.1.1 
(Toxicology), 16.1
Addition of a statement that preliminary results from a rat fertility study will be available 
before long-term exposure (>3 months) in human studies.
Section 9.7 
(Adverse Events)
Added: “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.”
Rationale: A reduction of the planned number of subjects in this study to be appropriate for an exploratory study 
Synopsis, Section 
3.1, Figure 1, 
Section 11.2, 11.3, 
References (67)
Reduced the planned number of subjects from a total of 120 to 100 in this study, that 
allows sufficient power (approximately 92%) at a 1-sided 0.10 significance level for an 
exploratory study.
Rationale: Current criterion was too restrictive for effective subject recruitment
Section 4.1 
Inclusion Criteria 
#4
Changed the maximum duration current antidepressant treatment from “…for no greater 
than 6 months, at screening” to “…for no greater than 12 months, at screening” 
Rationale: Adjustment/clarification of inclusion and exclusion criteria
Section 4.1 
Inclusion Criteria 
#12
“A woman using oral contraceptives must use an additional birth control method (see list 
of highly effective methods of contraception above). Subjects should use a barrier method 
(eg, male condom or diaphragm or cervical cap with or without spermicide).”
Section 4.2 
Exclusion Criteria 
#19
“Has received any prior treatment with electroconvulsive therapy, vagal nerve stimulation, 
or a deep brain stimulation device. Has received ketamine or esketamine for the treatment 
of depression.”
Rationale: Clarification of evaluations 
Synopsis, Section 
2.1, Section 9.6
Removal of analysis parameters for adverse events (removal of falls as it is not an event 
observed previously and therefore, not of special interest) and for HRUQ (removed 
parameters not collected on eCRF), and removed the statement that analysis of HRUQ will 
be performed separately from the study report.
Time and Event 
Schedule 
(induction phase)
Added CSD-M evaluation at Week 18 for consistency with planned assessments.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
10
Status: Approved, Date: 26 April 2018
Applicable 
Section(s)
Description of Change(s)
Section 4
“Exceptional and limited retesting of abnormal screening values (particularly, if the initial 
laboratory testing was not done under fasting conditions) that would otherwise lead to 
exclusion may be allowed after discussion and approval by the sponsor during the 
screening phase (to reassess eligibility). This should only be considered if there is no 
anticipated impact on subject safety.”
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
11
Status: Approved, Date: 26 April 2018
SYNOPSIS
A 6-Month, Multicenter, Double-Blind, Randomized, Flexible-Dose, Parallel-Group Study to 
Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 versus Quetiapine Extended-
Release 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 major depressive 
disorder (MDD) and insomnia.
While preclinical evidence supports a role for the orexin system in modulating the HPA axis and stress-
responsiveness, clinical data in support of a role for orexin in depression are fairly limited. In depressed 
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, with a trend toward elevated 
orexin levels in CSF across the entire diurnal period. The most striking elevation has been noted at the 
physiologic nighttime nadir. 
 
 
 
 
s. The 
exploratory efficacy results from a multiple-dose study (42847922MDD1001) of 20 mg of JNJ-42847922 
in 48 subjects with MDD showed an early onset (as early as Day 11 of exposure) and a clinically relevant 
antidepressant effect that was sustained at least 14 days after treatment discontinuation. The effect of 
JNJ-42847922 was largely related to a change in the core symptoms of depression and overall unrelated 
to its impact on sleep-related items.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Endpoints
Primary

To assess, in subjects with MDD who have had 
an inadequate response to current antidepressant 
therapy with an SSRI or SNRI, the efficacy of 
flexibly dosed JNJ-42847922 (20 mg or 40 mg) 
compared to flexibly dosed quetiapine XR (150 
mg or 300 mg) as adjunctive therapy to an 
antidepressant drug in delaying time to all-cause 
discontinuation of study drug over a 6-month
(24-week) treatment period. 

Time to all-cause discontinuation of 
study drug. 
Secondary

To 
assess 
the 
efficacy 
of 
JNJ-42847922 
compared to quetiapine XR in the adjunctive 
treatment of MDD based on:

Achieving and sustaining remission of 
depressive symptoms

The 
proportion 
of 
subjects 
achieving 
(at 
Week 
12) 
and 
sustaining remission at Weeks 18 
CCI
CCI


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
12
Status: Approved, Date: 26 April 2018
Objectives
Endpoints
and 24. Remission is defined as 
MADRS total score ≤12.

Achieving and sustaining response of 
depressive symptoms

The 
proportion 
of 
subjects 
achieving 
(at 
Week 
12) 
and 
sustaining response at Weeks 18 
and 24. Response is defined as 
≥50% improvement from baseline 
MADRS total score.

Improving depressive symptoms in subjects 
with significant insomnia versus those 
without significant insomnia

Change from baseline to Weeks 12, 
18, and 24 in the MADRS total 
score in subjects with significant 
insomnia 
(baseline 
Insomnia 
Severity Index [ISI] score ≥15) 
versus those without significant 
insomnia (baseline ISI score <15).

Improving anxiety symptoms

Change from baseline to Weeks 12, 
18, and 24 in the 14-item Hamilton 
Anxiety Rating Scale (HAM-A) 
total score.  

To assess the effect of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD 
on metabolic parameters during long-term (6 
months) treatment, including:

Weight

The proportion of subjects with weight 
gain ≥7% of baseline body weight at 
end- of-study assessment.

Lipids
Triglycerides

The proportion of subjects with shifts in 
triglycerides 
from 
normal 
to 
high 
(<150 mg/dL at baseline to ≥200 mg/dL 
at any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline to high 
(≥150 and <200 mg/dL at baseline to 
≥200 
mg/dL 
at 
any 
post-baseline 
assessment).

The proportion of subjects with shifts in 
triglycerides from normal to very high 
(<150 mg/dL at baseline to ≥500 mg/dL 
at any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline to very high 
(≥150 mg/dL and <200 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
13
Status: Approved, Date: 26 April 2018
Objectives
Endpoints

The proportion of subjects with shifts in 
triglycerides from high to very high 
(≥200 mg/dL and <500 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).

Blood Glucose 
Fasting glucose

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
borderline (<100 mg/dL at baseline to 
≥100 and <126 mg/dL at any post-
baseline assessment).

The proportion of subjects with shifts in 
fasting blood glucose from borderline to 
high (≥100 to <126 mg/dL at baseline to 
≥126 mg/dL at any post-baseline 
assessment).

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
high (<100 mg/dL at baseline to ≥126 
mg/dL at any post-baseline assessment).

To 
assess 
the 
efficacy 
of 
JNJ-42847922 
compared to quetiapine XR as adjunctive therapy 
for MDD in the improvement of global 
depressive symptom severity. 

Change from baseline to Weeks 12 and 
24 in the Clinical Global Impression—
Severity (CGI-S) score.

To characterize subject perceptions of global 
MDD severity.

Change from baseline to Weeks 12 and 
24 
in 
the 
Patient 
Global 
Impression-Severity (PGI-S) score.

To assess the effect of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD 
on the subject’s assessment of quality of life.

Change from baseline to Weeks 12 and 
24 in Quality of Life in Depression Scale 
(QLDS).

To assess the effect of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD 
on the subject's assessment of sleep impairment 
and daytime problems due to lack of sleep.

Change from baseline to Weeks 12 and 
24 
in 
Patient 
Reported 
Outcomes 
Measurement Information System-Sleep 
Disturbance (PROMIS-SD Short Form 
8a).

Change from baseline to Weeks 12 and 
24 
in 
Patient 
Reported 
Outcomes 
Measurement 
Information 
System-
Sleep-Related Impairment (PROMIS-SRI 
Short Form 8a). 

To assess the effect of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD 
on the subject’s assessment of reduction of 
depressive symptoms.

Change from baseline to Weeks 12 and 
24 in Symptoms of Major Depressive 
Disorder Scale (SMDDS)

To assess the effect of JNJ-42847922 compared 

Change from baseline to Weeks 6, 12, 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
14
Status: Approved, Date: 26 April 2018
Objectives
Endpoints
to quetiapine XR as adjunctive therapy for MDD 
on cognitive function.
and 24 in Symbol Digit Modalities Test 
(SDMT).  

Change from baseline to Weeks 6, 12, 
and 24 in Trail Making Test - Part B 
(TMT-Part B).

Change from baseline to Weeks 6, 12, 
and 24 in Hopkins Verbal Learning Test-
Revised (HVLT-R).

To assess the effect of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD 
on hormonal stress-response via HPA axis 
function.

Change from baseline to Weeks 6 and 24 
in salivary cortisol levels as measured at 
home upon awakening and at home 
during the evening.

To assess the safety and tolerability of 
JNJ-42847922 compared with quetiapine XR as 
adjunctive treatment in subjects with MDD.

Safety assessments including:

Adverse events (AEs). 

Proportion of all SAEs and events 
of 
special 
interest 
(eg, 
parasomnias).

Vital signs, physical examinations, 
ECG, and laboratory parameters.

Sexual 
functioning 
using 
the 
Arizona Sexual Experiences Scale 
(ASEX).

Extrapyramidal symptoms assessed 
by the Extrapyramidal Symptom 
Rating 
Scale-Abbreviated 
(ESRS-A).

Suicidality 
assessed 
using 
the 
C-SSRS.

Potential 
withdrawal 
effects 
assessed 
by 
the 
Physician 
Withdrawal Checklist (PWC).
Exploratory

To collect medical resource utilization (MRU) 
data that may be used in future economic 
modeling.

Healthcare Resource Use Questionnaire 
(HRUQ).

To assess the effect of JNJ-42847922 compared 
with quetiapine XR as adjunctive therapy for 
MDD on self-reported measures of sleep.

Change from baseline in subjective sleep 
parameters as measured by the 
Consensus Sleep Diary-Morning 
Administration (CSD-M) after the first 6 
weeks of treatment (using the average of 
3 morning measurements in Week 6).

Change from baseline in subjective sleep 
parameters as measured by the CSD-M 
after 3 to 6 months of treatment (using 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
15
Status: Approved, Date: 26 April 2018
Objectives
Endpoints
the average of 3 morning measurements 
in Weeks 12, 18, and 24, respectively).

To identify diagnostic biomarkers and to 
investigate changes in MDD-related biomarkers 
 
 in relation 
to clinical response on depression symptoms 
upon adjunctive treatment with JNJ-42847922 
compared to quetiapine XR.

Correlation between baseline biomarkers 
and clinical outcome at Week 6.

Correlation between change in baseline 
biomarker at Weeks 6 and 24 and 
clinical outcome.
Hypothesis
The primary hypothesis of this study is that, in adult subjects with MDD who have had an inadequate 
response to treatment with an SSRI/SNRI, adjunctive treatment with JNJ-42847922 will delay the time to 
all-cause discontinuation of study drug when compared to adjunctive treatment with quetiapine XR.
OVERVIEW OF STUDY DESIGN
This is a multicenter, randomized, double-blind, active-controlled, parallel-group, flexible-dose, 6-month 
(24-week) study in adult subjects with MDD who have an inadequate response to current antidepressant 
therapy with an SSRI/SNRI. 
The study will consist of 3 phases: an up to 4-week screening phase, a 6-month double-blind treatment 
phase, and a 2-week follow-up phase culminating in a follow-up/end-of-study visit. Approximately 100 
subjects will be randomized in a 1:1 ratio to receive either flexibly dosed JNJ-42847922 (20 or 40 mg) or 
flexibly dosed quetiapine XR (150 or 300 mg) as adjunctive therapy to their current SSRI or SNRI.
Subjects will continue to take their baseline SSRI/SNRI antidepressant (at the same dose, without change, 
every day and at approximately the same time as prior to entering the study) throughout the screening, 
double-blind, and follow-up phases.
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]). Each potential subject must have 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.
DOSAGE AND ADMINISTRATION
All subjects randomized to JNJ-42847922 will receive 20 mg as a starting dose. Subjects randomized to 
quetiapine XR will receive 50 mg once daily for 2 days, followed by an increase to 150 mg once daily on 
Day 3, as per prescribing guidelines in the product label. After the initial dosing period, dose adjustments 
may be made starting with the first scheduled clinic visit (Day 14). The first dose adjustment must be 
upwards. Subsequent adjustments may be made upwards or downwards within the study dose ranges 
(20 or 40 mg for subjects randomized to JNJ-42847922 or 150 or 300 mg for subjects randomized to 
CCI


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
16
Status: Approved, Date: 26 April 2018
quetiapine XR) if necessary, depending upon the investigator’s assessment of the subject’s clinical 
response and tolerability.
Description of Interventions
Treatment name
JNJ-42847922
Quetiapine XR
Dose per delivery 
(ie, total daily dose)
20 mg or 40 mg
50 mg for the first 2 days and then 
150 mg or 300 mg 
Study drugs will be over-encapsulated tablets to be taken orally, once daily at bedtime, approximately 
3 hours after the last meal, with approximately 100 mL of plain water and swallowed whole. Tablets 
must not be chewed, divided, dissolved or crushed.
EFFICACY EVALUATIONS
The primary endpoint of this study is time to all-cause discontinuation of study drug. The investigator will 
be required to complete a detailed summary of the discontinuation, such as reasons and times, utilizing 
the CRF page. If it is caused by an AE, the clinical course of the AE and the outcome (recovered, 
resolving, or ongoing) of the AE should be documented.
The efficacy of the study drugs (JNJ-42847922 and quetiapine XR) will be evaluated using the MADRS 
(SIGMA version), SIGH-A (HAM-A), CGI-S, SDMT, TMT-Part B, HVLT-R, PGI-S, PROMIS-SD 
(Short Form 8a), PROMIS-SRI (Short Form 8a), SMDDS, QLDS, and CSD-M.
PHARMACOKINETIC EVALUATIONS
Blood samples will be collected for measurement of plasma concentrations of JNJ-42847922 and the 
metabolites M12 and M16 in the morning of Days 42, 84 and 168, within 12 hours after the previous 
dose. 
BIOMARKER 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).
Saliva samples for the measurement of cortisol concentrations will be collected by using an oral swab 
method just before bedtime (before dosing) and upon awakening as indicated in the Time and Events 
Schedule.
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 pharmacokinetics (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.
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS
Medical resource utilization will be assessed using the HRUQ.
SAFETY EVALUATIONS
Safety evaluations will include collection of AEs and concomitant medications, as well as assessment 
with physical examination, body weight, waist circumference, vital signs, 12-lead ECG, urine drug test 


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
17
Status: Approved, Date: 26 April 2018
(screening only), alcohol breath test, pregnancy testing (serum or urine pregnancy test, performed at 
investigator judgment), and clinical laboratory tests (hematology, chemistry panel, lipid panel, 
hemoglobin A1c [HbA1c], thyroid-stimulating hormone [TSH], 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). 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 primary purpose of the study is to investigate potential differentiating features between 
JNJ-42847922 and quetiapine XR. Although the sample size was not chosen based on a specific set of 
endpoints, for evaluating the time to discontinuation of study drug in the JNJ-42847922 group versus the 
quetiapine XR group, a one-sided log-rank test with an overall sample size of 100 subjects (50 in the JNJ-
42847922 group and 50 in the quetiapine XR group) provides approximately 92% power at a 1-sided 0.10 
significance level to detect a hazard ratio of 0.415, assuming the proportion of subjects who discontinue 
from study drug in the quetiapine XR group is 50%. The planned sample size of the study is consistent 
with the nature of Phase 2 exploratory study.
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.
The primary efficacy endpoint, time to all-cause discontinuation of study drug, will be estimated by the 
Kaplan-Meier method and summarized (number of discontinuations, number of censored subjects, 
median, 25th and 75th percentile, if estimable) by treatment group. Time to all-cause discontinuation of 
study drug is defined as the number of days from the first dose of study drug to the last dose of study 
drug. Subjects who complete treatment are not considered to have discontinued. A stratified log-rank test 
(stratified for baseline insomnia status) will be used to test the hypothesis that there is no difference 
between the JNJ-42847922 group and quetiapine XR in the probability of discontinuing study drug, using 
a 1-sided 0.10 significance level.
Biomarker Analysis
Cortisol levels will be tabulated for each time point and summary statistics will be calculated. Post-
treatment 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. Post-treatment changes in exploratory biomarkers will be summarized by treatment group. 
Associations between baseline biomarker levels and clinical endpoints may be explored. Additional 
exploratory analyses may also be performed. Results of all exploratory analysis will be presented in a 
separate report.
Pharmacokinetic Analysis
Concentration-time data will be summarized using descriptive statistics by dose, visit date and time 
(relative to dose) for JNJ-42847922, and metabolites M12 and M16 (as applicable).


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
18
Status: Approved, Date: 26 April 2018
Pharmacogenomic Analysis
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.
Safety Analysis
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.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All 
reported AEs with onset during the double-blind treatment phase and AEs 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.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
19
Status: Approved, Date: 26 April 2018
TIME AND EVENTS SCHEDULE 
Phase
Screening 
Phase
Double-Blind Treatment Phasea
End-of-Study/Follow-upb
Visit Number 
1
2
3
4
5
6
7
8
9
10
Study Day
-28
1
7
14
28
42
84
126
168
182
Study Week
-4
1
1
2
4
6
12
18
24
25-26
Visit Window (days)
±3
±3
±3
±4
±7
±7
±7
7 to 14 days after the last dose
Clinic (C), Phone (P)
C
C
Pc
C
C
C
C
C
C
C
Study Proceduresk
Screening/Administrative Procedures
Informed consentd
X
Informed consent for optional genetic 
research samples
X
Medical/psychiatric history
X
Demographic information
X
Prestudy therapy
X
X
Preplanned surgery/procedure(s)
X
Height
X
Alcohol (breath) test
X
X
Urine drug test
X
Urine or blood sample for 
antidepressant compliancee
X
X
Inclusion/exclusion criteriaf
X
X
SCID-CT
X
MGH-ATRQ
X
ISI
X
X
Study Drug Administration
Randomization
X
Dispense study medication 
X
X
X
X
X
X
Study drug accountability
X
X
X
X
X
X
Study drug administrationg
continuous
Safety Assessments
Physical examination 
X
X
Xs
Serum/Urine pregnancy testError! 
Reference source not found.
Clinical laboratory tests: hematology, 
serum chemistry, and urinalysisi
X
Xr
X
X
X
Xs
HbA1c
X
X
X
Xs


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
20
Status: Approved, Date: 26 April 2018
Phase
Screening 
Phase
Double-Blind Treatment Phasea
End-of-Study/Follow-upb
Visit Number 
1
2
3
4
5
6
7
8
9
10
Study Day
-28
1
7
14
28
42
84
126
168
182
Study Week
-4
1
1
2
4
6
12
18
24
25-26
Visit Window (days)
±3
±3
±3
±4
±7
±7
±7
7 to 14 days after the last dose
Clinic (C), Phone (P)
C
C
Pc
C
C
C
C
C
C
C
Safety Assessments (continued)
Lipid panel
X
Xr
X
X
X
Xs
Vital signs
X
X
X
X
X
X
X
X
X
TSH and FT4
j
X
X
X
Weight
X
X
X
X
X
Xs
Waist circumference 
X
X
X
X
X
ECG
X
X
X
X
Xs
ASEX
X
X
X
Xs
ESRS-A
X
X
X
X
X
Xs
C-SSRS 
X
X
X
X
X
X
X
X
X
PWC
X
AE 
Continuous
Concomitant medications 
Continuous
PK, Biomarkers and PGx
Salivary cortisol (pm and am)l
X
X
X
X
X
Biomarkersk,m
Xk
Xk
X
Xk
PGxk,n
Xk
Xk
PKk,o
Xk
X
Xk
Menstrual cycle trackingp
X
X
X
X
X
X
X
Efficacy Assessments
MADRS (SIGMA)
X
X
X
X
X
X
X
X
X
CGI-S
X
X
X
X
X
X
X
X
PGI-S
X
X
X
X
X
X
X
X
HAM-A (SIGH-A)
X
X
X
X
X
X
SDMT
X
X
X
X
TMT-Part B
X
X
X
X
HVLT-R
X
X
X
X
QLDS
X
X
X
X
X
X
X
Xs
SMDDS
X
X
X
X
X
X
X
Xs
PROMIS-SD (short form 8a)
X
X
X
X
X
X
Xs
PROMIS-SRI (short form 8a)
X
X
X
X
X
X
Xs
CSD-Mq
X
X
X
X
X


