Clinical trial NCT04080752
Conditions: Major Depressive Disorder With Anxious Distress
Sponsor: Janssen Research & Development, LLC
Start date: 2019-09-17; Completion date: 2021-09-02
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive placebo, as assessed by the change from baseline to week 6 on a 17-item Hamilton Depression Rating Scale (HDRS-17) in participants with major depressive disorder (MDD) with anxious distress with a score greater than or equal to (\>=) 2 on item 26 or 27 of the Inventory of Depressive Symptomatology, Clinician Rating -30 (IDS-C30), who have a suboptimal response to current treatment with a standard antidepressant.

Detailed description:

Arms: arm 1: Participants will receive JNJ-61393215 135 mg (3\*45 mg capsules) orally once daily for 6 weeks along with the prescribed standard oral antidepressants (without dose change) throughout the study. arm 2: Participants will receive matching placebo for 6 weeks along with the prescribed standard oral antidepressants (without dose change) throughout the study.
Interventions: intervention 1: JNJ-61393215 intervention 2: Placebo
Intervention descriptions: intervention 1: JNJ-61393215 will be administrated orally. intervention 2: Matching placebo will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 30 Sep 2021
Janssen Research & Development
Clinical Protocol
Double-Blind, Placebo-Controlled, Multi-Center Study Investigating the Efficacy, Safety, 
and Tolerability of JNJ-61393215 as Adjunctive Treatment in Adults with Major 
Depressive Disorder with Anxious Distress with Suboptimal Response to Standard 
Antidepressants.
Short Title:
A study to explore the efficacy JNJ-61393215 in the treatment of depression.
Protocol 61393215MDD2001; Phase 2a
AMENDMENT 4
JNJ-61393215  orexin-1
*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 Pharmaceutica NV; 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
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s):
IND: 135469     
EudraCT NUMBER:         2019-001683-29
Status:
Approved
Date:
30 Sep 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-185788878; 5.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 5
1.
PROTOCOL SUMMARY ................................................................................................................... 10
1.1.
Synopsis......................................................................................................................................... 10
1.2.
Schema .......................................................................................................................................... 20
1.3.
Schedule of Activities (SoA)........................................................................................................... 21
2.
INTRODUCTION................................................................................................................................ 25
2.1.
Study Rationale.............................................................................................................................. 25
2.2.
Background .................................................................................................................................... 26
2.2.1.
Nonclinical Studies ..................................................................................................................... 26
2.2.2.
Clinical Studies ........................................................................................................................... 31
2.3.
Benefit-Risk Assessment ............................................................................................................... 36
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 36
3.1.
Primary........................................................................................................................................... 36
3.2.
Secondary ...................................................................................................................................... 37
3.3.
Exploratory..................................................................................................................................... 37
4.
STUDY DESIGN ................................................................................................................................ 38
4.1.
Overall Design................................................................................................................................ 38
4.2.
Scientific Rationale for Study Design............................................................................................. 42
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 44
4.3.
Justification for Dose...................................................................................................................... 45
4.4.
End of Study Definition................................................................................................................... 46
5.
STUDY POPULATION ...................................................................................................................... 46
5.1.
Inclusion Criteria ............................................................................................................................ 46
5.2.
Exclusion Criteria ........................................................................................................................... 49
5.3.
Lifestyle Considerations................................................................................................................. 52
5.4.
Screen Failures .............................................................................................................................. 53
6.
STUDY INTERVENTION................................................................................................................... 53
6.1.
Study Intervention(s) Administered................................................................................................ 53
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 54
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 55
6.4.
Study Intervention Compliance...................................................................................................... 56
6.5.
Concomitant Therapy..................................................................................................................... 56
6.6.
Intervention After the End of the Study.......................................................................................... 58
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 58
7.1.
Discontinuation of Study Intervention ............................................................................................ 58
7.2.
Participant Discontinuation/Withdrawal from the Study................................................................. 59
7.2.1.
Withdrawal from the Use of Research Samples......................................................................... 59
7.3.
Lost to Follow-up............................................................................................................................ 59
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 60
8.1.
Efficacy Assessments .................................................................................................................... 61
8.2.
Safety Assessments....................................................................................................................... 63
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 66