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
21
Status: Approved, Date: 26 April 2018
Phase
Screening 
Phase
Double-Blind Treatment Phasea
End-of-Study/Follow-upb
Visit Number 
1
2
3
4
5
6
7
8
9
10
Study Day
-28
1
7
14
28
42
84
126
168
182
Study Week
-4
1
1
2
4
6
12
18
24
25-26
Visit Window (days)
±3
±3
±3
±4
±7
±7
±7
7 to 14 days after the last dose
Clinic (C), Phone (P)
C
C
Pc
C
C
C
C
C
C
C
Medical Resource Utilization
HRUQ
X
X
X
X
X
X
Abbreviations:
AE=adverse event, ASEX=Arizona Sexual Experiences Scale, CGI-S=Clinical Global Impression – Severity, CSD-M=Consensus Sleep Diary-Morning Administration Version, 
C-SSRS =Columbia Suicide Severity Rating Scale, ECG=electrocardiogram, ESRS-A= Extrapyramidal Symptom Rating Scale-Abbreviated, FSH=follicle stimulating hormone,
FT4= free thyroxine, HAM-A=Hamilton Anxiety Rating Scale, HbA1c=hemoglobin A1c, HRUQ=Healthcare Resource Use Questionnaire, HVLT-R=Hopkins Verbal Learning Test-
Revised, ISI = Insomnia Severity Index, MADRS = Montgomery-Åsberg Depression Rating Scale, MGH-ATRQ=Massachusetts General Hospital-Antidepressant Treatment Response 
Questionnaire, PK=pharmacokinetic, PGx=pharmacogenomic, PGI-S= Patient Global Impression-Severity, PROMIS-SD =Patient Reported Outcomes Measurement Information 
System-Sleep Disturbance, PROMIS-SRI=Patient Reported Outcomes Measurement Information System-Sleep-Related Impairment, PWC=Physician Withdrawal Checklist, QLDS 
=Quality of Life in Depression Scale, SCID-CT = Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version, SDMT = Symbol Digit Modalities Test, 
SMDDS= Symptoms of Major Depressive Disorder Scale, SIGH-A=structured interview guide for the Hamilton Anxiety Scale, SIGMA=structured interview guide for the 
Montgomery-Asberg Depression Rating Scale, TMT- Part B =Trail Making Test Part B, TSH= thyroid-stimulating hormone. 
a.
Unscheduled visits may be made at the discretion of the investigator. Adverse events, concomitant medications, and C-SSRS should be collected at all visits. Dose adjustment of 
study medication can only be made during an in-person study visit. If the dose is changed, then at a minimum the CGI-S, PGI-S, and SMDDS should be collected along with the 
ESRS-A.
b.
End-of-study/follow-up assessments will be conducted within 7 to 14 days after the last dose in the double-blind treatment phase. If a subject discontinues study treatment before 
the end of the double-blind phase, end-of-study/follow-up assessments should be obtained as soon as possible.
c.
A telephone interview will be conducted at the end of Week 1 to collect any adverse events and assess any other issues with tolerability to the study medication.
d.
Must be signed before first study-related activity.
e.
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.
f.
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation.
g.
Subjects will administer the assigned study drug once daily at bedtime, approximately 3 hours after the last meal, from Day 1 to Day 167. 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.
h.
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. A FSH test may also be performed at investigator judgment to assist in determining if a woman is of non-childbearing potential.
i.
Blood sample should be collected in fasting condition (at least 8 hours fasting). The serum chemistry also includes fasting glucose and insulin.
j.
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.
k.
Where multiple procedures are scheduled for the same visit, procedures are recommended to be performed in the following order: ECGs, vital signs, blood draws, PRO 
assessments and then other procedures.
l.
Salivary cortisol samples (morning and evening) will be collected by subjects at home. Evening salivary cortisol samples (ie, on Days -1, 13, 41, 83, and 167) will be collected 
pre-dose, at bedtime. The morning sample will be collected upon awakening (ie, on Days 1, 14, 42, 84, and 168). 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.


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m.
Biomarker samples should be collected under fasting conditions. Subjects should not participate in strenuous exercise or consume alcohol for 24 hours prior to collection.
n.
The pharmacogenomic (DNA) sample should be collected at the specified time point. Pharmacogenomic blood samples will be collected only from subjects who have consented 
to provide optional DNA samples for research.
o.
PK samples will be collected at the study site in the morning within 12 hours of the last dose the previous night. As this is a blinded study, blood samples for PK will be collected 
from quetiapine XR-dosed subjects, but not analyzed for PK. These samples will be stored and may be analyzed if needed (eg, suspicion of an incorrect dose).
p.
Start date (first day) of last menstrual period and average length of menstrual cycle (days) will be collected from premenopausal women.
q.
The CSD-M should be completed by the subjects at home after their normal morning routine and preferably within an hour of waking for the day. The CSD-M will be completed 
for 3 mornings before the targeted study day for Visits 2, 6, 7, and 9.
r.
The screening laboratory sample does not need to be repeated at baseline as long as the time between the screening sample and Day 1 of the study is 14 days or less and there 
were no clinically meaningful abnormalities with the screening labs.
s.
Only needs to be completed if the subject withdraws early from the study (ie, did not complete Visit 9).


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ABBREVIATIONS
ADR
adverse drug reaction
ADT
antidepressant therapy
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
ARC
Anticipated Event Review Committee
ASEX
Arizona Sexual Experiences Scale
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BMI
body mass index 
CGI-S
Clinical Global Impression-Severity 
Cmax
maximum drug concentration
CNS
central nervous system
CRF
case report form
CSD-M
Consensus Sleep Diary-Morning Administration
CSF
cerebrospinal fluid 
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
D2
dopamine type 2
DCS
direct current stimulation
DNA
deoxyribonucleic acid
DORA
dual orexin receptor antagonist
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-5th Edition
ECG
electrocardiogram
eDC
electronic data capture
EPS
extrapyramidal symptoms
ESRS-A
Extrapyramidal Symptom Rating Scale-Abbreviated
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
HRUQ
Healthcare Resource Use Questionnaire
HVLT-R
Hopkins Verbal Learning Test-Revised
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-Åsberg Depression Rating Scale
MAOI
monoamine oxidase inhibitor
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MGH-ATRQ
Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire
MRU
medical resource utilization
NMS
neuroleptic malignant syndrome
NOAEL
no observed adverse effect level


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NREM
non-rapid eye movement
OX1R
orexin-1 receptor
OX2R
orexin-2 receptor
PD
pharmacodynamic(s)
PGI-S
Patient Global Impression-Severity
PI
Package Insert
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
PROMIS-SD
Patient Reported Outcomes Measurement Information System-Sleep Disturbance
PROMIS-SRI
Patient Reported Outcomes Measurement Information System-Sleep Related Impairment
PSG
polysomnography
PWC
Physician Withdrawal Checklist
QIDS-SR14
Quick Inventory of Depressive Symptomatology-Self Report, 14 item scale
QLDS
Quality of Life in Depression Scale
RBC
red blood cell
REM
Rapid Eye Movement
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCID-CT
Structured Clinical Interview for DSM-5 Axis I Disorders– Clinical Trials Version
SDLP
standard deviation of lateral position
SDMT
Symbol Digit Modalities Test
SIGH-A
structured interview guide for the Hamilton Anxiety Scale
SIGMA
structured interview guide for the Montgomery-Asberg Depression Rating Scale
SMDDS
Symptoms of Major Depressive Disorder Scale
SmPC
Summary of Product Characteristics
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
SSS
Stanford Sleepiness Scale
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
tmax
time to maximum drug concentration
TMS
transcranial magnetic stimulation
TMT-Part B
Trail Making Test-Part B
TSH
thyroid-stimulating hormone
TST
total sleep time
ULN
Upper Limit of Normal
US
United States
WASO
wake after sleep onset
WBC
white blood cell
WOCBP
women of childbearing potential
WONCBP
women of non-childbearing potential
XR
extended-release


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1.
INTRODUCTION
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 
major depressive disorder (MDD) and insomnia.
The orexinergic circuits innervate most of the structures implicated in the pathophysiology of 
mood disorders, as well
as in emotional behavior, stress responses, and reward 
processing.4,25,29,34,38,44,63 In its role in mediating arousal, orexinergic transmission is driven 
partly by the amygdala, a limbic structure that organizes other behavioral, endocrine, autonomic 
and emotional responses to stressors, threats, rewards, and novelty.44 In patients with mood 
disorders, the amygdala manifests abnormally elevated activity under stress in response to 
emotionally negative or aversive stimuli, and during sleep.34
While preclinical evidence supports a role for the orexin system in modulating the HPA axis and 
stress-responsiveness, clinical data in support of a role for orexin in depression are fairly limited. 
In depressed 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, with a trend toward elevated orexin levels in CSF across the entire 
diurnal period. The most striking elevation has been noted at the physiologic nighttime nadir. A 
pathologically elevated limbic drive from the amygdala in depressed patients may explain this 
finding, and it is possible that normalizing cortisol during that particularly exaggerated cortisol 
elevation (ie, during sleep) may significantly reduce depressive symptoms.
The orexins stimulate two distinct G-protein coupled receptors, orexin-1 (OX1R) and OX2R that 
are co-located or selectively located in specific brain areas suggesting differentiated roles. The 
best-characterized orexinergic system involves the OX2R located on histaminergic neurons in 
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the tuberomammillary nuclei of the hypothalamus, where these receptors play a critical role in 
wake promotion12,30,62 The most extensive clinical data available on an orexin antagonist is for 
suvorexant, a DORA which was approved in the United States (US) and Japan in 2014 for the 
treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. 
Warnings and precautions for suvorexant include the risk of next day impairment, including 
impaired driving skills and the potential to fall asleep while driving, and symptoms similar to 
mild cataplexy have been reported with the use of suvorexant. A contributing factor to these risks 
for suvorexant is its long half-life (about 12 hours). In contrast, such risks appear to be mitigated 
by the short half-life (2-3 hours) of JNJ-42847922. 
 
 
 
 
 
 
 
The exploratory efficacy results from a multiple-dose study (42847922MDD1001) of
20 mg of JNJ-42847922 in 48 subjects with MDD showed an early onset (as early as Day 11 of 
exposure) and a clinically relevant antidepressant effect that was sustained at least 14 days after 
treatment discontinuation. The effect of JNJ-42847922 was largely related to a change in the 
core symptoms of depression and overall unrelated to its impact on sleep-related items. 
A Phase 2b study (42847922MDD2001) is currently ongoing to investigate the antidepressant 
effects of JNJ-42847922 (up to 3 doses [10, 20, and 40 mg] versus placebo), as adjunctive 
treatment to standard of care and to further assess the safety and tolerability of JNJ-42847922
over a treatment duration of 6 weeks. The study utilizes the change in the Montgomery-Åsberg 
Depression Rating Scale (MADRS) total score from baseline to the end of Week 6 as the primary 
endpoint.  
The present study is being conducted to compare the efficacy of JNJ-42847922 (20 or 40 mg) 
versus quetiapine XR (150 or 300 mg) as adjunctive treatment to standard of care over a 
treatment duration of 6 months (24 weeks). The primary endpoint will be time to all-cause 
treatment discontinuation. Efficacy, safety, and tolerability will also be assessed to evaluate the 
maintenance of antidepressant effect over time (including response and remission rates), to 
provide long-term (6-month) safety information for JNJ-42847922, and to compare the efficacy 
and tolerability of JNJ-42847922 versus quetiapine XR over 6 months of treatment. The doses of 
JNJ-42847922 being evaluated in the present study (20 and 40 mg) were selected on the basis of 
efficacy, safety and tolerability data from Phase 1 clinical studies. Quetiapine XR was chosen as 
the active comparator as it is one of only 3 drugs approved for the adjunctive treatment of 
patients with MDD in the US and is a commonly-used medication in this treatment setting. The 
doses of quetiapine XR selected for this study (150 and 300 mg) are consistent with the 
recommended dose range indicated in the US prescribing information.
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For the most comprehensive nonclinical and clinical information regarding JNJ-42847922, refer 
to the latest version of the Investigator's Brochure for JNJ-42847922.21
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
Safety Pharmacology
JNJ-42847922 was evaluated in a variety of in vitro and in vivo models for effects on the 
cardiovascular system. These included the in vitro ion channel assay in human Ether-à-go-go 
Related Gene (hERG)-transfected HEK293 cells, the isolated rabbit Purkinje fibers assay, an in 
vivo study in anesthetized guinea pigs and dogs, and a Good Laboratory Practice (GLP) study in 
conscious dogs. JNJ-42847922 did not show any potential for adverse cardiovascular effects. In 
a rat study to investigate neurobehavioral effects, treatment related changes at ≥250 mg/kg were 
likely related to exaggerated pharmacology. Findings at 250 mg/kg included slight narrowing of 
the palpebral fissure in all animals with one also displaying a tendency to decreased body 
temperature, and a minor retardation of visual placing.
Pharmacokinetics and Product Metabolism in Animals
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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), single dose.
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), single 
dose.
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), multi-
ascending dose up to10 
days
Healthy subjects
40/39/30
42847922EDI1004
Bioavailability, food effect, 
safety and tolerability.
Oral suspension vs 
tablet/20 mg (morning, 
fasted), single dose.
Healthy male 
subjects
18/17/18
42847922EDI1005
Effect of itraconazole on 
PK, safety and tolerability 
of JNJ-42847922.
Suspension/5 mg 
(morning, fasted), single 
dose
Healthy male 
subjects
16/16/16
42847922EDI1006
Effect of rabeprazole on 
PK, safety and tolerability 
of JNJ-42847922.
Tablet/ 20 mg (morning, 
fasted), single dose
Healthy male 
subjects
16/16/16
42847922EDI1009
Effect of rifampin on PK, 
safety and tolerability of 
JNJ-42847922.
Tablet/40 mg (morning, 
fasted), single dose
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), up to 9 days.
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), single dose.
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), single 
ascending dose.
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), 
up to 28 days.
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), 
for 5 days.
Subjects with 
insomnia disorder 
without psychiatric 
comorbidity
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Pharmacokinetics (PK)
In the study of subjects with insomnia disorder without psychiatric comorbidity 
(42847922ISM2002), both peak and total (AUC0-12h) exposures observed were much higher than 
exposures seen in previous studies with the 40-mg dose; the metabolite exposures were 
proportionately higher. The higher exposures seen in this study might be due to increased 
absorption as a result of dosing at bedtime, after dinner. Despite the higher exposure, there were 
no new safety findings, deaths or serious adverse events (SAEs) observed. None of the subjects 
discontinued the study due to an adverse event (AE).
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Pharmacodynamics (PD)
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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
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1.2.
Comparator Drug
Quetiapine Fumarate Extended-release Tablets 
Quetiapine extended-release (XR) will be included in this study as an active comparator to 
investigate potential differentiating features between JNJ-42847922 and quetiapine XR in the 
augmentation of selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake 
inhibitor (SNRI) treatment of MDD.
Quetiapine is a combined dopamine type 2 (D2) and serotonin type 2A (5HT2A) antagonist that 
belongs to the atypical antipsychotic class. Well-known class effects include neuroleptic 
malignant syndrome (NMS), somnolence/sedation, metabolic changes (eg, hyperglycemia, 
dyslipidemia, and weight gain), extrapyramidal symptoms (EPS) including tardive dyskinesia, 
orthostatic hypotension, and hematologic effects (eg, neutropenia and agranulocytosis), QT 
prolongation, seizures, and hyperprolactinemia.55 Additionally, cataract development has been 
observed in dogs after quetiapine exposure during chronic toxicity studies.51
Although the immediate-release formulation was initially approved for use in schizophrenia, 
quetiapine XR has been shown to be effective for bipolar disorder and as adjunctive treatment 
with antidepressants for MDD.3 It is approved in the US and EU for the adjunctive treatment of
MDD based on well-controlled studies.
For further information regarding quetiapine XR (including list of adverse reactions, dosage and 
administration, warnings and precautions, etc) refer to the local prescribing information.51
1.3.
Overall Rationale for the Study
Major depressive disorder is a common, serious, recurrent disorder, with worldwide lifetime 
prevalence estimates ranging from 8% to 12% in most countries. 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.27 As of October 
2015, 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.61
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Inadequate response to first-line pharmacologic treatment for MDD is common and represents an 
important unmet medical need. 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 
SSRI.46 For inadequate response to an optimized trial of first-line antidepressant therapy (ADT), 
current guidelines recommend switching the ADT, adding a second ADT or adding adjunctive 
therapy with a non-ADT.10,40,52 All currently approved drugs indicated for adjunctive therapy in 
patients with MDD (including quetiapine, aripiprazole, and brexipiprazole) belong to the atypical 
antipsychotic family, and have tolerability issues that, in some cases, may lead to non-adherence. 
Aside from serious risks such as NMS and tardive dyskinesia, these agents are well-known to be 
more commonly associated with risks such as hyperglycemia/diabetes mellitus, dyslipidemia, 
weight gain, and next day drowsiness. 
It 
is well-established that symptoms of insomnia commonly occur with major depression episodes.1
In fact, chronic insomnia may be present for years prior to the onset of the first depressive 
episode and increases the risk of non-depressed persons to develop depression by twofold 
compared to persons without insomnia. Therefore, insomnia is not only a symptom of 
depression, but also a predictor of depression.24 Ongoing sleep problems may contribute to the 
persistence of a depressive episode or may be a residual symptom of a current depressive 
episode, despite other symptoms of depression having responded to treatment. Significant sleep 
symptoms are known to increase relapse risk in patients with MDD.39
 
 
 At present, about two-
thirds of depressed patients take sleep medications in addition to their antidepressant regimen. 
The drugs prescribed for this purpose include benzodiazepines, atypical antipsychotics (eg, 
quetiapine), trazodone, antihistamines, non-benzodiazepines sleep agents such as zolpidem, as 
well as non-prescription sleep aids. Some of the most common side effects of these medications 
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include cognitive impairment, risk of dependence and abuse, risk of respiratory depression, next 
day sedation, and weight gain.
1.4.
Overall Risk and Benefit Assessment
As further described in Section 1 and the rationale for this study (Section 1.3), MDD is a 
common, serious, recurrent mental disorder. MDD is the leading cause of disability, and its 
prevalence is rising.61
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 AEs, such as weight gain and sexual 
side effects. Currently approved adjunctive treatments are limited to the atypical antipsychotic 
drug class, which present considerable tolerability concerns (eg, metabolic syndrome, akathisia, 
and 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 currently available data (see Section 1.1.2, Clinical Studies, and the JNJ-42847922 
Investigator’s Brochure21) 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 
first-line 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 
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 Brochure21 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 as follows: WOCBP will be 
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excluded from the study, since a female rat fertility study suggested that JNJ-42847922 reduced
female rat fertility rates at all doses studied; 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, Prohibitions and Restrictions); paying special attention to clinically significant AEs 
that are known to have been reported in drugs of the same pharmacological class (Section 9.7,
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 9.7, 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 9.7, Safety Evaluations) at the 
doses selected for further investigation.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess, in subjects with MDD who have had an 
inadequate response to current antidepressant 
therapy with an SSRI or SNRI, the efficacy of 
flexibly dosed JNJ-42847922 (20 mg or 40 mg) 
compared to flexibly dosed quetiapine XR (150 mg 
or 300
mg) as adjunctive therapy to an 
antidepressant drug in delaying time to all-cause 
discontinuation of study drug over a 6-month 
(24-week) treatment period. 

Time to all-cause discontinuation of study 
drug. 
Secondary

To assess the efficacy of JNJ-42847922 compared 
to quetiapine XR in the adjunctive treatment of 
MDD based on:

Achieving 
and 
sustaining 
remission 
of 
depressive symptoms

The proportion of subjects achieving 
(at 
Week 
12) 
and 
sustaining 
remission at Weeks 18 and 24. 
Remission is defined as MADRS 
total score ≤12.

Achieving 
and 
sustaining 
response 
of 
depressive symptoms

The proportion of subjects achieving 
(at 
Week 
12) 
and 
sustaining 
response at Weeks 18 and 24. 
Response 
is 
defined 
as 
≥50% 
improvement from baseline MADRS 
total score.

Improving depressive symptoms in subjects 
with significant insomnia versus those without 
significant insomnia

Change from baseline to Weeks 12, 
18, and 24 in the MADRS total score 
in subjects with significant insomnia 


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Objectives
Endpoints
(baseline Insomnia Severity Index 
[ISI] score ≥15) versus those without 
significant insomnia (baseline ISI 
score <15).

Improving anxiety symptoms

Change from baseline to Weeks 12, 
18, and 24 in the 14-item Hamilton 
Anxiety Rating Scale (HAM-A) total 
score.  

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
metabolic parameters during long-term (6 months) 
treatment, including:

Weight

The proportion of subjects with weight 
gain ≥7% of baseline body weight at end-
of-study assessment.

Lipids
Triglycerides

The proportion of subjects with shifts in 
triglycerides 
from 
normal 
to 
high 
(<150 mg/dL at baseline to ≥200 mg/dL at 
any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline to high 
(≥150 and <200 mg/dL at baseline to 
≥200 
mg/dL 
at 
any 
post-baseline 
assessment).

The proportion of subjects with shifts in 
triglycerides from normal to very high 
(<150 mg/dL at baseline to ≥500 mg/dL at 
any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline to very high 
(≥150 mg/dL and <200 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).

The proportion of subjects with shifts in 
triglycerides from high to very high 
(≥200 mg/dL and <500 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).

Blood Glucose 
Fasting glucose

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
borderline (<100 mg/dL at baseline to 
≥100 and <126 mg/dL at any post-
baseline assessment).


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Objectives
Endpoints

The proportion of subjects with shifts in 
fasting blood glucose from borderline to 
high (≥100 to <126 mg/dL at baseline to 
≥126 mg/dL at any post-baseline 
assessment).

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
high (<100 mg/dL at baseline to ≥126 
mg/dL at any post-baseline assessment).

To assess the efficacy of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD in 
the improvement of global depressive symptom 
severity.

Change from baseline to Weeks 12 and 
24 in the Clinical Global Impression—
Severity (CGI-S) score.

To characterize subject perceptions of global MDD 
severity.

Change from baseline to Weeks 12 and 
24 
in 
the 
Patient 
Global 
Impression-Severity (PGI-S) score.

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject’s assessment of quality of life.

Change from baseline to Weeks 12 and 
24 in Quality of Life in Depression Scale 
(QLDS).

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject's assessment of sleep impairment and 
daytime problems due to lack of sleep.

Change from baseline to Weeks 12 and 24 
in 
Patient 
Reported 
Outcomes
Measurement Information System-Sleep 
Disturbance (PROMIS-SD Short Form
8a).

Change from baseline to Weeks 12 and 24 
in 
Patient 
Reported 
Outcomes
Measurement 
Information 
System-
Sleep-Related Impairment (PROMIS-SRI 
Short Form 8a).

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject’s assessment of reduction of depressive 
symptoms.

Change from baseline to Weeks 12 and 24 
in 
Symptoms 
of 
Major 
Depressive 
Disorder Scale (SMDDS)

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
cognitive function.

Change from baseline to Weeks 6, 12, and 
24 in Symbol Digit Modalities Test 
(SDMT).  

Change from baseline to Weeks 6, 12, and 
24 in Trail Making Test - Part B (TMT-
Part B).

Change from baseline to Weeks 6, 12, and 
24 in Hopkins Verbal Learning Test-
Revised (HVLT-R).

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
hormonal stress-response via HPA axis function.

Change from baseline to Weeks 6 and 24 
in salivary cortisol levels as measured at 
home upon awakening and at home 


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Objectives
Endpoints
during the evening.

To 
assess 
the 
safety 
and 
tolerability 
of 
JNJ-42847922 compared with quetiapine XR as 
adjunctive treatment in subjects with MDD.

Safety assessments including:

Adverse events (AEs).

Proportion of all SAEs and events of 
special interest (eg, parasomnias).

Vital signs, physical examinations, 
ECG, and laboratory parameters.

Sexual 
functioning 
using 
the 
Arizona Sexual Experiences Scale 
(ASEX).

Extrapyramidal symptoms assessed 
by the Extrapyramidal Symptom 
Rating 
Scale-Abbreviated 
(ESRS-A).

Suicidality 
assessed 
using 
the 
C-SSRS.

Potential withdrawal effects assessed 
by 
the 
Physician 
Withdrawal 
Checklist (PWC).
Exploratory

To collect medical resource utilization (MRU) data 
that may be used in future economic modeling.

Healthcare Resource Use Questionnaire 
(HRUQ).

To assess the effect of JNJ-42847922 compared 
with quetiapine XR as adjunctive therapy for MDD
on self-reported measures of sleep.

Change from baseline in subjective sleep 
parameters as measured by the Consensus 
Sleep Diary-Morning Administration 
(CSD-M) after the first 6 weeks of 
treatment (using the average of 3 morning 
measurements in Week 6).

Change from baseline in subjective sleep 
parameters as measured by the CSD-M 
after 3 to 6 months of treatment (using the 
average of 3 morning measurements in 
Weeks 12, 18, and 24, respectively).

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 compared 
to quetiapine XR.

Correlation between baseline biomarkers 
and clinical outcome at Week 6.

Correlation between change in baseline 
biomarker at Weeks 6 and 24 and clinical 
outcome.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.


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2.2.
Hypothesis
The primary hypothesis of this study is that, in adult subjects with MDD who have had an 
inadequate response to treatment with an SSRI/SNRI, adjunctive treatment with JNJ-42847922 
will delay the time to all-cause discontinuation of study drug when compared to adjunctive 
treatment with quetiapine XR.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, randomized, double-blind, active-controlled, parallel-group, flexible-dose, 
6-month (24-week) study in adult subjects with MDD who have an inadequate response to 
current antidepressant therapy with an SSRI/SNRI.
The study will consist of 3 phases: an up to 4-week screening phase, a 6-month double-blind 
treatment phase, and a 2-week follow-up phase culminating in a follow-up/end-of-study visit. 
Approximately 100 subjects will be randomized in a 1:1 ratio to receive either flexibly dosed 
JNJ-42847922 (20 or 40 mg) or flexibly dosed quetiapine XR (150 or 300 mg) as adjunctive 
therapy to their current SSRI or SNRI. A diagram of the study design is presented in Figure 1
below.
Figure 1: Study Design Schematic


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Subjects will continue to take their baseline SSRI/SNRI antidepressant (at the same dose, 
without change, every day and at approximately the same time as prior to entering the study) 
throughout the screening, double-blind, and follow-up phases.
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. To be eligible for the study, subjects must meet the following criteria:

Diagnostic and Statistical Manual of Mental Disorders-5th Edition (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).

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. It is expected that there will be a minimum of 5 days between screening 
and baseline MADRS.

Inadequate response to at least 1 but no more than 3 antidepressants, administered at an 
adequate dose and duration (at least 4 weeks) 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
At the start of the study, subjects will be randomized to receive either JNJ-42847922 or 
quetiapine XR once daily taken orally while continuing their current antidepressant on which 
they have had an inadequate response at the time of screening. The assigned study drug will be 
self-administered at bedtime by the subject at home.
Study procedures during the double-blind treatment phase to assess efficacy, safety, tolerability, 
compliance, and other evaluations (eg, PK and biomarker) will occur as per the Time and Events 
Schedule. Subjects will be seen at the study site at baseline, and at Weeks 2, 4, 6, 12, 18, and 24 
of the double-blind phase. A telephone interview will be conducted at the end of Week 1 to 
collect AEs and assess any other issues with tolerability to the study medication.
See Section 9.1.3, Double-blind Treatment Phase for additional details.
End-of-Study/Follow-Up Visit
All subjects will return to the study site for a follow-up visit within 7 to 14 days after completion 
of the double-blind phase. At the follow-up visit, safety assessments/procedures will be 
completed per the Time and Events Schedule. 
If a subject prematurely withdraws from the study, the End-of-Study Visit assessments should be 
performed as soon as possible. 


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The duration of participation in the study for an individual subject (including screening and 
follow-up visit) will be up to 30 weeks.
See Section 9.1.4 End-of-Study Visit/Follow-Up for additional details.
Study Evaluations
The primary endpoint of this study is time to all-cause discontinuation of study drug. The 
investigator will be required to complete a detailed summary of the discontinuation, such as 
reasons and times, utilizing the CRF page. If it is caused by an AE, the clinical course of the AE 
and the outcome (recovered, resolving, or ongoing) of the AE should be documented.
The efficacy of the study drugs (JNJ-42847922 and quetiapine XR) will be evaluated using the 
MADRS (SIGMA version), SIGH-A (HAM-A), CGI-S, SDMT, TMT-Part B, HVLT-R, PGI-S, 
PROMIS-SD (Short Form 8a), PROMIS-SRI (Short Form 8a), SMDDS, QLDS, and CSD-M. 
These evaluations will be performed at the timepoints specified in the Time and Events 
Schedule.
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, 
ESRS-A, C-SSRS, and PWC. Medical resource utilization will be assessed using the HRUQ.
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 
by subjects at home, on the days 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 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.
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.6,7,23,24,58 While the 
orexin system promotes wakefulness, increasingly it is also associated with hyperarousal5 and 
motivational behaviors.48 Hyperarousal characterizes a major subgroup of patients with MDD.15
OX2R antagonists may have utility to normalize hyperarousal in patients with MDD and thereby 
have an antidepressant effect independent from their utility as hypnotics. 
 
 
Therefore, OX2R 
antagonists, such as JNJ-42847922 may have clinical efficacy in the treatment of MDD, 
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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),14 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).
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. Women have a two-fold increased risk of 
depression over men, and separation and divorce are additional risk factors across the sexes.27
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, 
WOCBP will not be included in this study until more is learned about the effect of 
JNJ-42847922 on female reproduction.
Blinding, Control, Treatment Groups
Quetiapine XR will be included as an active comparator to investigate potential differentiating 
features between JNJ-42847922 and quetiapine XR. While 3 drugs (quetiapine, aripiprazole, and 
brexpiprazole) have been approved in the US for the adjunctive treatment of MDD, 
quetiapine XR is the only drug approved for the same indication in the EU. The data collected 
from this study will be used to guide phase 3 studies and these studies will be international 
studies. Quetiapine XR is also most likely to maintain the blind with JNJ-42847922 in that both 
drugs cause sleep and sedation, while aripiprazole and brexpiprazole do not. Unlike 
JNJ-42847922, the other 2 drugs cause significant akathisia which would also potentially unblind 
them from JNJ-42847922. 
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.
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 ISI score <15 (subclinical or no clinically significant insomnia) and ≥15 
(moderate to severe insomnia). This distribution will approximately mimic the prevalence of 
significant insomnia in representative samples of subjects with MDD reported in the literature, 


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where mean ISI scores are reported to be approximately 14 (Kenter 201626: mean ISI score 
=13.8; SEM 6.3) or 15 (Mason 201431: mean ISI score=14.70; SEM=0.92).
Dose and Dose Administration Interval
The JNJ-42847922 doses selected for the study are: 20 and 40 mg. The doses chosen are within 
the range shown to be well tolerated in the Phase 1 studies. 
 
 
 
 
 
Subjects randomized to JNJ-42847922 will begin dosing at the 20 mg dose. After the initial 
dosing period, dose adjustments may be made starting with the first scheduled clinic visit 
(Day 14). The first dose adjustment must be upwards. Subsequent adjustments may be made 
upwards or downwards within the study dose range (20 or 40 mg) if necessary, depending upon 
the investigator’s assessment of the subject’s clinical response and tolerability.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
While there were no reports of severe somnolence reported in subjects exposed to 
JNJ-42847922, 
 
 
 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.
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The doses of quetiapine XR selected for this study (150 and 300 mg) are consistent with the 
recommended dose range indicated in the US prescribing information for adjunctive treatment of 
MDD. 
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 
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.
Medical Resource Utilization and Health Economics
In subjects who have shown an inadequate response to their current antidepressant therapy, 
adjunctive treatment with JNJ-42847922 versus quetiapine XR may result in lower utilization of 
services (ie, outpatient visits, emergency room visits or hospitalization) as assessed using the 
HRUQ. The HRUQ includes information regarding utilization of healthcare services, including 
the timing of services, enabling changes in level and quantity of services to be considered as a 
variable in economic models. Refer to Section 9.6 for additional details. 
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Efficacy Measures
Primary Efficacy Measure
The primary endpoint for this study will be time to all-cause discontinuation of study drug.
All currently approved drugs indicated for adjunctive therapy in patients with MDD (including 
quetiapine, aripiprazole, and brexipiprazole) belong to the atypical antipsychotic family that are 
associated with SAEs such as NMS and tardive dyskinesia, and more commonly associated with 
risks such as EPS, akathisia, weight gain, hyperglycemia/diabetes mellitus, and dyslipidemia. 
These serious tolerability issues may lead to medication non-adherence or treatment 
discontinuation. JNJ-42847922 was well tolerated and not associated with any of these AEs
based on clinical studies completed to date. JNJ-42847922 as an adjunctive therapy for MDD 
may have comparable efficacy and a lower over-all discontinuation rate when compared to 
quetiapine XR. Though antidepressant response may occur over 4 to 6 weeks (the length of a 
typical short-term trial for MDD), patients usually are treated for at least 6-12 months to prevent 
a recurrence of the MDD episode after successful treatment. Hence, long-term persistence on 
treatment (a combination of efficacy and tolerability) is important for the long-term treatment of 
patients with MDD.
Secondary Efficacy Measures
MADRS: The 10-item clinician-administered MADRS was designed to be used in subjects with 
MDD to measure the overall severity of depressive symptoms.33 The MADRS scale has been 
selected as a secondary 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.60
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.9,16,17,45
SIGH-A (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.18,19 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. 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.59
PROMIS-SD (short form 8a) and PROMIS-SRI (short form 8a): The PROMIS-SD (Sleep 
Disturbance) instruments assess self-reported perceptions of sleep quality, sleep depth, and 
restoration associated with sleep. This includes perceived difficulties and concerns with getting 


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to sleep or staying asleep, as well as perceptions of the adequacy of and satisfaction with sleep. 
The Sleep Disturbance short form is universal rather than disease-specific. It assesses sleep 
disturbance over the past seven days.
The PROMIS-SRI (Sleep-Related Impairment) scale consists of 8 items. The adult Sleep-Related 
Impairment item bank focuses on self-reported perceptions of alertness, sleepiness, and tiredness 
during usual waking hours, and the perceived functional impairments during wakefulness 
associated with sleep problems or impaired alertness. The Sleep-Related Impairment short form 
is universal rather than disease-specific. It assesses sleep-related impairment over the past seven 
days.
QLDS: The QLDS is a disease specific patient reported outcome (PRO) designed to assess 
health related quality of life in patients with MDD.
SMDDS: The SMDDS is a 16-item instrument which assesses patient-reported symptoms 
associated with MDD.41,42,43 ,47,56 It is a newly developed PRO developed according to the latest 
standards for PRO development. Initial measurement properties of the SMDDS have been 
assessed in a quantitative pilot study.11 Data from this non-interventional study indicate that the 
SMDDS has good measurement properties including internal (Crohbach’s Alpha 0.929) and test 
retest reliability (ICC 0.848 and Pearson’s r 0.850), and convergent construct and known groups 
validity. Sensitivity to change and interpretation of an important clinical change have yet to be 
evaluated for this new assessment. Its content addresses concepts of negative emotions, anxiety, 
low energy, cognition, sleep disturbance, eating behavior, low motivation, self-blame and self-
harm or suicide, which represent issues identified during item generation process with subjects 
with MDD.
Subjective sleep parameters: Subjects will be asked to provide answers to questions to 
determine their subjective experience of sleep by recording their answers in a daily sleep diary
(CSD-M).
SDMT: The SDMT is a widely used, paper-and-pencil assessment of complex scanning and 
visual tracking, requiring elements of attention, visuoperceptual processing, working memory, 
and cognitive/psychomotor speed.53 The test is viewed as a robust screening test for adult 
neuropsychological impairment52 and is sensitive to impairments in cognitive function associated 
with MDD.4
TMT-Part B: The TMT-Part B measures divided attention and executive function (tracking and 
sequencing) and is sensitive to cognitive decline associated with MDD.54
HVLT-R: The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall 
test. Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 
recognition list (including 12 target and 12 foil words).4 The test administrator reads instructions 
and word lists aloud, and records words recalled/recognized by the subject. Scores include 
learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used 
measure of verbal episodic memory.


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For additional details on efficacy measures, see Section 9.2.
Pharmacokinetic Assessments
Blood samples of approximately 3 mL will be collected for measurement of plasma 
concentrations of JNJ-42847922 and the metabolites M12 and M16 (as applicable) in the 
morning of Days 42, 84 and Day 168, within 12 hours after the previous dose.
Safety Evaluations
Standard safety evaluations including collection of AEs and concomitant medications, physical 
examination, body weight, waist circumference, vital signs, 12-lead ECG, urine drug test, 
alcohol breath test, pregnancy testing, and clinical laboratory tests will be performed to monitor 
subject safety throughout the study.
The homeostatic model assessment will be conducted to estimate changes in beta-cell function 
and insulin sensitivity. The model requires both glucose and insulin measurements. It is known 
that atypical antipsychotic medications, including quetiapine XR, may cause insulin resistance; 
at present, there is no evidence that JNJ-42847922 has any impact on glucose metabolism.
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.57
The effect on sexual functioning will be measured by the ASEX. The ASEX has shown 
satisfactory reliability and validity.32
Drug-induced EPS will be monitored using the ESRS-A. The ESRS-A is an abbreviated 
manualized version of the ESRS, a semi-structured interview that rates parkinsonian symptoms, 
dystonia, dyskinesias, and akathisia over the previous 7 days.10 The ESRS-A is being included 
since the comparator medication, quetiapine XR, is an antipsychotic with the potential to cause 
EPS and akathisia.
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.46
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.13 To date, 3 cases of sleep paralysis have been observed with 
JNJ-42847922:
 
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 
CCI


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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 AEs of special interest in this study.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 4 weeks 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 (particularly, if the initial laboratory testing was not done 
under fasting conditions) that would otherwise lead to exclusion may be allowed after discussion 
and approval by the sponsor during the screening phase (to reassess eligibility). This should only 
be considered if there is no anticipated impact on subject safety.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Criterion modified per Amendment 2
1.1
Male or female of non-childbearing potential (WONCBP) outpatients, 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.
o
If reproductive status is questionable, additional evaluation should be 
considered.
2.
Criterion modified per Amendment 2


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  2.1.
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. The length of the current depressive episode must be ≤18 months.
3.
Criterion modified per Amendment 2
  3.1.
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 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 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.
4.
Criterion modified per Amendment 1
  4.1.
  4.2.
Criterion modified per Amendment 2
Be 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 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.
5.
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.
Have a Body Mass Index (BMI) between 18 and 35 kg/m2 inclusive (BMI = 
weight/height2).
7.
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 there are 
abnormalities, they must be consistent with the underlying illness in the study 
population. 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.
8.
Be willing and able to adhere to the prohibitions and restrictions specified in this 


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Status: Approved, Date: 26 April 2018
protocol.
9.
Must sign an informed consent form (ICF) indicating that he or she understands the 
purpose of and procedures required for the study including peripheral biomarkers 
research (ie, blood, saliva) and is willing to participate in the study.
10.
Sign a separate ICF if he or she agrees to provide an optional DNA sample for research. 
Refusal to give consent for the optional DNA research sample does not exclude a subject 
from participation in the study.
11.
Criterion deleted per Amendment 2
12.
Criterion deleted per Amendment 2
13.
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.
14.
Criterion modified per Amendment 2
  14.1
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.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Criterion modified per Amendment 2
  1.1.
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), 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 


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Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
least 2 months prior to screening.
2.
Has a fasting triglyceride concentration ≥500 mg/dL at screening.
3.
Has Cushing’s Disease, Addison’s Disease, primary amenorrhea, or other evidence of 
significant medical disorders of the HPA axis.
4.
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.
Has had clinically significant acute illness within 7 days before the first dose of study 
drug.
6.
Has a history of epilepsy, NMS or Tardive Dyskinesia.
7.
Has a history of previous non-response to an adequate trial of quetiapine as an 
adjunctive treatment for MDD (adequate trial defined as ≥150 mg for 4 weeks or 
more). 
8.
Criterion modified per Amendment 2
  8.1.
Has a history of lack of response 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). 
9.
Has a history or evidence of noncompliance with current antidepressant therapy.
10.
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 until the follow-up visit. See Attachment 1 for examples of strong inhibitor or 
inducer of CYP3A4 and CYP2C9 or a dual inhibitor of CYP3A4 and CYP2C9.
Fluvoxamine is a moderate CYP2C9 inhibitor and a mild CYP3A inhibitor, and will 
not be excluded from the study.
11.
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. These are allowed as secondary diagnoses as long as 


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Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
MDD is the primary focus of treatment according to the investigator.
12.
Current active DSM-5 diagnosis of obsessive-compulsive disorder, posttraumatic 
stress disorder, anorexia nervosa, or bulimia nervosa is exclusionary. These disorders 
need for be in remission for at least 1 year for the subject to be enrolled.
13.
Has history or current diagnosis of a psychotic disorder, bipolar disorder, intellectual 
disability, autism spectrum disorder, borderline personality disorder, somatoform 
disorders, or fibromyalgia.
14.
Has any significant primary sleep disorder, including but not limited to obstructive 
sleep apnea, restless leg syndrome, narcolepsy or parasomnias.
15.
Has significant hypersomnia that is not related to insomnia disorder or MDD (based 
on clinical judgment of the investigator).
16.
Has a history of a bariatric surgical procedure within 3 years before the screening 
visit.
17.
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).
18.
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). 

Features of new ischemia

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.
19.
Criterion modified per Amendment 1
  19.1.
Has received any prior treatment with electroconvulsive therapy, vagal nerve 
stimulation, or a deep brain stimulation device. Has received ketamine or esketamine 
for the treatment of depression.