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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 67
8.3.2.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 67
8.3.3.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 67
8.3.4.
Pregnancy................................................................................................................................... 68
8.4.
Treatment of Overdose .................................................................................................................. 68
8.5.
Pharmacokinetics........................................................................................................................... 68
8.5.1.
Evaluations ................................................................................................................................. 68
8.5.2.
Analytical Procedures................................................................................................................. 69
8.5.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 69
8.6.
Genetics ......................................................................................................................................... 69
8.7.
Biomarkers ..................................................................................................................................... 69
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 70
9.1.
Sample Size Determination ........................................................................................................... 70
9.2.
Statistical Analyses ........................................................................................................................ 71
9.2.1.
Efficacy analyses ........................................................................................................................ 71
9.2.2.
Safety Analyses .......................................................................................................................... 72
9.2.3.
Other Analyses ........................................................................................................................... 73
9.3.
Interim Analysis.............................................................................................................................. 74
9.4.
Unblinded Data Review.................................................................................................................. 74
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 75
10.1.
Appendix 1: Abbreviations ............................................................................................................. 75
10.2.
Appendix 2: Anticipated Events ..................................................................................................... 77
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 78
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 88
10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information........................... 93
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments.................................. 96
10.7.
Appendix 7: Moderate and Strong Inhibitors/Inducers of CYP3A4.............................................. 100
10.8.
Appendix 8: Guidance on Study Conduct during the COVID-19 Pandemic................................ 101
10.9.
Appendix 9: Protocol Amendment History ................................................................................... 103
11.
REFERENCES................................................................................................................................. 104
INVESTIGATOR AGREEMENT ............................................................................................................... 106


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LIST OF IN-TEXT TABLES AND FIGURES 
FIGURES
Figure 1:
Schematic study overview ........................................................................................................ 39
TABLES
Table 1:
Summary of Clinical Studies With JNJ-61393215 .................................................................... 31


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
30 Sep 2021
Amendment 3
24 June 2021
Amendment 2
5 August 2020
Amendment 1
24 June 2019
Original Protocol
13 May 2019
Amendment 4 (30 Sep 2021)
Overall Rationale for the Amendment: Feedback was received from the FDA, advising against performing
the primary analysis on a population that excludes patients that were ongoing at the time of trial suspension due to the
COVID-19 pandemic. Hence the primary data analysis set is revised to include those patients.
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis; 
9.2.1. Efficacy 
Analyses
Revising the primary analysis dataset so patients 
who were ongoing at the time of the trial suspension 
due to the COVID-19 pandemic are included.
Excluding patients that were
ongoing at the time of trial
suspension from the primary
analysis violates the intent-to-treat
principle and may limit
interpretation of the study results.
1.1 Synopsis
Removed ‘if the data are potentially impacted 
(missing values or interpretability) by the COVID-
19 pandemic’ as reason for sample size re-
estimation.
This was inconsistent with the other
sections in the protocol.
Amendment 3 (24 June 2021)
Overall Rationale for the Amendment: The overall reason for the amendment is to revise the primary data
analysis set with regards to the patients who were ongoing at the time of the trial suspension due to the COVID-19
pandemic.
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis; 4.1 
Overall Design; 9.1 
Sample Size; 9.2.1. 
Efficacy Analyses; 
9.3 Interim Analysis
Revising the primary analysis dataset by excluding 
patients who were ongoing at the time of the trial 
suspension due to the COVID-19 pandemic.
The unexpected and unprecedented 
circumstances around the COVID-
19 pandemic may be associated 
with increased anxiety and thus 
might impact primary and 
secondary outcome measures in the 
study population of participants 
with MDD with anxious distress.
10.8 Guidance on 
Study Conduct 
during the COVID-
19 Pandemic
Add guidelines around COVID-19 vaccination for 
enrolled patients.
As COVID-19 vaccination has 
started in the participating 
countries, guidance on how to 


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Section number
and Name
Description of Change
Brief Rationale
handle this for enrolled patients is 
needed. 
Amendment 2 (5 Aug 2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to update the list of
disallowed antidepressants and concomitant therapies, to remove the PDSS-SR, to update dosing instructions, to
adapt the definition of overdose, to allow re-screening and adjust sample size re-estimation due to the COVID-19
pandemic, to optimize specific procedures for operational reasons and to make some clarifications.
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis; 4.1 
Overall Design
Allow prescription records or a letter from a treating 
physician to document previous treatment for MDD
In some countries it is challenging 
to get pharmacy or medical records, 
therefore we allow a letter from the 
treating physician.
1.1 Synopsis; 3.3 
Exploratory 
Objectives
Remove objective related to the PDSS-SR.
PDSS-SR will not be performed in 
the study, due to logistical reasons.
1.1 Synopsis; 6.1 
Study 
Intervention(s) 
Administered 
Change requirement for study intervention intake 
‘at same time every day within a +/- 3 hours
window’ to ‘intake in the morning’.
As time of administration during 
clinic visits is later than 
administration at home, the +/- 3 
hours window is not feasible.
1.1 Synopsis; 
1.3 Schedule of 
Activities; 6.1 Study 
Intervention(s) 
administered
Requirement to use capsules from the blisters 
dispensed at the previous study visit removed.
Logistical reasons
1.1 Synopsis; 8. 
Study Assessments 
and Procedures
Clarify that SIGH-D done by the qualified site raters 
will be recorded at all visits.
Clarification
1.1 Synopsis; 4.1 
Overall Design; 9.1 
Sample Size; 9.2.1. 
Efficacy Analyses; 
9.3 Interim Analysis
Foresee the option to replace early withdrawals due 
to the COVID-19 pandemic and completers who 
exhibit an abnormal pattern of anxiety symptoms
during this period.
The COVID-19 pandemic is an 
unforeseen circumstance that was 
not taken into account for the 
sample size calculation/criteria for 
sample size re-evaluation. In 
addition, the unexpected and 
unprecedented circumstances 
around the COVID-19 pandemic 
may be associated with increased 
anxiety and thus might impact 
primary and secondary outcome 
measures in the study population of 
participants with MDD with 
anxious distress.
1.1 Synopsis; 9.2.1. 
Efficacy Analyses
Pre-specify an order for alternative variance-
covariance structures.
Following submission of protocol 
amendment 1, FDA provided some 
recommendations to avoid potential 
inflation of type I error rate when 
the same data set is used for model 
selection and subsequently 
hypothesis testing. In addition, if a 
structured variance-covariance is 
used, then a robust sandwich 


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Section number
and Name
Description of Change
Brief Rationale
estimator needs to be used for 
estimating the variance of the 
treatment effect estimate. 
1.3 Schedule of 
Activities
Allow a 2-days window for the follow-up/early 
withdrawal visit
Operational reasons
1.3 Schedule of 
Activities
Remove footnote ‘n’
This was an error. α-1-acid-
glycoprotein is a separate plasma 
sample, as correctly stated in 
section 8.5.1
1.3 Schedule of 
Activities
- Update time of collection for biomarker samples 
- Allow a +/- 1 hr window from the collection time 
at baseline
-
Literature shows that samples
for ACTH are best collected 
before 10am.
-
As participants have to come for 
clinic visits, it is not always 
feasible to collect the 
biomarker samples at the same 
time.
5.2 Exclusion 
Criteria
- Exclusion criterion added about use of 
antidepressants at subtherapeutic doses
- Exclusion criterion 21 updated to exclude use of 
all anxiolytics
- Exclusion criteria 14 and 15 updated for HIV and 
HCV treatment
- Exclusion criteria 17 and 18 clarified
Clarify that:
-
use of not allowed 
antidepressants at 
subtherapeutic doses for 
indications other than MDD (or 
to treat specific symptoms) is 
exclusionary
-
use of any anxiolytic is 
exclusionary
-
participants negative for HIV 
RNA or HCV RNA are eligible
5.4 Screen Failures
Allow re-screening.
Due to the COVID-19 related 
measures, some participants
who were screened and eligible 
could not be randomized. 
These participants can be re-
screened.
6.5 Concomitant 
Therapy
Add other anxiolytics to disallowed concomitant 
therapy, clarify that CYP3A4 inducers are not 
allowed and clarify that use of other 
antidepressants than the allowed therapies, even if 
at subtherapeutic dosed for indications other than 
MDD are not allowed
-
Anxiolytics can mask a 
potential signal from the 
compound
-
To consistently mention 
CYP3A4 inducers in the 
exclusion criteria, in Appendix 
7, and in the disallowed 
concomitant therapy.
8. Study 
Assessments and 
Procedures
Remove the requirement to perform PRO’s first 
and make the sequence of scales a 
recommendation.
SIGH-D is the primary outcome 
measure and thus has to be 
performed first. For the other scales 
the order is less important and for 
operational reasons the sites are 
given more flexibility.
8.1 Efficacy 
Assessments
Remove description of PDSS-SR.
PDSS-SR will not be performed in 
the study, due to logistical reasons.
8.2 Safety 
Assessments
- Clarify when FSH needs to be done.
- HbA1c added, in diabetic participants at 
screening only.
-
Make wording in section 8.2 
consistent with inclusion 
criterion 14.