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Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
20.
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. 
21.
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.
22.
Has known allergies, hypersensitivity, or intolerance or any contraindication to 
JNJ-42847922, quetiapine XR, or their excipients (refer to Investigator's Brochure for 
JNJ-4284792221 and Summary of Product Characteristics [SmPC]/Package Insert 
[PI]51 for quetiapine XR).
23.
Has either donated 1 or more units (approximately 450 mL) of blood or acutely lost an 
equivalent amount of blood within 60 days before the first dose of study drug.
24.
Has cognitive impairment that would render the informed consent invalid, or limit the 
ability of the subject to comply with the study requirements.
25.
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.
26.
Has taken any disallowed therapies as noted in Section 8 Prestudy and Concomitant 
Therapy before the planned first dose of study drug.
27.
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.
28.
Criterion modified per Amendment 2
28.1
Is pregnant or breastfeeding while enrolled in this study or within 1 month after the 
last dose of study drug.
29.
Plans to father a child while enrolled in this study or within 3 months after the last 
dose of study drug.
30.
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 


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Status: Approved, Date: 26 April 2018
during the time the subject is expected to participate in the study.
Note: Subjects with planned surgical procedures to be conducted under local 
anesthesia may participate.
31.
Is an employee of the investigator or study center, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study center, 
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 (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.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
The use of limited amounts of alcohol (up to 2 units daily eg, one pint of ordinary 
strength beer, lager or cider [3% to 4% alcohol by volume]; or a pub measure [50 mL] 
of spirits (40% alcohol by volume); or 2 standard pub measure [100 mL] of fortified 
wine [20% alcohol by volume]) will be allowed during the study, with the exception of 
the evenings before study visits and 12 hours before salivary cortisol sample collections.
4.
Strenuous exercise may affect study specified assessments and safety laboratory results; 
for this reason, strenuous exercise should be avoided within 24 hours before all planned 
study visits
5.
Biomarker blood samples are to be collected under fasting conditions (≥8 hrs, water 
permitted); for saliva samples, no food or drink (water permitted) ≥1 hour prior to 
collection.
6.
Subjects will be advised not to donate blood during the study and for at least 3 months 
after completion of the study.


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Status: Approved, Date: 26 April 2018
7.
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.
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 to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by insomnia status (significant insomnia 
symptoms [ISI score ≥15]2 at baseline versus no significant insomnia symptoms [ISI score <15] 
at baseline).
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, 
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 


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Clinical Protocol 42847922MDD2002 Amendment 2
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Status: Approved, Date: 26 April 2018
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 an end-of-
study visit.
6.
DOSAGE AND ADMINISTRATION
JNJ-42847922 will be supplied for this study as 20-mg tablets. Quetiapine XR will be supplied 
as 50- and 150-mg tablets. In some instances, subjects will receive both active drug and a 
placebo capsule. All tablets will be over-encapsulated to ensure blinding. 
All subjects will take 2 capsules daily. For subjects taking the lower dose, they will either take 
1 capsule of 20-mg JNJ-42847922 or 150-mg quetiapine XR (after the first 2 days) along with 
1 placebo capsule. For subjects taking the higher dose, they will take 2 capsules of either 20-mg 
JNJ-42847922 or 150-mg quetiapine XR. (Table 2)
Table 2:
Dose Description
Dose Level
Capsules
20-mg JNJ-42847922
20 mg and placebo
40-mg JNJ-42847922
20 mg and 20 mg
50-mg Quetiapine XR
50 mg and placebo
150-mg Quetiapine XR
150 mg and placebo
300-mg Quetiapine XR
150 mg and 150 mg
All subjects randomized to JNJ-42847922 will receive 20 mg as a starting dose. Subjects 
randomized to quetiapine XR will receive 50 mg once daily for 2 days, followed by an increase 
to 150 mg once daily on Day 3, as per prescribing guidelines in the product label. After the initial 
dosing period, dose adjustments may be made starting with the first scheduled clinic visit (Day 
14). The first dose adjustment must be upwards. Subsequent adjustments may be made upwards 
or downwards within the study dose ranges (20 or 40 mg for subjects randomized to JNJ-
42847922 or 150 or 300 mg for subjects randomized to quetiapine XR) if necessary, depending 
upon the investigator’s assessment of the subject’s clinical response and tolerability. 


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Status: Approved, Date: 26 April 2018
Adjustments of dose should only be made after a clinic visit (if needed may be an unscheduled 
visit) and assessment of efficacy and tolerability of the medication.
Subjects for whom tolerability at the lowest dose is either unacceptable or cannot be 
appropriately managed should be withdrawn from the study, and the AE recorded as a reason for 
discontinuation. For subjects on the highest doses, if there is a lack of response after a clinically 
appropriate treatment time, the investigator should consider discontinuing the subject due to lack 
of efficacy.
Subjects will administer the assigned study drug once daily at bedtime, approximately 3 hours 
after the last meal, from Day 1 to Day 167. 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. 
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed (see 
Table 3) for description of interventions.
Table 3:
Description of Interventions
Treatment name
JNJ-42847922
Quetiapine XR
Dose per delivery 
(ie, total daily dose)
20 mg or 40 mg
50 mg for the first 2 days and then 
150 mg or 300 mg
Study drugs will be over-encapsulated tablets to be taken orally, once daily at bedtime, approximately 
3 hours after the last meal, with approximately 100 mL of plain water and swallowed whole. Tablets 
must not be chewed, divided, dissolved or crushed.
Subjects will continue to take their baseline SSRI/SNRI antidepressant at the same dose, without 
change, every day, at approximately the same time as prior to entering the study throughout the 
screening, double-blind, and follow-up phases.
Study medication will be supplied in blister packs identified by a number. Study-site personnel 
will instruct subjects on how to store study drug for at-home use.
For this study, any dose of JNJ-42847922 greater than 2 capsules each day will be considered an 
overdose (see Section 12.2, Special Reporting Situations for reporting requirements).
7.
TREATMENT COMPLIANCE
The study drug will be self-administered by subjects at home. 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.
If appropriate, additional details may be provided in a study site investigational product manual 
that is provided separately and noted in Section 15, Study-Specific Materials.


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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 AEs 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 psychotherapy, 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. 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 3, Study 
Design and Rationale.
For safety reasons, the use of hypnotic drugs or some food supplements (see the following list of 
prohibited medication or food supplements) is prohibited from Day 1 until the last study visit. 
JNJ-42847922 has hypnotic properties and potential pharmacodynamic interactions with other 
hypnotic drugs have not been investigated yet. Apart from hypnotic drugs, no necessary 
medication should be stopped for the sole purpose of making subjects eligible for enrollment in 
the study. Rebound effects of stopping pre-study sleep medication should be prevented. 
Aspirin, ibuprofen, or other non-steroidal anti-inflammatory drugs (NSAIDs) should not be taken 
within 12 hours of blood draws.
Subjects must not use the following medication or food supplements during the study:

Monoamine oxidase inhibitors (MAOIs) within 4 weeks before Day 1 until the follow-up 
visit.

Antipsychotic drugs (D2 antagonists and D2 partial agonist) within 4 weeks before Day 1 
until the follow-up visit.

Benzodiazepines, hypnotics (eg, zolpidem, zopiclone, zaleplon, eszopiclone, suvorexant and 
ramelteon), sedating antidepressants (eg, doxepin, trazodone, mirtazapine, and tricyclic
antidepressants), sedating antihistamines including over-the-counter hypnotics (eg, 
diphenhydramine, doxylamine, and hydroxyzine), and melatonin from at least 7 days prior 
to Day 1 until the follow-up visit. Sleep medication should be tapered off to prevent rebound 
insomnia.


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
S-adenosyl methionine (SAMe), bupropion, opiates, and mood stabilizers (eg Lithium and 
anticonvulsants) from at least 7 days prior to Day 1 until the follow-up visit.

Stimulants (dexamphetamine, methylphenidate, dexmethylphenidate), oral systemic 
steroids, and appetite suppressants (such as ephedrine), and isoxsuprine from at least 7 days 
before Day 1 until the follow-up visit. Limited use of decongestants will be permitted, as 
needed, and must not exceed 7 consecutive days or be used within 24 hours of a scheduled 
visit. 

Prescription weight-loss medications (including but not limited to orlistat, lorcaserin, 
combination 
therapy 
with 
naltrexone/bupropion, 
liraglutide 
3 mg 
[Saxenda], 
topiramate/phentermine [or its individual components]) or over-the-counter weight-loss 
therapies from 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 strong inhibitor or inducer of CYP3A4 
and CYP2C9 or a dual inhibitor of CYP3A4 and CYP2C9. 

St. John’s wort, ephedra, Chinese herbal medications, ginkgo, ginseng, or kava from at least 
7 days before Day 1 until the follow-up visit.
The use of magnetic and electrical stimulation therapies is not allowed from screening to the
end-of-study visit. These include ECT, vagal nerve stimulation, deep brain stimulations (any 
history of these treatments is exclusionary), transcranial magnetic stimulation (TMS) of any type, 
or direct current stimulation (DCS). For the last two (TMS, DCS), use prior to screening is not 
exclusionary.  
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 as soon as possible 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.
Throughout the study, subjects will complete self-assessments (PRO). Where multiple 
procedures are scheduled for the same visit, procedures are recommended to be performed in the 
following order: ECGs, vital signs, blood draw, 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.


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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.
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. 
A table listing standard volumes of blood taken for tests and PK samples is provided in 
Attachment 3. These volumes may vary slightly from site to site although the maximum amount 
of blood drawn (including retesting) from each subject in this study will not exceed 250 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. The current depressive 
episode duration 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, for any particular 
antidepressant. The inadequate response must include the subject’s current antidepressant 
treatment. 
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) 

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
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, lipid panel, and urinalysis)

Alcohol (breath) test

Urine drug test

Serum or urine pregnancy testing, per investigator’s judgment

Menstrual cycle tracking (premenopausal women only)

Recording of AEs and concomitant medication

C-SSRS

ISI
Exceptional and limited retesting of abnormal screening values that lead to exclusion may be 
allowed once 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 who meet all inclusion criteria and none of the exclusion criteria and who have 
completed all screening procedures will be randomized to receive either JNJ-42847922 or 
quetiapine XR once daily taken orally while continuing their current antidepressant on which 
they have had an inadequate response at the time of screening. The assigned study drug will be 
self-administered at bedtime by the subject at home.
All subjects randomized to JNJ-42847922 will receive 20 mg as a starting dose. Subjects 
randomized to quetiapine XR will receive 50 mg once daily for 2 days, followed by an increase 
to 150 mg once daily on Day 3, as per prescribing guidelines in the product label. After the initial 
dosing period, dose adjustments may be made starting with the first scheduled clinic visit (Day 
14). The first dose adjustment must be upwards. Subsequent adjustments may be made upwards 
or downwards within the study dose ranges (20 or 40 mg for subjects randomized to JNJ-
42847922 or 150 or 300 mg for subjects randomized to quetiapine XR) if necessary, depending 
upon the investigator’s assessment of the subject’s clinical response and tolerability. 
Adjustments of dose should only be made after a clinic visit (if needed may be an unscheduled 
visit) and assessment of efficacy and tolerability of the medication. If the dose is changed, then at 
a minimum the CGI-S, PGI-S, and SMDDS should be collected along with the ESRS-A.
Study procedures during the double-blind treatment phase to assess efficacy, safety, tolerability, 
compliance, and other evaluations (eg, PK and biomarker) will occur as per the Time and Events 
Schedule. Subjects will be seen at the study site at baseline, and at Weeks 2, 4, 6, 12, 18, and 24 


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of the double-blind phase. A telephone interview will be conducted at the end of Week 1 to 
collect AEs and assess any other issues with tolerability to the study medication. 
9.1.4.
End-of-Study Visit/Follow-Up Visit
All subjects will return to the study site for a follow-up visit within 7 to 14 days after completion 
of the double-blind phase. At the follow-up visit, safety assessments/procedures will be 
completed per the Time and Events Schedule. If a subject prematurely withdraws from the study, 
the End-of-Study Visit assessments should be performed as soon as possible. 
At the start of the follow-up phase, further clinical/standard of care for the treatment of 
depression will be arranged by the study investigator and/or the subject’s treating physician. 
The study will be considered completed after the final study visit (Week 26) for the last subject 
participating in the study.
The duration of participation in the study for an individual subject (including screening and 
follow-up visit) will be up to 30 weeks.
9.2.
Efficacy Evaluations
The following efficacy assessments will be performed at the timepoints indicated in the Time 
and Events Schedule. The MADRS (SIGMA) and CGI-S will be administered by independent, 
centralized remote raters; the SIGH-A (HAM-A), SDMT, TMT-Part B, and HVLT-R will be 
administered by the investigators or designee; and the PGI-S, PROMIS-SD (Short Form 8a), 
PROMIS-SRI (Short Form 8a), SMDDS, QLDS, and CSD-M will be completed by the subjects.
9.2.1.
Montgomery-Åsberg 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.33 The scale consists of 10 items, each of which is scored 
from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a 
total possible score of 60. Higher scores represent a more severe condition. The MADRS 
evaluates apparent sadness, reported sadness, inner tension, 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.
Clinical Global Impression-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.17 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 


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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.
9.2.3.
Patient Global Impression-Severity (PGI-S)
The PGI-S is a self-report scale to measure severity of illness (1=none, 2=mild, 3=moderate, 
4=severe).45 Considering all aspects of depression, subjects will rate their severity on the PGI-S. 
Its completion time is less than 1 minute.
9.2.4.
Structured Interview Guide Version (SIGH-A) 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.18,19 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. 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.59
9.2.5.
Patient Reported Outcomes Measurement Information System-Sleep 
Disturbance (PROMIS-SD) and Sleep-Related Impairment (PROMIS-
SRI) Short Forms
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.64
The PROMIS-SD Short Form subscale consists of a static 8 item questionnaire. The 
PROMIS-SD instruments assess self-reported perceptions of sleep quality, sleep depth, and 
restoration associated with sleep. This includes perceived difficulties and concerns with getting 
to sleep or staying asleep, as well as perceptions of the adequacy of and satisfaction with sleep. 
Sleep Disturbance does not focus on symptoms of specific sleep disorders, nor does it provide 
subjective estimates of sleep quantities (total amount of sleep, time to fall asleep, amount of 
wakefulness during sleep). The Sleep Disturbance short form is universal rather than disease-
specific. It assesses sleep disturbance over the past seven days. Its completion time is estimated 
to be less than 5 minutes.
The PROMIS-SRI Short Form subscale consists of a static 8 item questionnaire. The PROMIS 
adult Sleep-Related Impairment item bank focuses on self-reported perceptions of alertness, 
sleepiness, and tiredness during usual waking hours, and the perceived functional impairments 
during wakefulness associated with sleep problems or impaired alertness. Though Sleep-Related 
Impairment does not directly assess cognitive, affective, or performance impairment, it does 
measure waking alertness, sleepiness, and function within the context of overall sleep-wake
function. The Sleep-Related Impairment short form is universal rather than disease-specific. It 


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assesses sleep-related impairment over the past seven days. Its completion time is estimated to be 
less than 5 minutes.
9.2.6.
Quality of Life in Depression Scale (QLDS)
The QLDS is a disease specific PRO designed to assess health related quality of life in patients 
with MDD.20 The instrument has a recall period of "at the moment", contains 34-items with 
"yes"/"no" response options and takes approximately 5 to 10 minutes to complete. The score 
range is from 0 (good quality of life) to 34 (very poor quality of life).
9.2.7.
Symptoms of Major Depressive Disorder Scale (SMDDS)
The SMDDS assesses patient-reported symptoms associated with MDD.41,42, 43,47,56 The target 
population includes adults (aged 18 and older) with a clinical diagnosis of MDD who are being 
treated in an ambulatory setting. The SMDDS has been developed in a patient sample including 
both males and females, varying levels of age, race, education, marital status, and severity. This 
16-item instrument has a 7-day recall period, and subjects respond to each question using a rating 
scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”). The total score ranges 
from 0 to 60 with a higher score indicating more severe depressive symptomatology.
9.2.8.
Subjective Sleep Parameters (Consensus Sleep Diary-Morning 
Administration [CSD-M])
Subjects will be asked to provide answers to questions to determine their subjective experience 
of sleep by recording their answers in a daily sleep diary (CSD-M). The CSD-M is the only sleep 
diary developed with rigorous methodology for patient reported outcome development, including 
employing user/focus group feedback and expert feedback to establish construct validity. It has 
undergone psychometric testing and its content validity has been confirmed by patient focus 
groups.8 The parameters recorded include:

self-reported sleep onset latency (sSOL) 

subjective TST (sTST) 

subjective WASO (sWASO) 

subjective number of nighttime awakenings (s nNAW) 

subjective quality of sleep (sQUAL)  

subjective refreshed feeling on waking (sFRESH)
9.2.9.
Symbol Digit Modalities Test (SDMT)
The SDMT is a widely used, paper-and-pencil assessment of complex scanning and visual 
tracking, requiring elements of attention, visuoperceptual processing, working memory, and 
cognitive/psychomotor speed.53 The test is viewed as a robust screening test for adult 
neuropsychological impairment52 and is sensitive to impairments in cognitive function associated 
with MDD.4 The SDMT measures the time to pair abstract symbols with specific numbers. The 
test includes a coding key consisting of 9 abstract symbols, each paired with a number ranging 


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from 1 to 9. Following the key, the subject is presented with randomly ordered symbols and is 
required to write the number corresponding to each symbol as fast as possible. The number of 
correct substitutions within 90 seconds is recorded.
9.2.10.
Trail Making Test Part B (TMT-Part B)
The TMT-Part B measures divided attention and executive function (tracking and sequencing). 
The subject is instructed to draw a line to connect a set of 25 consecutively numbered and 
lettered circles, alternating sequentially between numbers and letters (ie, 1-A-2-B). The subject is 
instructed to work as quickly as possible while still maintaining accuracy. The TMT-Part B has 
acceptable reliability; reliability coefficients have typically been reported as exceeding 
0.65.29The TMT-Part B is sensitive to cognitive decline associated with MDD.54
9.2.11.
Hopkins Verbal Learning Test-Revised (HVLT-R)
The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. 
Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 
recognition list (including 12 target and 12 foil words).4 The test administrator reads instructions 
and word lists aloud, and records words recalled/recognized by the subject. Scores include 
learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used 
measure of verbal episodic memory.
9.3.
Pharmacokinetics 
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 42, Day 84 and Day 168 PK sampling 

A single sample will be collected in the morning of Visits 6, 7 and 9 within 12 hours 
after the previous dose.
As this is a blinded study, blood samples for PK will be collected from quetiapine-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.
Subject confidentiality will be maintained. 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. The exact time of the last meal intake prior 
to dosing before PK sampling on Days 42, 84 and 168 will also be recorded.


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9.3.1.
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.
9.3.2.
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.
9.4.
Biomarkers 
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). 
Saliva samples for the measurement of cortisol concentrations will be collected by using an oral 
swab method just before bedtime (before dosing) and upon awakening as indicated in the Time 
and Events Schedule. 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.


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9.5.
Pharmacogenomic (DNA) Evaluations
A pharmacogenomic blood sample will be collected from subjects who consent separately to this 
component of the study (where local regulations permit) to allow for additional research. 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 and will not affect the ability 
of a subject to participate in this study. 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 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.
9.6.
Medical Resource Utilization and Health Economics 
Medical resource utilization data, associated with medical encounters, will be collected using the 
HRUQ during the double-blind and follow-up phases of the study. This questionnaire28 was 
designed to assess utilization of the following resources: hospitalization (refers to ≥1-night stay), 
emergency room visits without hospitalization, day or night clinic stays, outpatient treatment.
The questionnaire will be used in the study as an exploratory tool. Study personnel will 
administer the questionnaire. If possible, for a given subject, the same person should administer 
this scale at all visits. Note that any resource utilization that is required by the protocol should 
not be captured on the questionnaire.
9.7.
Safety Evaluations
The collection of AEs 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:


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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 AEs 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 AEs 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 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, FT4, hematology, serum chemistry, HbA1c, lipid panel, and 
urinalysis) should be performed under fasting conditions.
The following tests will be performed by the central laboratory:


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
Hematology Panel
-hemoglobin
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential

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

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

Serum pregnancy testing, as determined by the investigator

TSH 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)

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In addition, the following tests will be performed at the study site:

Urine pregnancy testing, as needed per investigator’s judgment

Urine drug test (screening only): opiates (including methadone), cocaine, amphetamines, 
methamphetamines, cannabinoids, barbiturates, XTC and benzodiazepines. Urine drug 
screens will be done by the site using a dipstick

Alcohol breath test
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, the procedures 
should be performed in the following order: ECG, vital signs, blood draw.
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.
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, and at study visits as outlined in the Time and 
Events Schedule.
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). The scale should be calibrated before the first 
subject is enrolled at the site. Calibration must be documented in the calibration log. 


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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.
Additional blood and urine samples may be taken or vital signs and ECGs recorded at the 
discretion of the investigators as needed.
Physicians Withdrawal Checklist (PWC)
Potential withdrawal effects will be assessed by the 20-item physician withdrawal checklist 
(PWC).46 The PWC is a simple, accurate, reliable, and sensitive instrument for the assessment of 
potential withdrawal symptoms following cessation of treatment.
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 FDA guidance.57
Arizona Sexual Experiences Scale (ASEX)
The ASEX is a patient reported 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.32
The Extrapyramidal Symptom Rating Scale—Abbreviated (ESRS-A) 
The ESRS-A is an abbreviated manualized version of the ESRS, a semi-structured interview that 
rates parkinsonian symptoms, dystonia, dyskinesias, and akathisia over the previous 7 days.10
The ratings include a motor examination for rigidity, tremor, reduced facial expression or speech, 
impaired gait/posture, postural instability, and bradykinesia/hypokinesia. Twenty-four individual 
items are rated on a 6-point scale: 0=Absent, 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, or 
5=Extreme. Frequency is included as an index of severity. Symptoms are divided into the 
4 corresponding subscales and each subscale is summarized in a Clinical Global Impression of 
Movement Severity (CGI-MS) score.
9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.


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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 Week 24 (ie, Day 168) of the double-blind phase.
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 175-182).
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
Because the primary endpoint of this study is time to all-cause discontinuation, investigators 
should ensure that appropriate withdrawal criteria have been met when withdrawing a subject 
from the study, especially when subjects are withdrawn due to lack of efficacy. The investigator 
should complete a detailed summary of the discontinuation, including the reasons for withdrawal 
and time of the withdrawal, in the CRF and in the source document. If the withdrawal results 
from an AE, the clinical course of the AE and the outcome (recovered, resolving, or ongoing) of 
the AE should be documented.
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Noncompliance with study drug administration (ie, missing either 4 or more consecutive 
doses of study medication or a total of 20 or more doses during the 6-month 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 or sponsor believes that for safety reasons or tolerability reasons 
(eg, AE) 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


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
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 168), 
end-of-study/follow-up assessment 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. If a subject leaves the study due to withdrawal of 
consent, the investigator will make sure that there is not a reason for the withdrawal of consent 
such as lack of efficacy or poor tolerance (ie, due to an AE).
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.
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.


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11.
STATISTICAL METHODS
Statistical analysis will be done 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.
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 primary purpose of the study is to investigate potential differentiating features between 
JNJ-42847922 and quetiapine XR. Although the sample size was not chosen based on a specific 
set of endpoints, for evaluating the time to discontinuation of study drug in the JNJ-42847922 
group versus the quetiapine XR group, a one-sided log-rank test with an overall sample size of 
100 subjects (50 in the JNJ-42847922 group and 50 in the quetiapine XR group) provides 
approximately 92% power at a 1-sided 0.10 significance level to detect a hazard ratio of 0.415, 
assuming the proportion of subjects who discontinue from study drug in the quetiapine XR group 
is 50%. The planned sample size of the study is consistent with the nature of a Phase 2 
exploratory study.67
11.3.
Efficacy Analyses 
The primary efficacy endpoint, time to all-cause discontinuation of study drug, will be estimated 
by the Kaplan-Meier method and summarized (number of discontinuations, number of censored 
subjects, median, 25th and 75th percentile, if estimable) by treatment group. Time to all-cause 
discontinuation of study drug is defined as the number of days from the first dose of study drug 
to the last dose of study drug. Subjects who complete treatment are not considered to have 
discontinued. A stratified log-rank test (stratified for baseline insomnia status) will be used to 
test the hypothesis that there is no difference between the JNJ-42847922 group and quetiapine 
XR in the probability of discontinuing study drug, using a 1-sided 0.10 significance level.
The analyses for the secondary efficacy endpoints will be described in the SAP. For all other 
efficacy endpoints, no multiplicity adjustment will be done and nominal p-values will be 
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11.4.
Biomarker Analyses
Cortisol levels will be tabulated for each time point and summary statistics will be calculated. 
Post-treatment 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. Post-treatment changes in exploratory biomarkers will be summarized by 
treatment group. Associations between baseline biomarker levels and clinical endpoints may be 
explored. Additional exploratory analyses may also be performed. Results of all exploratory 
analysis 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.
11.5.
Pharmacokinetic Analyses 
Concentration-time data will be summarized using descriptive statistics by dose, visit date and 
time (relative to dose) for JNJ-42847922, and metabolites M12 and M16 (as applicable).
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.
11.7.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics will be descriptively summarized by treatment 
group.
11.8.
Safety Analyses
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). 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 TEAEs will be included 
in the analysis. For each TEAE, 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 those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a 
serious adverse event.


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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.
The homeostatic model assessment will be conducted to estimate changes in beta-cell function 
and insulin sensitivity based on insulin and glucose laboratory values.
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.
Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment.
Physicians Withdrawal Checklist (PWC)
Results from the PWC will be tabulated by treatment.
Arizona Sexual Experiences Scale (ASEX)
Results from the ASEX will be tabulated by treatment.
Extrapyramidal Symptom Rating Scale—Abbreviated (ESRS-A)
Results from the ESRS-A will be tabulated by treatment.


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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 AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
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 AE 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 AE 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) and quetiapine XR with marketing authorization the expectedness of 
an AE will be determined by whether or not it is listed in the locally approved SmPC/ PI.
Adverse Event Associated With the Use of the Drug
An AE 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 AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).


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Very Likely
An AE 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 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 from 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 AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure, which may include contact for follow-up of safety. Serious adverse events, including 
those spontaneously reported to the investigator within 30 days after the last dose of study drug, 
must be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 


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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 AEs, 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 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). 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.
All subjects will 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 AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered serious adverse events. Any AE 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 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 
provided as a separate document.


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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 20 mg. 
The 20 mg dose will consist of 1 active and 1 placebo capsule. The 40 mg dose will consist of two 
20 mg tablets. It will be manufactured and provided under the responsibility of the sponsor. Refer 
to the Investigator's Brochure for a list of excipients.
Quetiapine XR will be supplied as 50 and 150 mg tablets. The 50 and 150 mg doses will consist of 
1 active and 1 placebo capsule each. The 300-mg quetiapine XR dose will consist of two 150 mg 
tablets. Refer to the SmPC/PI for the physical description and a list of excipients.
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 AEs 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 or quetiapine will be randomized to a treatment 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. 
 
 
 
 
CCI


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Major depressive disorder is a chronic illness, and a typical depressive episode is treated for at least 
6 to 12 months in clinical practice. This 6-month study is intended to better understand the 
long-term safety and efficacy of JNJ-42847922. Based on currently available data, JNJ-42847922 
may have similar efficacy, 
 
 compared to quetiapine XR as an adjunctive treatment of MDD. The potentially favorable 
safety profile of JNJ-42847922 may improve long-term adherence to treatment and overall 
effectiveness, which only can be demonstrated in a longer-term study.
 
 
 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.
 
 
 
 
 
 Based on the PK characteristics of JNJ-42847922, the available safety data from 
completed clinical trials, as well as the extensive 6-month safety data of a drug of a similar 
mechanism of action (a dual orexin antagonist), it is likely that JNJ-42847922 will be reasonably 
tolerated over a 6-month study.
CCI
CCI
CCI
CCI


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In this study, adult men and WONCBP subjects with MDD who have had an inadequate 
response to current antidepressant therapy with an SSRI/SNRI will be selected. 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.
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 250 mL, which is considered to be safe and acceptable in comparison to a Red Cross 
blood donation.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on 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.


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16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, 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 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)


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
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, 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 


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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 consent to provide optional samples for 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 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.
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.


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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. 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).
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.


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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable


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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source 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 AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
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, HVLT-R, ESRS-A, 
HRUQ, and C-SSRS


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The following questionnaires are completed by the subject using the PROs provided. These 
patient completed documents are considered source documents:

PGI-S, PROMIS-SRI [Short Form], PROMIS-SD [Short Form], QLDS, SMDDS, ASEX, 
SDMT, TMT-Part B
The following scales will be completed electronically by the central rater: 

MADRS (SIGMA version) and CGI-S.
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

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 the electronic source system is utilized, references made to 
the CRF in the protocol include the electronic source system but information collected through 
the electronic source system 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.


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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 
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.


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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 
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.


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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. 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 


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be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study subject identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and 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. 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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Attachment 3: Standard Blood Volumes Collected
Volume of Blood to be Collected From Each Subject 
Type of Sample
Volume per 
Sample (mL)
No. of Samples 
per Subject
Approximate 
Total Volume of 
Blood (mL)a
Safety (including screening and end-of-study assessments)
- Hematology (includes HbA1c)
2
5
10
- Serum chemistryb
4.5
5
22.5
Serum pregnancy testsc
1
1
1
-
TSH and FT4
3.5
3
10.5
Pharmacokinetic samples
3
3
9
Biomarker samples
30
4
120
Pharmacogenomic sampled
6
2
12
Approximate Totale
185
Abbreviations:
FT4= free thyroxine, HbA1c= hemoglobin A1c, TSH= thyroid-stimulating hormone
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Serum chemistry includes fasting glucose, insulin and lipid panel.
c. Blood tests for pregnancy testing 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. A FSH test may also be 
performed at investigator judgment to assist in determining if a woman is of non-childbearing potential. Test is 
drawn in the same tube as the chemistry but involves a 1 mL larger blood draw (3.5 mL total for all subjects).
d. Blood samples will be collected only from subjects who have consented to provide optional DNA samples for 
research.
e. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples.


JNJ-42847922 (Seltorexant/Selective Orexin-2 Receptor Antagonist)
Clinical Protocol 42847922MDD2002 Amendment 2
108
Status: Approved, Date: 26 April 2018
INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
1
Approved, Date: 2 July 2019
Janssen Research & Development *
Statistical Analysis Plan
Amendment 2
A 6-Month, Multicenter, Double-Blind, Randomized, Flexible-Dose, Parallel-Group Study 
to Compare the Efficacy, Safety, and Tolerability of JNJ-42847922 versus Quetiapine 
Extended-Release as Adjunctive Therapy to Antidepressants in Adult Subjects With Major 
Depressive Disorder Who Have Responded Inadequately to Antidepressant Therapy
Protocol 42847922MDD2002; Phase 2
JNJ-42847922 (Selective Orexin-2 Receptor Antagonist)
Status:
Approved
Date:
2 July 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-153916699 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.
NCT03321526


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2002
2
Approved, Date: 2 July 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.2.
Trial Design .................................................................................................................................... 12
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 12
1.4.
Sample Size Justification ............................................................................................................... 12
1.5.
Randomization and Blinding .......................................................................................................... 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Study Reference Start and End Dates........................................................................................... 13
2.2.
Analysis Phases............................................................................................................................. 14
2.3.
Visit Windows................................................................................................................................. 14
2.4.
Pooling Algorithm for Analysis Centers.......................................................................................... 17
2.5.
Analysis Sets.................................................................................................................................. 17
2.5.1.
All Randomized Analysis Set...................................................................................................... 17
2.5.2.
Efficacy Analysis Set .................................................................................................................. 17
2.5.2.1.
Full Analysis Set ...................................................................................................................... 17
2.5.3.
Safety Analysis Set..................................................................................................................... 17
2.6.
Definition of Subgroups.................................................................................................................. 17
2.7.
Study Day and Relative Day .......................................................................................................... 18
2.8.
Baseline and End point (DB).......................................................................................................... 18
2.9.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 19
2.10.
Imputation Rules for Missing Prior/Concomitant Medication Dates............................................... 20
2.10.1.
Prior Medications ........................................................................................................................ 20
2.10.2.
Concomitant Medications Taken During the Double-blind Phase.............................................. 20
2.10.3.
Concomitant Medications Taken During the Follow-up Phase................................................... 22
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 22
4.
SUBJECT INFORMATION................................................................................................................ 22
4.1.
Demographics and Baseline Characteristics ................................................................................. 23
4.2.
Disposition Information................................................................................................................... 24
4.3.
Treatment Compliance................................................................................................................... 24
4.3.1.
Treatment Compliance With Study Agent .................................................................................. 24
4.3.2.
Treatment Compliance With Baseline SSRI/SNRI Antidepressant............................................ 25
4.4.
Extent of Exposure......................................................................................................................... 25
4.5.
Protocol Deviations ........................................................................................................................ 26
4.6.
Prior and Concomitant Medications ............................................................................................... 26
5.
EFFICACY ......................................................................................................................................... 27
5.1.
Analysis Specifications................................................................................................................... 28
5.1.1.
Level of Significance................................................................................................................... 28
5.1.2.
Data Handling Rules................................................................................................................... 29
5.1.3.
Imputation Methods for Missing Items........................................................................................ 29
5.2.
Primary Efficacy Endpoint.............................................................................................................. 29
5.2.1.
Definition..................................................................................................................................... 29
5.2.2.
Estimand..................................................................................................................................... 29
5.2.3.
Analysis Methods........................................................................................................................ 30
5.2.3.1.
Subgroup Analyses ................................................................................................................. 30
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 31
5.3.1.
Change in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score..................... 31


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5.3.1.1.
Definition.................................................................................................................................. 31
5.3.1.2.
Analysis Methods .................................................................................................................... 31
5.3.2.
Achieving and Sustaining Remission of Depressive Symptoms ................................................ 33
5.3.2.1.
Definition.................................................................................................................................. 33
5.3.2.2.
Analysis Methods .................................................................................................................... 33
5.3.3.
Achieving and Sustaining Response of Depressive Symptoms................................................. 33
5.3.3.1.
Definition.................................................................................................................................. 33
5.3.3.2.
Analysis Methods .................................................................................................................... 33
5.3.4.
Change in Hamilton Anxiety Rating Scale (HAM-A)................................................................... 34
5.3.4.1.
Definition.................................................................................................................................. 34
5.3.4.2.
Analysis Methods .................................................................................................................... 35
5.3.5.
Clinical Global Impression-Severity (CGI-S) .............................................................................. 35
5.3.5.1.
Definition.................................................................................................................................. 35
5.3.5.2.
Analysis Methods .................................................................................................................... 36
5.3.6.
Patient Global Impression-Severity (PGI-S)............................................................................... 36
5.3.6.1.
Definition.................................................................................................................................. 36
5.3.6.2.
Analysis Methods .................................................................................................................... 36
5.3.7.
Quality of Life in Depression Scale (QLDS) ............................................................................... 36
5.3.7.1.
Definition.................................................................................................................................. 36
5.3.7.2.
Analysis Methods .................................................................................................................... 37
5.3.8.
Patient Reported Outcome Measurement Information System-Sleep Disturbance 
(PROMIS-SD) ............................................................................................................................. 37
5.3.8.1.
Definition.................................................................................................................................. 37
5.3.8.2.
Analysis Methods .................................................................................................................... 38
5.3.9.
Patient Reported Outcome Measurement Information System- Sleep Related 
Impairment (PROMIS-SRI)......................................................................................................... 39
5.3.9.1.
Definition.................................................................................................................................. 39
5.3.9.2.
Analysis Methods .................................................................................................................... 40
5.3.10.
Symptoms of Major Depressive Disorder Scale (SMDDS) ........................................................ 40
5.3.10.1.
Definition.................................................................................................................................. 40
5.3.10.2.
Analysis Methods .................................................................................................................... 40
5.3.11.
Symbol Digit Modalities Test (SDMT)......................................................................................... 41
5.3.11.1.
Definition.................................................................................................................................. 41
5.3.11.2.
Analysis Methods .................................................................................................................... 41
5.3.12.
Trail Making Test – Part B (TMT–Part B) ................................................................................... 41
5.3.12.1.
Definition.................................................................................................................................. 41
5.3.12.2.
Analysis Methods .................................................................................................................... 41
5.3.13.
Hopkins Verbal Learning Test-Revised (HVLT-R) ..................................................................... 42
5.3.13.1.
Definition.................................................................................................................................. 42
5.3.13.2.
Analysis Methods .................................................................................................................... 42
5.3.14.
MADRS-6.................................................................................................................................... 42
5.3.14.1.
Definition.................................................................................................................................. 42
5.3.14.2.
Analysis Methods .................................................................................................................... 42
5.4.
Exploratory Efficacy Endpoints ...................................................................................................... 43
5.4.1.
Consensus Sleep Diary – Morning Administration (CSD-M)...................................................... 43
5.4.1.1.
Definition.................................................................................................................................. 43
5.4.1.2.
Analysis Methods .................................................................................................................... 45
5.4.2.
MADRS-WOSI............................................................................................................................ 45
5.4.2.1.
Definition.................................................................................................................................. 45
5.4.2.2.
Analysis Methods .................................................................................................................... 46
6.
SAFETY............................................................................................................................................. 46
6.1.
Adverse Events .............................................................................................................................. 46
6.2.
Clinical Laboratory Tests................................................................................................................ 47
6.2.1.
Homeostatic Assessment (HOMA) Modeling.......................................................................... 49
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 49
6.4.
Electrocardiogram.......................................................................................................................... 50
6.5.
Other Safety Parameters ............................................................................................................... 52


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6.5.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 52
6.5.2.
Arizona Sexual Experiences Scale (ASEX)................................................................................ 53
6.5.3.
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A)................................................. 53
6.5.4.
Physicians Withdrawal Checklist (PWC) .................................................................................... 54
7.
SUMMARY OF PLASMA CONCENTRATIONS FOR JNJ-42847922, M12, AND M16 .................. 54
8.
BIOMARKERS................................................................................................................................... 54
9.
HEALTH ECONOMICS ..................................................................................................................... 54
9.1.
Healthcare Resource Use Questionnaire (HRUQ) ........................................................................ 54
ATTACHMENTS......................................................................................................................................... 57
ATTACHMENT 1 SCORING OF QLDS ITEMS ......................................................................................... 57
ATTACHMENT 2 CONVERSION OF RAW SCORE TO T-SCORE FOR PROMIS-SD............................ 59
ATTACHMENT 3 CONVERSION OF RAW SCORE TO T-SCORE FOR PROMIS-SRI........................... 60
ATTACHMENT 4 CRITERIA FOR TREATMENT-EMERGENT MARKEDLY ABNORMAL 
LABORATORY VALUES .................................................................................................................. 61


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
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AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
31 August 2018
Amendment 1
24 May 2019
Amendment 2
3 July 2019
Amendments below are listed beginning with the most recent amendment.
Amendment 1 (24 May 2019)
The overall reason for the amendment:    removed analysis windows for salivary cortisol; modified subgroups; 
added efficacy parameters MADRS-6 and MADRS-WOSI; added conversion rules for lab values; added analysis 
for plasma concentrations and removed biomarker analysis.
Applicable Section(s)
Description of Change (s)
Section 2.3
Removed analysis windows for salivary cortisol from Table 1 (this is moved to a 
separate biomarker SAP)
Section 2.6
Additional subgroups added: Baseline MADRS total score, Class of antidepressant 
study medication, and Final dose. Modifications made to subgroup categorizations 
of number of antidepressants used and number of major depressive episodes.
Section 4.6
Clarified that prior medications will be summarized by base preferred term.
Section 5
Added MADRS-6 Total score and MADRS-WOSI Total score to the efficacy 
variable table. Added section 5.3.14 and 5.4.2
Section 5.2.3
Possible sensitivity analysis added excluding a site with GCP issues
Section 5.3.1.2
Added BOCF definition and analysis for MADRS
Added subgroup analysis by mode dose
Section 5.4.1
Consensus Sleep Diary moved to exploratory efficacy endpoint
Modification made to average calculations for subjective sleep parameters
Section 6.2
Added conversion rules for chemistry laboratory values
Section 6.5.4
Added PWC-20 total score
Section 7
Added that Plasma concentrations for JNJ-42847922, M12, and M16 will be 
summarized using descriptive statistics
Section 8
Biomarker analysis removed to be defined in a separate document
Attachment 3
Updated conversion factor for Triglycerides


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2002
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Approved, Date: 2 July 2019
Amendment 2 (3 July 2019)
The overall reason for the amendment:    added sensitivity analyses, clarification of subgroup analysis 
methods, minor error fixes. 
Applicable Section(s)
Description of Change (s)
Section 2.3
Revised visit window definition for PWC
Section 5.2.3
Added an analysis for time to treatment-related discontinuation, and Kaplan-Meier 
curves for time to discontinuation by Week 12.
Section 5.2.3.1
Clarification on methods for subgroup analysis
Section 5.3.3.2
Added a summary of time to sustained response by modal dose
Section 5.4.1.2
Added an ANCOVA analysis on ranks for CSD parameters sFRESH and sQUAL
Section 5.4.2.2
Removed MADRS-WOSI ANCOVA analysis


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ABBREVIATIONS
AE
adverse event
ANCOVA
analysis of covariance
ASEX
Arizona Sexual Experiences Scale
BMI
body mass index
BOCF
baseline observation carried forward
CGI-S
Clinical Global Impression-Severity
CI
confidence interval
CRF
case report form
CSD-M
Consensus Sleep Diary-Morning Administration
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition
ECG
electrocardiogram
ESRS-A
Extrapyramidal Symptom Rating Scale-Abbreviated
FT4
free thyroxine
HAM-A
Hamilton Anxiety Rating Scale
HbA1c
hemoglobin A1c
HOMA
Homeostatic Assessment
HPA
hypothalamic-pituitary-adrenal
HRUQ
Healthcare Resource Use Questionnaire
HVLT-R
Hopkins Verbal Learning Test-Revised
IP
investigational products
ISI
Insomnia Severity Index
IWRS
interactive web response system
LOCF
last observation carried forward
LS
least-squares
MADRS
Montgomery-Asberg Depression Rating Scale
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
MRU
medical resource utilization
PGI-S
Patient Global Impression-Severity
PK
pharmacokinetic(s)
PRO
patient-reported outcome(s)
PROMIS-SD
Patient Reported Outcomes Measurement Information System-Sleep Disturbance
PROMIS-SRI
Patient Reported Outcomes Measurement Information System-Sleep Related Impairment
PWC
Physician Withdrawal Checklist
QLDS
Quality of Life in Depression 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
SDMT
Symbol Digit Modalities Test
SIGH-A
structured interview guide for the Hamilton Anxiety Scale
SMDDS
Symptoms of Major Depressive Disorder Scale
SNRI
serotonin-norepinephrine reuptake inhibitor
SSRI
selective serotonin reuptake inhibitor
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TMT-Part B
Trail Making Test-Part B
TSH
thyroid-stimulating hormone
TST
Total Sleep Time
US
United States
WASO
Wake after sleep onset
WHO-DD
World Health Organization Drug Dictionary
WOSI
Without Sleep Item
XR
extended-release


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2002
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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 
42847922MDD2002.
This SAP does not include planned analyses on biomarkers or pharmacogenomics data or on 
pharmacokinetic (PK) and exposure/response analyses, which will be specified as appropriate in 
separate documents.
1.1.
Trial Objectives
Objectives
Endpoints
Primary

To assess, 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), the efficacy
of flexibly dosed JNJ-
42847922 (20 mg or 40 mg) compared to flexibly 
dosed quetiapine extended-release (XR) (150 mg or 
300 mg) as adjunctive therapy to an antidepressant 
drug in delaying time to all-cause discontinuation 
of study drug over a 6-month (24-week) treatment 
period.