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Section number
and Name
Description of Change
Brief Rationale
-
Only HbA1c can indicate if a 
diabetic participant is stable or 
not (cfr exclusion criterion 
10.1)
8.4 Treatment of 
Overdose
Change definition of overdose from 6 capsules 
within 24 hours to 9 capsules
The definition for overdose of 6 
capsules within 24 hours was too 
strict. 
10. Appendix 8
Appendix 8 added: Guidance on Study Conduct 
during the COVID-19 Pandemic
Provide study-specific guidance for 
study conduct during the COVID-
19 pandemic.
Overall
Minor editorial corrections were made throughout 
not affecting the content or context of the protocol.
Minor editorial changes
Overall
Remove references to PDSS-SR throughout not 
affecting the content or context of the protocol.
PDSS-SR will not be performed in 
the study, due to logistical reasons.
Amendment 1 (24 June 2019)
Overall Rationale for the Amendment: To enable measuring total and free drug concentrations in 
patients and to investigate the relationship between fraction unbound and clinical variables of interest.
Section number
and Name
Description of Change
Brief Rationale
Synopsis 
Objectives; 
Synopsis PK 
Evaluations;
3.2 Secondary 
Objectives; 
8.5.1 Evaluations
Secondary objective added to evaluate directly 
and/or indirectly the impact of plasma protein 
binding on the PK of JNJ-61393215.
PK samples for plasma protein 
binding were added to collect 
additional data on the impact of 
plasma protein binding on the PK 
of JNJ-61393215, directly and/or 
indirectly evaluated.
Schedule of 
Activities
Blood sample for plasma protein binding added at 
week 6 predose and post dose; PK sample for 
JNJ-61393215 added at week 6 post dose to be 
collected together with the sample for plasma 
protein binding.
PK samples for plasma protein 
binding were added to collect 
additional data on the impact of 
plasma protein binding on the PK 
of JNJ-61393215, directly and/or 
indirectly evaluated.
Schedule of 
Activities
Last dosing will be at week 6 as such no study 
intervention dispensing is to occur at Week 6. SOA 
updated accordingly
No study intervention dispensing at 
Week 6.
4.2. Scientific 
Rationale for Study 
Design
The score range for the HAM-A was updated from 
0-52 to 0-56.
Incorrect score range described. 
5.4. Screen Failures
Following statement was added: Retesting of 
abnormal screening values (including laboratory 
values), at the discretion of the Investigator, that 
may lead to exclusion of a participant are allowed 
only once using an unscheduled visit during the 
screening phase.
Allow the retesting of any abnormal 
screening value only once. 
8. Study 
Assessments and 
Procedures
The table “Volume of Blood to be Collected from 
Each Participant” has been removed from the 
protocol as these details will be captured in a 
separate lab manual. The maximal volume to be 
The table “Volume of Blood to be 
Collected from Each Participant” 
has been removed as these details 
will be described in the lab manual. 


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Section number
and Name
Description of Change
Brief Rationale
collected per participant has not changed. In 
addition, a statement has been added that any 
changes to the lab manual will not lead to a 
protocol amendment.
No change in maximal blood 
volume to be collected occurred. 
9.2.3 Other 
Analyses
Text added for pharmacogenomic analysis related 
to alpha-1-acid glycoprotein.
To collect additional data on the 
impact of plasma protein binding 
on the PK of JNJ-61393215, 
directly and/or indirectly evaluated.
2.2.1 Nonclinical 
studies; 4.5 
Justification for 
Dose
Safety margin based on total exposure was added.
Provide safety margin based on 
total exposure, in addition to safety 
margin based on fraction unbound.
5.2 Exclusion 
Criteria; 8.2 Safety 
Assessments
Tests were added to drug screen
For logistical reasons drug screen 
tests were updated to match the 
drug screen kit provided to the sites 
by the central lab.
Overall
Minor editorial corrections were made throughout 
not affecting the content or context of the protocol.
Minor editorial changes