Time to all-cause discontinuation of study 
drug. 
Secondary

To assess the efficacy of JNJ-42847922 compared 
to quetiapine XR in the adjunctive treatment of 
MDD based on:

Achieving 
and 
sustaining 
remission 
of 
depressive symptoms

The proportion of subjects achieving 
(at 
Week 
12) 
and 
sustaining 
remission at Weeks 18 and 24. 
Remission 
is 
defined 
as 
Montgomery-Asberg 
Depression 
Rating Scale (MADRS) total score 
≤12.

Achieving 
and 
sustaining
response
of 
depressive symptoms

The proportion of subjects achieving 
(at 
Week 
12) 
and 
sustaining 
response at
Weeks
18
and 24. 
Response 
is 
defined 
as 
≥50% 
improvement from baseline MADRS 
total score.

Improving depressive symptoms in subjects 
with significant insomnia versus those without 
significant insomnia

Change from baseline to Weeks 12, 
18, and 24 in the MADRS total score 
in subjects with significant insomnia 
(baseline Insomnia Severity Index 
[ISI] score ≥15) versus those without
significant insomnia (baseline ISI 


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
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Objectives
Endpoints
score <15).

Improving anxiety symptoms

Change from baseline to Weeks 12,
18, and 24 in the 14-item Hamilton 
Anxiety Rating Scale (HAM-A) total 
score.  

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
metabolic parameters during long-term (6 months)
treatment, including:

Weight

The proportion of subjects with weight 
gain ≥7% of baseline body weight at end-
of-study assessment.

Lipids
Triglycerides

The proportion of subjects with shifts in 
triglycerides 
from 
normal 
to 
high 
(<150 mg/dL at baseline to ≥200 mg/dL at 
any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline
to high 
(≥150 and <200 mg/dL at baseline to 
≥200 
mg/dL 
at 
any 
post-baseline 
assessment).

The proportion of subjects with shifts in 
triglycerides from normal to very high 
(<150 mg/dL at baseline to ≥500 mg/dL at 
any post-baseline assessment).

The proportion of subjects with shifts in 
triglycerides from borderline to very high 
(≥150 mg/dL and <200 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).

The proportion of subjects with shifts in 
triglycerides from high to very high 
(≥200 mg/dL and <500 mg/dL at baseline 
to ≥500 mg/dL at any post-baseline 
assessment).

Blood Glucose 
Fasting glucose

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
borderline (<100 mg/dL at baseline to 
≥100 and <126 mg/dL at any post-
baseline assessment).

The proportion of subjects with shifts in 
fasting blood glucose from borderline to 
high (≥100 to <126 mg/dL at baseline to 


JNJ-42847922  (Selective Orexin-2 Receptor Antagonist)
Statistical Analysis Plan 42847922MDD2002
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Approved, Date: 2 July 2019
Objectives
Endpoints
≥126 mg/dL at any post-baseline 
assessment).

The proportion of subjects with shifts in 
fasting blood glucose from normal to 
high (<100 mg/dL at baseline to ≥126 
mg/dL at any post-baseline assessment).

To assess the efficacy of JNJ-42847922 compared 
to quetiapine XR as adjunctive therapy for MDD in 
the improvement of global depressive symptom 
severity.

Change from baseline to Weeks 12 and 
24 in the Clinical Global Impression-
Severity (CGI-S) score.

To characterize subject perceptions of global MDD 
severity.

Change from baseline to Weeks 12 and 
24 
in 
the 
Patient 
Global 
Impression-Severity (PGI-S) score.

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject’s assessment of quality of life.

Change from baseline to Weeks 12 and 
24 in Quality of Life in Depression Scale 
(QLDS).

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject's assessment of sleep impairment and 
daytime problems due to lack of sleep.

Change from baseline to Weeks 12 and 24 
in 
Patient 
Reported
Outcomes
Measurement Information System-Sleep 
Disturbance (PROMIS-SD Short Form
8a).

Change from baseline to Weeks 12 and 24 
in 
Patient 
Reported
Outcomes
Measurement 
Information 
System-
Sleep-Related Impairment (PROMIS-SRI 
Short Form 8a).

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on 
the subject’s assessment of reduction of depressive 
symptoms.

Change from baseline to Weeks 12 and 24 
in 
Symptoms 
of 
Major 
Depressive 
Disorder Scale (SMDDS)

To assess the effect of JNJ-42847922 compared to 
quetiapine XR as adjunctive therapy for MDD on
cognitive function.

Change from baseline to Weeks 6, 12, and 
24 in Symbol Digit Modalities
Test 
(SDMT).  

Change from baseline to Weeks 6, 12, and 
24 in Trail Making Test - Part B (TMT-
Part B).

Change from baseline to Weeks 6, 12, and 
24 in Hopkins Verbal Learning Test-
Revised (HVLT-R).

Change from baseline to Weeks 6 and 24
in salivary cortisol levels as measured at 
home upon awakening and at home 
during the evening.
CCI


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Objectives
Endpoints

To 
assess 
the 
safety 
and 
tolerability 
of 
JNJ-42847922 compared with quetiapine XR as 
adjunctive treatment in subjects with MDD.

Safety assessments including:

Adverse events (AEs).

Proportion of all serious adverse 
events (SAEs) and events of special 
interest (e.g., parasomnias).

Vital signs, physical examinations, 
electrocardiogram 
(ECG), 
and 
laboratory parameters.

Sexual 
functioning 
using 
the 
Arizona Sexual Experiences Scale 
(ASEX).

Extrapyramidal symptoms assessed 
by the Extrapyramidal Symptom 
Rating 
Scale-Abbreviated
(ESRS-A).

Suicidality 
assessed 
using 
the 
Columbia Suicide Severity Rating 
Scale (C-SSRS).

Potential withdrawal effects assessed 
by 
the 
Physician 
Withdrawal 
Checklist (PWC).
Exploratory

To collect medical resource utilization (MRU) data 
that may be used in future economic modeling.

Healthcare Resource Use Questionnaire 
(HRUQ).

To assess the effect of JNJ-42847922 compared 
with quetiapine XR as adjunctive therapy for MDD 
on self-reported measures of sleep.

Change from baseline in subjective sleep 
parameters as measured by the Consensus 
Sleep Diary-Morning Administration 
(CSD-M) after the first 6 weeks of 
treatment (using the average of 3 morning 
measurements in Week 6).

Change from baseline in subjective sleep 
parameters as measured by the CSD-M
after 3 to 6 months of treatment (using the 
average of 3 morning measurements in 
Weeks 12, 18, and 24, respectively).

Correlation between baseline biomarkers 
and clinical outcome at Week 6.

Correlation between change in baseline 
biomarker at Weeks 6 and 24 and clinical 
outcome.
CCI


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1.2.
Trial Design
This is a multicenter, randomized, double-blind, active-controlled, parallel-group, flexible-dose, 
6-month study in adult subjects with MDD who have an inadequate response to current 
antidepressant therapy with an SSRI/SNRI.
The study will consist of 3 phases: an up to 4-week screening phase, a 6-month double-blind 
treatment phase, and a 2-week follow-up phase culminating in a follow-up/end-of-study visit. A 
total of 100 subjects will be randomized in a 1:1 ratio to receive either flexibly dosed 
JNJ-42847922 (20 or 40 mg) or flexibly dosed quetiapine XR (150 or 300 mg) as adjunctive 
therapy to their current SSRI or SNRI. Subjects will continue to take their baseline SSRI/SNRI 
antidepressant (at the same dose, without change, every day and at approximately the same time 
as prior to entering the study) throughout the screening, double-blind, and follow-up phases.
A schematic overview of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study Design
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is the time to all-cause discontinuation of study drug.  The null 
hypothesis to be tested to address the primary objective of the study is that there is no difference 
between JNJ-42847922 and quetiapine XR, as adjunctive treatment to an SSRI/SNRI, in the time 
to all-cause discontinuation of study drug, based on the primary efficacy endpoint.
1.4.
Sample Size Justification
The primary purpose of the study is to investigate potential differentiating features between 
JNJ-42847922 and quetiapine XR. Although the sample size was not chosen based on a specific 


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set of endpoints, for evaluating the time to discontinuation of study drug in the JNJ-42847922 
group versus the quetiapine XR group, a one-sided log-rank test with an overall sample size of 
100 subjects (50 in the JNJ-42847922 group and 50 in the quetiapine XR group) provides 
approximately 92% power at a 1-sided 0.10 significance level to detect a hazard ratio of 0.415, 
assuming the proportion of subjects who discontinue from study drug in the quetiapine XR group 
is 50%. The planned sample size of the study is consistent with the nature of a Phase 2 
exploratory study.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups (JNJ-42847922 or quetiapine XR) based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. 
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
insomnia status (significant insomnia symptoms [ISI score ≥15] at baseline versus no significant 
insomnia symptoms [ISI score <15] at baseline). 
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.
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.
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).


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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 agent in the double-blind treatment phase.  The screening phase 
end date is left missing for those subjects who did not receive study agent.
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.
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 agent 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 endpoints. 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.
Table 1 – Visit Windows


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Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
MADRS, Vital 
Signs, C-SSRS
Screening
1
Screening
<1
-28 to -1
DB
2
Baseline
≤1
1
4
Week 2
2 to 21
14
5
Week 4
22 to 35
28
6
Week 6
36 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
Follow-up
10
Follow-up
End of DB + 1 to 
end of FU
182
CGI-S,
PGI-S
DB
2
Baseline
≤1
1
4
Week 2
2 to 21
14
5
Week 4
22 to 35
28
6
Week 6
36 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
Follow-up
10
Follow-up
End of DB + 1 to 
end of FU
182
HAM-A
DB
2
Baseline
≤1
1
6
Week 6
2 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
Follow-up
10
Follow-up
End of DB + 1 to 
end of FU
182
SDMT, 
TMT-Part B, 
HVLT-R
DB
2
Baseline
≤1
1
6
Week 6
2 to 63
42
7
Week 12
64 to 126
84
9
Week 24
127 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
QLDS, SMDDS
DB
2
Baseline
≤1
1
4
Week 2
2 to 21
14
5
Week 4
22 to 35
28
6
Week 6
36 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
PROMIS-SD, 
PROMIS-SRI
DB
2
Baseline
≤1
1
4
Week 2
2 to 28
14
6
Week 6
29 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
CSD-M
DB
Prior to Visit 2
Average Predose
≤1
-2, -1, 1
Prior to Visit 6
Week 6 
(Average)
2 to 63
40, 41, 42


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Parameter 
Analysis
Phase
Scheduled 
Visit
Number
Time Interval
(label on output)
Time Interval
(Day)*
Target Time 
Point 
(Day/Time)
Prior to Visit 7
Week 12 
(Average)
64 to 105
82, 83, 84
Prior to Visit 8
Week 18 
(Average)
106 to 147
124, 125, 126
Prior to Visit 9
Week 24 
(Average)
148 to end of DB
166, 167, 168
DB last visit
End point (DB)
2 to end of DB
HRUQ
DB
2
Baseline
≤1
1
6
Week 6
2 to 63
42
7
Week 12
64 to 105
84
8
Week 18
106 to 147
126
9
Week 24
148 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
Follow-up
10
Follow-up
End of DB + 1 to 
end of FU
182
Physical Exam
Screening
1
Screening
<1
-28 to -1
DB
1
Baseline
≤1
-28 to -1
9
Week 24
2 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
ISI
Screening
1
Screening
<1
-28 to -1
DB
2
Baseline
≤1
1
Serum 
Chemistry, 
Urinalysis, 
Hematology, 
Lipid Panel, 
Weight, BMI, 
Waist 
Circumference
Screening
1
Screening
<1
-28 to -1
DB
2
Baseline
≤1
1
6
Week 6
2 to 63
42
7
Week 12
64 to 126
84
9
Week 24
127 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
HbA1c, TSH, 
FT4
Screening
1
Screening
<1
-28 to -1
DB
1
Baseline
≤1
-28 to -1
7
Week 12
2 to 126
84
9
Week 24
127 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
ECG
DB
1
Screening
<1
-28 to -1
1, 2
Predose
≤1
-28 to 1
1, 2
Average Predose
≤1
1
6
Week 6
2 to 105
42
9
Week 24
106 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
ASEX
DB
2
Baseline
≤1
1
7
Week 12
2 to 126
84
9
Week 24
127 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
ESRS-A
DB
4
Week 2
2 to 21
14
5
Week 4
22 to 35
28
6
Week 6
36 to 63
42
7
Week 12
64 to 126
84
9
Week 24
127 to end of DB
168
DB last visit
End point (DB)
2 to end of DB
PWCa
DB
10
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
10
Follow-up
End of DB + 1 to 
end of FU
182
*Relative to Study Day 1; DB=double-blind; FU=follow-up
a PWC was collected at one timepoint. For subjects who discontinued the study, PWC was 
collected at time of withdrawal.  Otherwise, it was collected at the follow-up visit.
2.4.
Pooling Algorithm for Analysis Centers
Subjects will be enrolled at sites in the United States (US).  Actual site enrollment rates will be 
monitored to avoid gross imbalances across centers.  Sites will not be pooled for analyses.
2.5.
Analysis Sets
Subjects will be classified into the following analysis sets: all randomized, full analysis set, and 
safety analysis set.
2.5.1.
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 study agent was received. 
2.5.2.
Efficacy Analysis Set
2.5.2.1.
Full Analysis Set
The full analysis set includes all randomized subjects who received at least 1 dose of study agent
except subjects who received potentially defective investigational products (IP) and were
subsequently discontinued early because of the IP issue.
2.5.3.
Safety Analysis Set
The safety analysis set includes all randomized subjects who received at least 1 dose of study 
agent.
2.6.
Definition of Subgroups
Subgroup
Definition
Baseline ISI score
≥15
<15
using the randomization stratification factor as entered into IWRS; 
this will also be used in the analyses as the baseline insomnia 
status
Baseline MADRS total score
≤ median
> median
MDD subtype based on SCID-CT
With anxious distress 
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)
Sex
Male


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Subgroup
Definition
Female
Undifferentiated
Age Group
18-34
35-54
55-64
65-70
Sex and Age Group

Adults (18-64) male, Elderly (≥65) male, Adults (18-64) 
female, Elderly (≥65) female
MDD with Anxiety based on HAMA-A
Yes, defined as baseline HAM-A total score ≥18
No, defined as baseline HAM-A total score <18
Class of antidepressant study medication
SNRI
SSRI
Final dose
Seltorexant 20mg
Seltorexant 40mg
Quetiapine XR 150mg
Quetiapine XR 300mg
Number of antidepressants of sufficient dose 
and with inadequate response taken for at least 
4 weeks during the current episode 
1
2 or more
based on the Massachusetts General Hospital-Antidepressant 
Treatment Response Questionnaire (MGH-ATRQ)
Number of major depressive episodes in 
lifetime, including current episode
≤3
>3
Prior medication use of adjunctive 
antipsychotics
Yes
No
Prior medication use of benzodiazepines
Yes
No
Baseline body mass index (BMI)
underweight <18.5 kg/m2
normal 18.5-<25 kg/m2
overweight 25-<30 kg/m2
obese ≥30 kg/m2
Race
categories as collected on eCRF
Ethnicity
categories as collected on eCRF
2.7.
Study Day and Relative Day
Study Day 1 or Day 1 refers to the start of the first study agent administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

Visit date - (date of Study Day 1) +1, if visit date is ≥date of Day 1

Visit date - Date of Day 1, if visit date <date of Day 1
There is no ‘Day 0’.
2.8.
Baseline and End point (DB)
Baseline is defined as the last observation prior to the start of the first study agent administration, 
with the exception of the average predose ECG measurement and the average predose CSD-M 
measurement, which is defined as the average of all predose ECG results collected up to and 


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including the day of the first dose of study agent and the average of all predose CSD-M 
measurements collected up to and including the day of the first dose of study agent, respectively.
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 
value if the unscheduled visit result is the last postbaseline result available within the double-
blind phase.
2.9.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
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:

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 agent start

The day of study agent start, if the month/year of the onset of AE is the same as 
month/year of the study agent start date and month/year of the AE resolution date is 
later

The day of study agent start or day of AE resolution date, whichever is earliest, if 
month/year of the onset of AE and month/year of the study agent start date and 
month/year of the AE resolution date are same.

If the onset date of an AE is missing both day and month, it will be set to the earliest of:

January 1 of the year of onset, as long as this date is on or after the study agent start 
date

Month and day of the study agent start date, if this date is the same year that the AE 
occurred

Last day of the year if the year of the AE onset is prior to the year of the study agent 
start date

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an AE is missing day only, it will be set to the earliest of the last day 
of the month of occurrence of resolution or the day of the date of death, if death occurred in 
that month.

If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of the year or the day and month of the date of death, if 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:

A missing time of onset of an AE will be set to:


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
00:01 as long as the onset date is different from the study agent start date

The time of the study agent start if this is the same day the AE occurred.

The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing 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 
agent. Medications will be classified as prior if the medication start date is complete and prior to 
the date of first dose of study agent or the medication end date is complete and prior to the date 
of first dose of study agent.
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 agent 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 agent 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 agent 
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 agent 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.
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 


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date is on or after the first dose of study agent. 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 agent administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent 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 agent administration, or

The stop date month and year (day is missing) of the medication is on or after the initial 
study agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent administration 
then the medication is classified as concomitant during the double-blind phase.
If the medication start date is completely missing then if: 

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 agent administration, or


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
The stop date month and year (day is missing) of the medication is on or after the initial 
study agent administration, or

The stop date year (day and month are missing) of the medication is on or after the initial 
study agent 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 concomitant medications are those that started after the analysis reference end date of 
the double-blind phase.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
There is no planned interim analysis for this study.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group
and overall. In addition, the distribution of subjects by site ID will be presented for the full
analysis set.


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4.1.
Demographics and Baseline Characteristics
Table 2 presents a list of the demographic variables that will be summarized by treatment group 
and overall for the full analysis set.  
Table 2: Demographic Variables
Continuous Variables:
Summary Type
Age (years), calculated based on date of informed consent
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Weight (kg)
Height (cm)
Body Mass Index (BMI) (kg/m2) calculated as Weight (kg)/[Height (m)]2
Waist circumference (cm)
Categorical Variables
Age (18-34 years, 35-54 years, 55-64 years, 65-70 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Not 
Reported, Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI (underweight <18.5 kg/m2, normal 18.5-<25 kg/m2, overweight 25-
<30 kg/m2, obese ≥30 kg/m2)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'.
Table 3 presents a list of the psychiatric history variables that will be summarized by treatment 
group and overall for the full analysis set.  
Table 3: Psychiatric History Variables
Continuous Variables:
Summary Type
Age (years) when diagnosed with MDD
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum]).
Duration (weeks) of current depressive episode
Baseline MADRS total score
Baseline CGI-S score
Baseline PGI-S score
Baseline ISI score per eDC
Categorical Variables
Current antidepressant type (SSRI, SNRI)
Frequency distribution with the 
number and percentage of subjects 
in each category.
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)
MDD with Anxiety based on HAMA-A (Yes=defined as baseline HAM-A 
total score ≥18, No=defined as baseline HAM-A total score <18)
Prior medication use of adjunctive antipsychotics (Yes, No)
Prior medication use of benzodiazepines (Yes, No)
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)
Baseline PGI-S score (1=none, 2=mild, 3=moderate, 4=severe)
Baseline ISI score per IWRS (≥15, <15)


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Baseline ISI score per eDC (≥15, <15) (if different from IWRS)
Number of major depressive episodes (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 general medical 
history, psychiatric history and tobacco use history will be provided.
4.2.
Disposition Information
The number of screen failures will be summarized overall.
The number of subjects in the following disposition categories will be summarized throughout 
the study by treatment group and overall:

Subjects randomized

Subjects receiving study agent

Subjects who completed 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
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 agent.
These summaries and listings will be provided for the all randomized analysis set.
4.3.
Treatment Compliance
4.3.1.
Treatment Compliance With Study Agent
Study agent compliance will be summarized descriptively. 


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Compliance for each subject will be calculated based on the percent of the scheduled number of 
capsules of study agent actually taken within the double-blind phase. Study agent compliance 
will be calculated as follows:
Study agent compliance (%) = (actual number of capsules taken/total number of capsules
supposed to be taken) x100.
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 agent – date of first dose of study agent 
+ 1) multiplied by 2 (since each “dose” of study agent 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 with baseline SSRI/SNRI antidepressant will be summarized descriptively.
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 with baseline SSRI/SNRI (%) = (number of days baseline SSRI/SNRI 
antidepressant taken / number of days in double-blind phase)*100.
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 
agent – date of first dose of study agent) + 1.  Number of doses is defined as the total number of 
dose 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.  


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The mode daily dose will be calculated for each subject, based on days on drug. The lowest 
mode dose is selected in case of ties. The frequency of mode daily dose will be presented by 
treatment group. 
The mean daily dose of study agent for a subject is calculated as the sum of total daily dose 
during the treatment phase divided by the total number of days exposed.  The final dose is the 
last non-zero dose received during the double-blind phase. The calculation of mean daily dose 
and final dose will exclude days off study drug. Descriptive statistics (N, mean, SD, median, 
minimum and maximum) for mean daily dose and final dose will be presented by treatment 
group.
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 study. 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 using the 
full 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 agent. Concomitant medications are defined as any therapy 
used on or after the same day as the first dose of study agent, including those that started before 
and continue after the first dose of study agent.
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 


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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 standardized medication name 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
Time to all-cause 
discontinuation of 
study drug

Time to all-cause discontinuation of study 
drug
Primary
MADRS

Change from baseline to Weeks 2, 4, 6, 12, 
18, and 24 in the MADRS total score
Secondary

The proportion of subjects achieving (at Week 
12) and sustaining remission at Weeks 18 and 
24. Remission is defined as MADRS total 
score ≤12.
Secondary

The proportion of subjects achieving (at Week 
12) and sustaining response at Weeks 18 and 
24. Response is defined as ≥50% 
improvement from baseline MADRS total 
score.
Secondary


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Efficacy Variable
Endpoint

Change from baseline to Weeks 12, 18, and 
24 in the MADRS total score in subjects with 
baseline ISI score >15 versus subjects with 
baseline ISI score <15
Secondary

Change from baseline to Weeks 2, 4, 6, 12, 
18, and 24 in the MADRS-6 total score
Secondary

Change from baseline to Weeks 2, 4, 6, 12, 
18, and 24 in the MADRS-WOSI total score
Exploratory
HAM-A

Change from baseline to Weeks 6, 12, 18, and 
24 in the HAM-A total score
Secondary
CGI-S

Change from baseline to Weeks 2, 4, 6, 12, 18
and 24
Secondary
PGI-S

Change from baseline to Weeks 2, 3, 6, 12, 18
and 24
Secondary
QLDS

Change from baseline to Weeks 2, 4, 6, 12, 18
and 24
Secondary
PROMIS-SD

Change from baseline to Weeks 2, 6, 12, 18
and 24
Secondary
PROMIS-SRI

Change from baseline to Weeks 2, 6, 12, 18
and 24
Secondary
SMDDS

Change from baseline to Weeks 2, 4, 6, 12, 18
and 24
Secondary
SDMT

Change from baseline to Weeks 6, 12, and 24
Secondary
TMT-Part B

Change from baseline to Weeks 6, 12, and 24
Secondary
HVLT-R

Change from baseline to Weeks 6, 12, and 24
Secondary
CSD-M

Change from baseline in subjective sleep 
parameters after the first 6 weeks of treatment
Exploratory

Change from baseline in subjective sleep 
parameters after 3 to 6 months of treatment
(using the average of up to 7 morning 
measurements in Weeks 12, 18, and 24, 
respectively)
Exploratory
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary efficacy endpoint will be evaluated at a two-sided significance level of 0.20. For all 
other efficacy endpoints, no multiplicity adjustment will be done and point estimates and 
confidence intervals will be presented.


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5.1.2.
Data Handling Rules
As sensitivity analyses, the change in MADRS total score and HAM-A 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 5.3.1.2 and 5.3.4.2.
For the analyses of remission of depressive symptoms based on MADRS total score (Section 
5.3.2) and response of depressive symptoms based on MADRS total score (Section 5.3.3), 
subjects with missing values will be imputed as non-responders/non-remitters.   
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 Week 24 for 
MADRS total score (Section 5.3.3.2), both observed and LOCF data will be presented.
5.1.3.
Imputation Methods for Missing Items
For MADRS, imputation of the total score when there are missing items is described in Section 
5.3.1.1.  Likewise, for PROMIS-SD and PROMIS-SRI, imputation of the total score when there 
are missing items is described in Sections 5.3.8.1 and 5.3.9.1, respectively.  For QLDS, 
imputation of the total score when there are missing items is described in Section 5.3.7.1. 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, time to all-cause discontinuation of study drug, is defined as the 
number of days from the first dose of study drug to the last dose of study drug. Subjects who 
complete double-blind treatment are not considered to have discontinued.
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:
Population: subjects with 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: time to all-cause discontinuation of study drug (see Section 5.2.1);
Intervention Effect: the effect of the initially randomized treatment together with the oral 
SSRI/SNRI antidepressant;
Summary Measure: the difference in survival distributions.
The primary analysis will be based on the full analysis set.


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5.2.3.
Analysis Methods
The primary efficacy endpoint, time to all-cause discontinuation of study drug, will be estimated 
by the Kaplan-Meier method and summarized (number of discontinuations, number of censored 
subjects, median, 25th and 75th percentile, if estimable) by treatment group.
A stratified log-rank test (stratified for baseline insomnia status) will be used to test the 
hypothesis that there is no difference between the JNJ-42847922 group and quetiapine XR in the 
probability of discontinuing study drug, using a two-sided 0.20 significance level.
As a sensitivity analysis, similar to the stratified log-rank test above, a log-rank test without 
adjusting for stratification factor will be carried out.
As an additional sensitivity analysis, the log-rank analysis may be repeated excluding 
 
 site due to possible GCP issues.
The estimate of the hazard ratio and its 80% confidence interval will be provided based on the 
Cox proportional hazards model with treatment and baseline insomnia status as the factors.  In 
addition, a similar model with treatment as the only factor will be carried out.
The distribution of the time to discontinuation of study agent will be displayed with Kaplan-
Meier curves, for the full analysis set. Subjects who discontinued the double-blind phase at any 
time due to any reason will be considered an ‘Event’ and their date of last dose of study agent 
based on the exposure dataset will be used in the time to event calculation. Subjects who 
complete the double-blind phase will be censored and the date of last dose of study agent based 
on the exposure dataset will serve as the time of censoring.  Kaplan-Meier curves will also be 
produced for the Week 12 timepoint (Day 84).  Subjects who do not experience an event prior 
Week 12 will be censored at day 84.
In addition to time to all-cause discontinuation, the stratified log-rank analysis described above 
will be repeated for time to treatment-related discontinuation. Examples of potentially non-
treatment related discontinuations include subjects relocating or traveling out of the area and 
unable to return for study visits.
5.2.3.1.
Subgroup Analyses
Descriptive statistics (number of discontinuations, number of censored subjects, median, 25th 
and 75th percentile, if estimable) will be provided for the primary efficacy endpoint (time to all-
cause discontinuation of study drug) by the subgroups identified in Section 2.6.  Subgroup 
analysis will be performed using the Cox proportional hazards model. The model will include 
terms for treatment, subgroup and treatment-by-subgroup. One subgroup at a time will be 
included in the model. A forest plot with the corresponding hazard ratios and 80% CI will be 
presented for the subgroups. If there are insufficient numbers in the subgroups to draw
meaningful conclusions, the subgroup analysis will not be performed. The Kaplan-Meier plots 
will be provided for the subgroups with baseline ISI ≥15 and baseline ISI <15.
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5.3.
Secondary Efficacy Endpoints
5.3.1.
Change in Montgomery-Asberg Depression Rating Scale (MADRS) 
Total Score
5.3.1.1.
Definition
A secondary efficacy endpoint is the change in MADRS total score from baseline to Weeks 12, 
18, and 24.  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, 
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 24 is calculated as (MADRS total score at Week 24
– Baseline MADRS total score).  Change from baseline to other time points is calculated 
similarly.  Negative changes in MADRS total score indicate improvement.
5.3.1.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 4, Week 6, Week 12, Week 
18, Week 24, and at follow-up and the change from baseline to each postbaseline time point 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.    
MMRM
A mixed model for repeated measures (MMRM) analysis of the observed data from the JNJ-
42847922 and quetiapine XR groups will be used to adjust for important covariates. The MMRM 
will include time (scheduled Week), treatment (JNJ-42847922 and quetiapine XR), baseline 
insomnia status (present/absent), and treatment-by-time interaction as factors and baseline 
MADRS total score as a covariate.  Data from the follow-up phase will not be used.  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 each time 
point, but will have less weight in the analysis than those subjects with complete data.  The 


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Kenward-Roger method will be used for approximating the denominator degrees of freedom.  
Based on the MMRM, the comparison between JNJ-42847922 and quetiapine XR will be 
performed using the appropriate contrasts directly from the MMRM analysis, using estimates at 
each postbaseline time point.  A 80% confidence interval (CI) for the difference in least-squares 
(LS) means will be calculated based on the contrast test statistic.
As a secondary analysis, age and gender will be added to the MMRM model.
Means and mean changes from baseline (+/- SE) in MADRS will be presented graphically over 
time. Least squares mean changes from baseline (+/- SE) in MADRS will be presented 
graphically over time.
ANCOVA
As a sensitivity analysis, the change in MADRS total score from baseline to each postbaseline 
time point in the double-blind phase will be analyzed using an ANCOVA model, using LOCF 
and BOCF data.  The ANCOVA model will include factors for treatment, baseline insomnia 
status (present/absent), and baseline MADRS total score as a continuous covariate.  A 80% CI 
for the difference in LS Means will be calculated based on the contrast test statistic.  
The last postbaseline observation during the double-blind phase will be carried forward as the 
“End Point (DB)” for that phase.  Besides the end point assessment, the LOCF values will be 
created for intermediate postbaseline time points as well.  These imputed time points will be 
labeled ‘WEEK X LOCF’.
For example, if a subject has a visit on Day 125 for the Week 18 visit and then a final visit on 
Day 130, the visit on Day 125 will be slotted to “Week 18” and “Week 18 LOCF” because Day 
125 is closer to the target Day 126 than Day 130. The Day 130 visit will be used as “Week 24 
LOCF” and “End Point (DB)”.
For subjects who discontinue treatment early, impute the missing MADRS scores post-
discontinuation as the baseline value, and label as “Week xx BOCF” or “End Point (DB) 
BOCF”.
As a secondary analysis, age and gender will be added to the ANCOVA model.
SUBGROUP ANALYSIS
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 the sum of each individual item and can range from 0 to 28 (28 = most severe insomnia).
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 each 
postbaseline time point in the MADRS total score in subjects with ISI score ≥15 versus subjects 


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with ISI score <15).  Descriptive statistics of the change from baseline to each postbaseline time
point in the MADRS total score will be presented by treatment group for these subgroups.
Mode Dose
Descriptive statistics of the change from baseline to each postbaseline time point in the MADRS 
total score will be presented by treatment group and mode dose as defined in Section 4.4.
5.3.2.
Achieving and Sustaining Remission of Depressive Symptoms
5.3.2.1.
Definition
A secondary efficacy endpoint is the proportion of subjects achieving (at Week 12) and 
sustaining remission at Weeks 18 and 24. Remission is defined as MADRS total score ≤12.  A 
subject must have a MADRS total score ≤12 at all 3 time points (Week 12, Week 18, and Week 
24) to be defined as a sustained remitter.  Subjects who do not meet such criterion will be 
considered as non-sustained remitters. The calculation of the MADRS total score is described in 
Section 5.3.1.1.
5.3.2.2.
Analysis Methods
The number and percentage of subjects who achieve and sustain remission will be summarized 
by treatment group.  In addition, the number and percentage of subjects who have a MADRS 
total score ≤12 at each postbaseline time point will be presented by treatment group.
The point estimate and 2-sided 80% confidence interval will be provided for the relative risk of 
achieving and sustaining remission using a Mantel-Haenszel test controlling for baseline 
insomnia status (present/absent).
5.3.3.
Achieving and Sustaining Response of Depressive Symptoms
5.3.3.1.
Definition
A secondary efficacy endpoint is the proportion of subjects achieving (at Week 12) and 
sustaining response at Weeks 18 and 24. Response is defined as ≥50% improvement from 
baseline MADRS total score.  A subject must have a ≥50% improvement from baseline MADRS 
total score at all 3 time points (Week 12, Week 18, and Week 24) to be defined as a sustained 
responder (yes=1).  Subjects who do not meet such criterion will be considered as non-sustained 
responders and will be assigned a value of 0 (i.e., no).  The calculation of the MADRS total score 
is described in Section 5.3.1.1. The percentage change from baseline for MADRS total score is 
calculated as 100*(MADRS total score at Week X – Baseline MADRS total score)/(Baseline 
MADRS total score). Negative percent changes in MADRS total score indicate improvement 
(e.g., percent change < -50% indicates improvement >50%). 
5.3.3.2.
Analysis Methods
The number and percentage of subjects who achieve and sustain a response will be summarized 
by treatment group.  In addition, the number and percentage of subjects who have a ≥50% 


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improvement from baseline MADRS total score at each postbaseline time point will be presented 
by treatment group.
The point estimate and 2-sided 80% confidence interval will be provided for the relative 
sustained response using a Mantel-Haenszel test controlling for 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 Week 24 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 that is 
maintained through the Week 24 assessment. Subjects who discontinue early are not considered 
to have sustained response.  A stratified log rank test (stratified for baseline insomnia status) will 
be used to test the hypothesis that there is no difference between JNJ-42847922 and quetiapine 
XR in the probability of achieving sustained response. In addition, time to sustained response 
will be summarized by modal dose.
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 Weeks 12, 18, and 24 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 24 is calculated as (HAM-A total score at Week 24
– Baseline HAM-A total score).  Change from baseline to other time points is calculated 
similarly.  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.


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5.3.4.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 6, Week 12, Week 18, Week 24, 
and at follow-up and the change from baseline to each postbaseline time point will be presented 
for HAM-A total score, and HAM-A somatic and psychic factor scores by treatment group.  
The change from baseline in HAM-A total score will be analyzed using the same MMRM as 
described in Section 5.3.1.2 for MADRS total score, 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 each postbaseline 
time point will be analyzed using an ANCOVA model, using LOCF data.  The derivation of the 
LOCF values is described in Section 5.3.1.2.  The ANCOVA model will include factors for 
treatment, baseline insomnia status (present/absent), and baseline HAM-A total score as a 
continuous covariate.  A 80% CI for the difference in LS Means will be calculated based on the 
contrast test statistic.  
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 categories (normal, mild, mild to moderate, moderate to severe, 
severe) from baseline to each time point will be presented by treatment group.
The correlations between HAM-A total score and MADRS total score will be evaluated using 
Pearson and Spearman correlation coefficients at each time point.  These correlations will look at 
the correlations of the change from baseline.  Scatter plots will also be presented.    
5.3.5.
Clinical Global Impression-Severity (CGI-S)
5.3.5.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 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 24 is calculated as (CGI-S score at Week 24 –
Baseline CGI-S score).  Change from baseline to other time points is calculated similarly.  
Negative changes in CGI-S score indicate improvement.


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5.3.5.2.
Analysis Methods
A frequency distribution over time of the CGI-S scores at Baseline, Week 2, Week 4, Week 6, 
Week 12, Week 18, Week 24, and at follow-up 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 each postbaseline time point will be 
performed using an ANCOVA model on the ranks of the change in score with treatment 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, separately, 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.    
5.3.6.
Patient Global Impression-Severity (PGI-S)
5.3.6.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 in the PGI-S 
score.  The PGI-S is a self-report scale to measure severity of illness (0=not depressed, 1=mildly 
depressed, 2=moderately depressed, 3=very depressed, 4=extremely depressed). Considering all 
aspects of depression, subjects will rate their severity on the PGI-S.
The PGI-S change from baseline at Week 24 is calculated as (PGI-S score at Week 24 – Baseline 
PGI-S score).  Change from baseline to other time points is calculated similarly.  Negative 
changes in PGI-S score indicate improvement.
5.3.6.2.
Analysis Methods
A frequency distribution over time of the PGI-S scores at Baseline, Week 2, Week 4, Week 6, 
Week 12, Week 18, Week 24, and at follow-up 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 each postbaseline time point will be 
performed using an ANCOVA model on the ranks of the change in score with treatment and 
baseline insomnia status as factors, and unranked baseline PGI-S score as a covariate.
5.3.7.
Quality of Life in Depression Scale (QLDS)
5.3.7.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 in the QLDS
score.  The QLDS is a disease specific patient-reported outcome (PRO) designed to assess health 
related quality of life in patients with MDD.  The instrument has a recall period of "at the present 
time", contains 34-items with "true"/"not true" response options, and takes approximately 5 to 10 
minutes to complete. 


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Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of 
adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good 
quality of life) to 34 (very poor quality of life).
As the measure contains positive as well as negative items, item scores are not always in the 
same order - that is, not all ‘true’ responses are allocated a score of “1”. The scores for each item 
can be found in Attachment 1.
Imputation of the total score will be performed only when between 1 to 6 items are missing 
responses. If 7 or more items are missing, the total score will be left missing.  The total score will 
be imputed as follows:
 =

34 −
 ×  34
where T is the final total score, x is the item summation score, and m is the number of missing 
items.
5.3.7.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 4, Week 6, Week 12, Week 
18, and Week 24 and the change from baseline to each postbaseline time point will be presented 
for QLDS total score by treatment group.  
The change from baseline in QLDS total score will be analyzed using the same MMRM as 
described in Section 5.3.1.2 for MADRS total score, with the continuous covariate “baseline 
MADRS total score” changed to “baseline QLDS total score”.
Frequency distributions of the QLDS individual items will be provided at each assessment time 
point by treatment group.
5.3.8.
Patient Reported Outcome Measurement Information System-Sleep 
Disturbance (PROMIS-SD)
5.3.8.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 in the PROMIS-
SD.  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.  


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“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 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-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.
5.3.8.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 6, Week 12, Week 18, and 
Week 24 and the change from baseline to each postbaseline time point will be presented for 
PROMIS-SD raw score and the T-score by treatment group.  
The change from baseline to each postbaseline time point in the PROMIS-SD raw score and the 
T-score will be analyzed using the same MMRM as described in Section 5.3.1.2 for MADRS 
total score, 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 by treatment group.