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Double-Blind, Placebo-Controlled, Multi-Center Study Investigating the Efficacy, Safety, and 
Tolerability of JNJ-61393215 as Adjunctive Treatment in Adults with Major Depressive Disorder 
with Anxious Distress with Suboptimal Response to Standard Antidepressants.
JNJ-61393215 is a novel, selective, high affinity/potent orexin-1 receptor (OX1R) antagonist and is a 
potential therapy for the treatment of panic, substance abuse, and different neuropsychiatric disorders 
including anxiety disorders, mood disorders, addictive behaviors, and major depressive disorder.
Orexin neurons are “multi-tasking” neurons that regulate multiple physiological functions (circadian 
rhythm, reward, wakefulness, autonomic nervous system, endocrine system, energy balance, sleep, 
emotion). The role of OX1Rs in complex emotional behavior is emerging. There is evidence for the 
overactivation of the OX1R pathway in hyperarousal states (for example panic attacks), and consequently 
a selective OX1R antagonist might normalize overexcited networks without inducing sedation.
Non-clinical data suggest potential antidepressant-like effects of OX1R inhibitors1,21 although the role of 
OX1R in depressive-like behaviors has not been systematically investigated and the results from the limited 
number of studies published in the literature so far are not entirely consistent. Overall, existing non-clinical
data support a potential role of OX1R inhibitors as novel treatment strategies for different neuropsychiatric 
disorders, including anxiety disorders, addictive behaviors, and potentially depression. To date, 4 Phase 1 
clinical studies have been conducted with JNJ-61393215: first-in-human [FIH] study 61393215EDI1001 
and study 61393215EDI1002, to evaluate the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of JNJ-61393215 in healthy participants both for single dose and multiple dose 
respectively, study 61393215EDI1003 to evaluate the effects of a cytochrome P450 (CYP) 3A4 inhibitor 
(ritonavir) on the single-dose PK of JNJ-61393215 in healthy participants and study 61393215EDI1004, to 
evaluate safety, tolerability, and PK of JNJ-61393215, administered at single and multiple doses higher 
than explored in the FIH study and to evaluate relative bioavailability (relative to the suspension) as well 
as food effect of a solid formulation. In the 61393215EDI1002 study, dosing of JNJ-61393215 (90 mg) and 
alprazolam (1 mg) was associated with a statistically significant reduction in fear and anxiety symptoms 
induced by CO2 inhalation according to the Panic Symptom List IV (PSL-IV) assessment. The observed 
anxiolytic effect of JNJ-61393215 provides the rationale for testing the efficacy of JNJ-61393215 in 
participants with mood disorders and clinically significant mood and anxiety symptoms. The current study 
will be conducted to assess the efficacy, safety, tolerability, PK, and PD of JNJ-61393215 as adjunctive 
treatment in participants with Major Depressive Disorder (MDD) with anxious distress.
OBJECTIVES AND ENDPOINTS
Primary Objectives
The primary objective of this study is to evaluate the efficacy of JNJ-61393215 as adjunctive treatment 
compared to adjunctive placebo, as assessed by the change from baseline to Week 6 on a 17-item Hamilton 
Depression Rating Scale (HDRS17) in participants with MDD with anxious distress with a score ≥2 on item 
26 or 27 of the Inventory of Depressive Symptomatology, Clinician Rating -30 (IDS-C30), who have a 
suboptimal response to current treatment with a standard antidepressant.


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Secondary Objectives
The key secondary objective is to evaluate the impact of adjunctive treatment with JNJ-61393215 compared 
to adjunctive placebo on the severity of anxiety as measured by the change in the Hamilton Anxiety Rating 
scale (HAM-A) from baseline to Week 6.
Other secondary objectives are:

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive 
placebo on the severity of anxiety as measured by the change in HAM-A from baseline to 
weeks 2 and 4.

To evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive placebo, as 
assessed by the change from baseline to Week 6 on the HDRS17 in participants with a baseline HAM-A 
score ≥20.

To evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive placebo, as 
assessed by the change from baseline to Week 6 on the HAM-A in participants with a baseline HAM-A 
score ≥20.

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive placebo on 
participant-reported severity of anxiety as measured by the change in the General Anxiety Disorder-7 
scale (GAD-7) from baseline to Week 6.

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive placebo on 
participant-reported severity of symptoms of MDD, as measured by the change in the Patient Health 
Questionnaire (PHQ-9) from baseline to weeks 2, 4 and 6.