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5.3.9.
Patient Reported Outcome Measurement Information System- Sleep 
Related Impairment (PROMIS-SRI)
5.3.9.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 in the PROMIS-
SRI.  The PROMIS-SRI Short Form subscale consists of a static 8 item questionnaire. The 
PROMIS adult Sleep-Related Impairment item bank focuses on self-reported perceptions of 
alertness, sleepiness, and tiredness during usual waking hours, and the perceived functional 
impairments during wakefulness associated with sleep problems or impaired alertness. Though 
Sleep-Related Impairment does not directly assess cognitive, affective, or performance 
impairment, it does measure waking alertness, sleepiness, and function within the context of 
overall sleep-wake function. The Sleep-Related Impairment short form is universal rather than 
disease-specific. It assesses sleep-related impairment over the past 7 days.
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 related impairment.  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 related impairment and sometimes a response of “not at all” indicates less sleep 
related impairment.  
“I had a hard time getting things done because I was sleepy” ranges from 1=not at all to 
5=very much
“I felt alert when I woke up” ranges from 5=not at all to 1=very much
“I felt tired” ranges from 1=not at all to 5=very much
“I had problems during the day because of poor sleep” ranges from 1=not at all to 5=very 
much
“I had a hard time concentrating because of poor sleep” ranges from 1=not at all to 
5=very much
“I felt irritable because of poor sleep” ranges from 1=not at all to 5=very much
“I was sleepy during the daytime” ranges from 1=not at all to 5=very much
“I had trouble staying awake during the day” ranges from 1=not at all to 5=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:  


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(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 total raw score or pro-rated score can be converted into a T-score for each participant based 
on the table in Attachment 3.  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-SRI score from baseline to each time point in the double-blind phase 
will be calculated, for both the raw score and the T-score.
5.3.9.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 6, Week 12, Week 18, and 
Week 24 and the change from baseline to each postbaseline time point will be presented for 
PROMIS-SRI raw score and the T-score by treatment group.  
The change from baseline to each postbaseline time point in the PROMIS-SRI raw score and the 
T-score will be analyzed using the same MMRM as described in Section 5.3.1.2 for MADRS 
total score, with the covariate “baseline MADRS total score” changed to “baseline PROMIS-SRI 
raw score” or “baseline PROMIS-SRI T-score”, respectively.
Frequency distributions of the PROMIS-SRI individual items will be provided at each 
assessment time point by treatment group.
5.3.10.
Symptoms of Major Depressive Disorder Scale (SMDDS)
5.3.10.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 12 and 24 in the SMDDS.  
The SMDDS assesses patient-reported symptoms associated with MDD. The target population 
includes adults (aged 18 and older) with a clinical diagnosis of MDD who are being treated in an 
ambulatory setting. The SMDDS has been developed in a patient sample including both males 
and females, varying levels of age, race, education, marital status, and severity. This 16-item 
instrument has a 7-day recall period, and subjects respond to each question using a rating scale 
between 0 (“Not at all” or “Never”) to 4 (“Extremely” or “Always”).  Before summing the items 
to create a total score, item 11 (“how often did you have a poor appetite”) and item 12 (“how 
often did you over eat”) are combined into a single score by selecting the highest severity on 
either item.  The total score is then created by summing the responses on the 15 items.  The total 
score ranges from 0 to 60 with a higher score indicating more severe depressive 
symptomatology.
5.3.10.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 4, Week 6, Week 12, Week 
18, and Week 24 and the change from baseline to each postbaseline time point will be presented 
for SMDDS total score by treatment group.  


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The change from baseline in SMDDS total score will be analyzed using the same MMRM as 
described in Section 5.3.1.2 for MADRS total score, with the continuous covariate “baseline 
MADRS total score” changed to “baseline SMDDS total score”.
Frequency distributions of the SMDDS individual items will be provided at each assessment 
time point by treatment group.
5.3.11.
Symbol Digit Modalities Test (SDMT)
5.3.11.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 6, 12, and 24 in the SDMT.  
The SDMT is a widely used, paper-and-pencil assessment of complex scanning and visual 
tracking, requiring elements of attention, visuoperceptual processing, working memory, and 
cognitive/psychomotor speed.
The test is viewed as a robust screening test for adult
neuropsychological impairment and is sensitive to impairments in cognitive function associated 
with MDD. The SDMT measures the time to pair abstract symbols with specific numbers. The 
test includes a coding key consisting of 9 abstract symbols, each paired with a number ranging 
from 1 to 9. Following the key, the subject is presented with randomly ordered symbols and is 
required to write the number corresponding to each symbol as fast as possible. The number of 
correct substitutions within 90 seconds is recorded.
5.3.11.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 6, Week 12, and Week 24 and the 
change from baseline to each postbaseline time point will be presented for SDMT score by 
treatment group.  
The change from baseline in SDMT score will be analyzed using the same MMRM as described 
in Section 5.3.1.2 for MADRS total score, with the continuous covariate “baseline MADRS total 
score” changed to “baseline SDMT score”.
5.3.12.
Trail Making Test – Part B (TMT–Part B)
5.3.12.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 6, 12, and 24 in the TMT-
Part B.  The TMT-Part B measures divided attention and executive function (tracking and 
sequencing). The subject is instructed to draw a line to connect a set of 25 consecutively 
numbered and lettered circles, alternating sequentially between numbers and letters (i.e., 1 A 2 
B). The subject is instructed to work as quickly as possible while still maintaining accuracy. The 
TMT-Part B is sensitive to cognitive decline associated with MDD.
5.3.12.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 6, Week 12, and Week 24 and the 
change from baseline to each postbaseline time point will be presented for TMT-Part B score by 
treatment group.  


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The change from baseline in TMT-Part B score will be analyzed using the same MMRM as 
described in Section 5.3.1.2 for MADRS total score, with the continuous covariate “baseline 
MADRS total score” changed to “baseline TMT-Part B score”.
5.3.13.
Hopkins Verbal Learning Test-Revised (HVLT-R)
5.3.13.1.
Definition
A secondary efficacy endpoint is the change from baseline to Weeks 6, 12, and 24 in the 
HVLT-R.  The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall 
test. Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word 
recognition list (including 12 target and 12 foil words). The test administrator reads instructions 
and word lists aloud, and records words recalled/recognized by the subject. Scores include 
learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used 
measure of verbal episodic memory.
5.3.13.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 6, Week 12, and Week 24 and the 
change from baseline to each postbaseline time point will be presented by treatment group for 
the following: total recall (sum of total correct responses for Trials 1, 2, and 3), delayed recall 
(number of correct responses for Trial 4), total number of true-positive errors, and recognition 
discrimination index (total number of true positives minus total number of false positives).
5.3.14.
MADRS-6
5.3.14.1.
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 24 is calculated as (MADRS-6 total score at 
Week 24 – Baseline MADRS-6 total score).  Negative changes in MADRS-6 total score indicate 
improvement.
5.3.14.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 4, Week 6, Week 12, Week 
18, Week 24 and at follow-up and the change from baseline to each postbaseline time point will 
be presented for MADRS-6 total score by treatment group.  


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The change from baseline over time in MADRS-6 total score will be analyzed using the same 
MMRM as described in Section 5.3.1.2, 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 each postbaseline 
time point will be analyzed using an ANCOVA model, using LOCF data.  The derivation of the 
LOCF values is described in Section 5.3.1.2.  The ANCOVA model will include factors for 
treatment, baseline insomnia status (present/absent), and baseline MADRS-6 total score as a 
continuous covariate.  A 80% CI for the difference in LS Means and p-value will be calculated 
based on the contrast test statistic.
5.4.
Exploratory Efficacy Endpoints
5.4.1.
Consensus Sleep Diary – Morning Administration (CSD-M)
5.4.1.1.
Definition
An exploratory efficacy endpoint is the change from baseline in subjective sleep parameters as 
measured by the CSD-M after the first 6 weeks of treatment and after 3 to 6 months of treatment.  
Subjects will be asked to provide answers to questions to determine their subjective experience 
of sleep by recording their answers in a daily sleep diary (CSD-M). The CSD-M is the only sleep 
diary developed with rigorous methodology for patient reported outcome development, including 
employing user/focus group feedback and expert feedback to establish construct validity. It has 
undergone psychometric testing and its content validity has been confirmed by patient focus 
groups. The parameters recorded include:

self-reported sleep onset latency (sSOL) 

subjective Total Sleep Time (sTST) 

subjective Wake After Sleep Onset (sWASO) 

subjective number of nighttime awakenings (s-nNAW) 

subjective quality of sleep (sQUAL)  

subjective refreshed feeling on waking (sFRESH)
Subjects will complete the CSD-M at home after their normal morning routine and preferably 
within an hour of waking for the day.  The CSD-M will be completed for 3 mornings leading up 
to and including the targeted study visit on Study Day 1, Week 6, Week 12, Week 18, and Week 
24.  
The definitions and computations for deriving the subjective sleep parameters of sSOL, sWASO, 
sTST, and s-nNAW are shown in Table 5.


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Table 5:
Calculation of Subjective Sleep Parameters
Parameter
Definition
Computation
sSOL 
(minutes)
How many minutes it takes to fall asleep, 
starting from the moment of intention to fall 
asleep
Derived from CSD-M, Question 3: “How long did it 
take you to fall asleep?” with the following 
instructions: “Beginning at the time you wrote in 
question 2 (i.e., ‘What time did you try to go to 
sleep?’), how long did it take you to fall asleep.”
sWASO 
(minutes)
Total amount of time awake during the 
night, excluding sSOL (how many minutes 
it takes to fall asleep) and amount of awake 
time between the final awakening and the 
time of getting out of bed
Derived from CSD-M, Question 5: “In total, how long 
did these awakenings last?” with the following 
instructions: “What was the total time you were awake 
between the time you first fell asleep and your final 
awakening.”
sTST 
(minutes)
Actual time slept
Derived from CSD-M, Question 8: “In total, how long 
did you sleep?” with the following instructions: “This 
should just be your best estimate, based on when you 
went to bed and woke up, how long it took you to fall 
asleep, and how long you were awake. You do not 
need to calculate this by adding and subtracting; just 
give your best estimate.”
s-nNAW 
(number of 
times)
Number of awakenings, excluding the final 
awakening before the final arising
Derived from CSD-M, Question 4: “How many times 
did you wake up, not counting your final awakening?” 
with the following instructions: “How many times did 
you wake up between the time you first fell asleep and 
your final awakening?”
Source: Buysse et al, 2006.[1] 
For sSOL, sTST, sWASO, s-nNAW, the average of up to 7 morning measurements will be used 
as the measurement for that time point. If only one measurement is provided, it will be used as 
the average.
The parameter sQUAL is derived from CSD-M, Question 9: “How would you rate the quality of 
your sleep?”, with the instructions “Sleep Quality is your sense of whether your sleep was good 
or poor.”  There are 5 possible responses: “Very poor”, “Poor”, “Fair”, “Good”, and “Very 
good”.  
The parameter sFRESH is derived from CSD-M, Question 10: “How rested or refreshed did you 
feel when you woke-up for the day?”, with the instructions “This refers to how you felt after you 
were done sleeping for the night, during the first few minutes that you were awake.”  There are 5 
possible responses: “Not at all rested”, “Slightly rested”, “Somewhat rested”, “Well-rested”, and 
“Very well-rested”.
For sQUAL and sFRESH, in order to create a single “average” response, the categorical 
responses will be mapped to a 0-4 scale and an average will be calculated.  This average will also 
be mapped back to the closest categorical response.  For example, if sQUAL is answered “Very 
poor”, “Poor” and “Good”, these would be mapped to scores of 0, 1, and 3, respectively, and the 
average would be calculated as 1.33.  As this is closest to 1, the average response would be 
“Poor”. 


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5.4.1.2.
Analysis Methods
Descriptive statistics of the actual values on Average predose, Week 6 (Average), Week 12 
(Average), Week 18 (Average), and Week 24 (Average) and the change from Average predose to 
each postbaseline time point will be presented by treatment group for sSOL, sTST, sWASO, and 
s-nNAW.
The change from Average predose for sSOL, sTST, sWASO, s-nNAW, sFRESH and sQUAL
will be analyzed using the same MMRM as described in Section 5.3.1.2 for MADRS total score, 
with the continuous covariate “baseline MADRS total score” changed to the corresponding 
baseline score for sSOL, sTST, sWASO, s-nNAW, sFRESH, and sQUAL respectively.  For 
sFRESH and sQUAL, an additional analysis of the change from average predose to each 
postbaseline time point will be performed using an ANCOVA model on the ranks of the change 
in score with treatment and baseline insomnia status as factors, and unranked average predose 
score as a covariate.
In addition, for sFRESH and sQUAL, a frequency distribution of the average categorical 
response will be provided for Average predose, Week 6 (Average), Week 12 (Average), Week 
18 (Average), and Week 24 (Average).  In addition, the shift in average categorical response 
from Average predose to each of the postbaseline time points will be presented. 
Descriptive statistics of the actual values on Average predose, Week 6 (Average), Week 12 
(Average), Week 18 (Average), and Week 24 (Average) and the change from Average predose to 
each postbaseline time point will be presented by treatment group for average number of naps, 
the average total duration of naps (in minutes), the average number of drinks containing alcohol, 
and the average number of caffeinated drinks.
5.4.2.
MADRS-WOSI
5.4.2.1.
Definition
MADRS-WOSI is defined as the full MADRS with the item Reduced Sleep excluded.  
A total score (0 to 54) is calculated by adding the scores of all 9 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., 9) to the number of non-missing items 
(i.e., 8).
The MADRS-WOSI change from baseline at Week 24 is calculated as (MADRS-WOSI total 
score at Week 24 – Baseline MADRS-WOSI total score).  Negative changes in MADRS-WOSI
total score indicate improvement.


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5.4.2.2.
Analysis Methods
Descriptive statistics of the actual values on Baseline, Week 2, Week 4, Week 6, Week 12, Week 
18, Week 24 and at follow-up and the change from baseline to each postbaseline time point will 
be presented for MADRS-WOSI total score by treatment group.  
The change from baseline over time in MADRS- WOSI total score will be analyzed using the 
same MMRM as described in Section 5.3.1.2, with the continuous covariate “baseline MADRS 
total score” changed to “baseline MADRS- WOSI total score”.
6.
SAFETY
All safety analyses will be based on the safety analysis set based on actual treatment received, 
unless otherwise specified.
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 agent 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 agent, and 
either AE time or time of administration are missing, then the AE will be assumed to be 
treatment-emergent. If the event date is recorded as partial or completely missing, then the event 
will be considered to be treatment-emergent unless it is known to be prior to the first 
administration of study agent 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 (and 
overall). 
Summary tables will be provided for:

TEAEs

TEAEs occurring in ≥5% of subjects in either treatment group

Treatment-emergent serious AEs (SAEs)

TEAEs leading to discontinuation of study agent

TEAEs by severity

TEAEs by most recent treatment dose

AEs by relationship to study agent

AEs leading to dose interruption (overall and by most recent treatment dose)

AEs leading to dose modification (increase or decrease)


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For the summaries of TEAEs by severity/relationship to study drug, the observation with the 
most severe occurrence/closest relationship to study agent 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

Had AEs leading to discontinuation of study agent

Had somnolence-related TEAEs

Had suicide-related TEAEs

Had TEAEs of special interest 
6.2.
Clinical Laboratory Tests
Descriptive statistics will be presented for thyroid-stimulating hormone (TSH) and free thyroxine 
(FT4), as well as 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, urinalysis (pH and specific gravity), TSH, and FT4 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 4.  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 4. 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.


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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
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), 
AST > 3*ULN, or total bilirubin >2*ULN will be presented for the double-blind phase. 
Additionally, incidence of treatment-emergent hepatic toxicity (suspected Hy’s Law4 cases)
defined as (ALT values >3*ULN or AST values > 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.


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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 (DB) and 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.
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 6, 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 6: Clinically Important Abnormalities in Vital Signs
Vital Sign Parameter Postbaseline value outside of normal limit if:


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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 7). The number and percentage of 
subjects who experience treatment-emergent orthostatic hypotension outside of predefined 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.
Table 7:
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 blood pressure (mm Hg) (SBP)
< -20 mm Hg
(2b)  Diastolic blood pressure (mm Hg) (DBP)
< -10 mm Hg
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, Week 6, and 


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Week 24.  The ECGs will be read by a central reader.  The ECG parameters 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)1/2
Fridericia’s formula: QTcF (msec) = QT (msec) * (HR(bpm)/60)1/3
Descriptive statistics for observed values and changes from average predose will be presented by 
treatment group for the above ECG parameters 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 Table 8. 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 h igh).  The number and percentage of subjects with treatment-emergent ECG 
values outside the pre-defined normal limits defined below will be presented by treatment group.  
Table 8: 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, ≤470 msec for female)

QTc (>450 to ≤480 msec for male, >470 to ≤480 msec for female)

QTc (>480 to ≤500 msec)


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
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 
QTc intervals >470 for female, and QTc interval changes >30 msec will also be provided.
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 (only applicable for post baseline)
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.


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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.
6.5.2.
Arizona Sexual Experiences Scale (ASEX)
Effect on sexual functioning will be assessed using the ASEX at Baseline, Week 12, and Week 
24. 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.
6.5.3.
Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A)
The ESRS-A is an abbreviated manualized version of the ESRS, a semi-structured interview that 
rates parkinsonian symptoms, dystonia, dyskinesias, and akathisia over the previous 7 days. The 
ratings include a motor examination for rigidity, tremor, reduced facial expression or speech, 
impaired gait/posture, postural instability, and bradykinesia/hypokinesia. Twenty-four individual 
items are rated on a 6-point scale: 0=Absent, 1=Minimal, 2=Mild, 3=Moderate, 4=Severe, or 
5=Extreme. Frequency is included as an index of severity. Symptoms are divided into the 4 
corresponding subscales and each subscale is summarized in a Clinical Global Impression of 
Movement Severity (CGI-MS) score.


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For each of the 24 individual items, as well as for the 4 subscales, a frequency distribution will 
be provided by treatment group at each time point.  
6.5.4.
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 
at the end of study or 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 for 
subjects with assessments at the time of discontinuation, and for subjects with assessments at the 
follow-up visit.  
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.
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 analysis are provided in a separate document.
9.
HEALTH ECONOMICS
9.1.
Healthcare Resource Use Questionnaire (HRUQ)
Medical resource utilization data, associated with medical encounters, will be collected using the 
HRUQ during the double-blind and follow-up phases of the study. 
The number and percentage of subjects who had at least one outpatient visit to a healthcare 
professional, related to their depression, in the period since the most recent assessment preceding 
each time point, will be summarized for each type of healthcare professional and for any 
healthcare professional by time point.  
The number and percentage of subjects who had at least one emergency room visit without 
hospitalization, related to their depression, in the period since the most recent assessment 
preceding each time point, will be summarized by time point.  
The number and percentage of subjects who had at least one day hospital or partial hospital visit
(no overnight stay), related to their depression, in the period since the most recent assessment 
preceding each time point, will be summarized by time point.  


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The number and percentage of subjects who had at least one hospitalization (minimum one 
overnight stay), related to their depression, in the period since the most recent assessment 
preceding each time point, will be summarized by time point.  
The total number of outpatient visits to each type of healthcare professional, related to 
depression, and the total number of outpatient visits to any healthcare professional, related to 
depression, in the period since the most recent assessment preceding each time point, will be 
summarized with descriptive statistics at each time point.
Likewise, the total number of emergency room visits without hospitalization, related to 
depression, the total number of day hospital or partial hospital visits (no overnight stay), related 
to depression, and the total number of hospitalizations (minimum one overnight stay), related to 
depression, will be summarized with descriptive statistics at each time point.
All 
summaries 
will 
be 
presented 
by 
treatment 
group.


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REFERENCES
1.
Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, Morin CM. Recommendations for a standard research
assessment of insomnia. Sleep; 2006; 29(9):1155-1173.
2.
Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. Psychological Methods; 2010;
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; 1985; 28:412–419.
4.
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 SCORING OF QLDS ITEMS
I just want time to pass
True
1
Not true
0
I feel hopeful about the future
True
0
Not true
1
I find it hard to hold a conversation
True
1
Not true
0
I like to know what is going on in the world
True
0
Not true
1
I feel as if my life is wasting away
True
1
Not true
0
I feel as if I am not in control of my life
True
1
Not true
0
I am reluctant to leave the house
True
1
Not true
0
On the whole, I enjoy the things I do
True
0
Not true
1
I have lost all pleasure in life
True
1
Not true
0
I feel as if I have nothing to offer anyone
True
1
Not true
0
I turn away from people I care about
True
1
Not true
0
I take good care of myself
True
0
Not true
1
I am able to think about the future
True
0
Not true
1
I just want to hide away
True
1
Not true
0
I look forward to things
True
0
Not true
1
I’ve forgotten what it’s like to enjoy myself
True
1
Not true
0


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I can’t be bothered with my friends
True
1
Not true
0
I can cope easily with everyday tasks
True
0
Not true
1
I cut myself off from other people
True
1
Not true
0
It is difficult for me to make even simple decisions
True
1
Not true
0
I feel as if I am a burden to people
True
1
Not true
0
Most of the time I just sit and stare into space
True
1
Not true
0
I can’t face anyone
True
1
Not true
0
I shut everything out
True
1
Not true
0
I’m neglecting my appearance
True
1
Not true
0
I can see the funny side of things
True
0
Not true
1
I don’t take in what people say to me
True
1
Not true
0
I feel as if I’m letting everyone down
True
1
Not true
0
I dread each coming day
True
1
Not true
0
I enjoy my food
True
0
Not true
1
I avoid people if I can
True
1
Not true
0
I am reluctant to answer the door or the telephone
True
1
Not true
0
My life has no meaning
True
1
Not true
0
I am able to cope with everyday problems
True
0
Not true
1


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ATTACHMENT 2 CONVERSION OF RAW SCORE TO T-SCORE FOR PROMIS-SD


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ATTACHMENT 3 CONVERSION OF RAW SCORE TO T-SCORE FOR PROMIS-SRI


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ATTACHMENT 4 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.