To evaluate the change in HDRS17 from baseline to weeks 2 and 4. 

To investigate the overall safety and tolerability of adjunctive treatment with JNJ-61393215 in 
participants with MDD with anxious distress.

To evaluate PK of JNJ-61393215 in participants with MDD with anxious distress.

To evaluate directly and/or indirectly the impact of plasma protein binding on the PK of JNJ-61393215 
in participants with MDD with anxious distress. 
Exploratory Objectives
The exploratory objectives are:

To explore the relationship between JNJ-61393215 pharmacokinetics and selected efficacy endpoints 
(e.g. HDRS17) or safety parameters after repeated dosing of JNJ-61393215, if deemed appropriate.

To explore the relationship between biomarkers of HPA axis, metabolic, and immune system function, 
and the clinical response of depression/anxiety symptoms upon adjunctive treatment with JNJ-
61393215, if deemed appropriate.

To explore the effect of JNJ-61393215 versus placebo on biomakers of the hypothalamic–pituitary–
adrenal (HPA) axis, if deemed appropriate.
Hypothesis
The primary hypothesis of this study is that treatment with JNJ-61393215 will lead to significant 
improvement in depressive symptoms from baseline compared to placebo when administered as an 
adjunctive treatment to a standard antidepressant in the treatment of MDD patients with anxious distress 


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with a score ≥2 on item 26 or 27 of the IDS-C30 who have a suboptimal response to current standard 
treatment. Significant improvement will be demonstrated by improvement in depressive symptoms from 
baseline to the 6-week endpoint in the HDRS17 total score.
OVERALL DESIGN
This is a double-blind, placebo-controlled, randomized, parallel-group, multi-center study in participants 
with MDD with anxious distress. An estimated target of approximately 218 participants will be randomly 
assigned in this study with 109 participants planned per treatment group. 
A blinded data review for purpose of sample size re-estimation may be performed. Sample size may be 
re-adjusted if the observed screening response rate, the drop-out rate (including drop-outs due to the 
COVID-19 pandemic), or the standard deviation substantially deviate from the assumed value. Overall 
sample size can increase with maximal 25%. The potential maximal number of participants to be enrolled 
in this trial would be 272 (see Section 9.1 and 9.3).
The target study population includes male and female participants, between 18 and 64 years of age 
inclusive, with a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of 
MDD with anxious distress, confirmed by the Mini International Neuropsychiatric Inventory (MINI) Plus 
with module for MDD with anxious distress2,13,23,24. Participants also need to:

have moderate to severe depression (IDS-C30 total score ≥35)

have symptoms of somatic anxiety (score ≥2 on item 26 or 27 of the IDS-C30) 

have a suboptimal response to the antidepressant in their current treatment (improvement <50%)

have failed no more than 3 antidepressants (of adequate dose and duration), including their current 
treatment, in the current major depressive episode.
Participants will continue to take their standard treatment at an adequate and tolerated stable dose 
throughout the study. No antidepressant dose changes are permitted from screening through the end of the 
study, including the post-treatment phase.
The study will consist of 3 phases: a screening phase of up to 4 weeks, a double-blind treatment phase of 6 
weeks, and a posttreatment follow-up phase of 2 weeks. The total duration of participation will be
approximately 12 weeks for each participant. The end of study is defined as the date of the last visit of the 
last participant in the study.
Screening
No trial specific screening procedures will be undertaken prior to finalization of the informed consent form 
(ICF) procedures and the provision of written informed consent by the participant. 
After giving written informed consent, participants will be screened between 28 days and 4 days prior to 
baseline to ascertain their eligibility for the study according to the inclusion and exclusion criteria. 
Screening will include assessment of study inclusion and exclusion criteria, medical history and 
demographics, physical examination, psychiatric and safety evaluations and standard lab tests. Recording
of adverse events (AEs) and concomitant medication will start as well.
During the screening phase, assessments will be done as described in the Schedule of Activities (SoA).


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The screening phase will consist of:
1) a screening visit,
2) a SAFER interview by phone, with an independent rater. [SAFER is an acronym for: State versus trait; 
Assessability; Face validity; Ecological validity; and Rule of three Ps (pervasive, persistent, and 
pathological)]
To define a diagnosis of MDD with anxious distress according to DSM-5 and exclude comorbid psychiatric 
disorders, the MINI 7.0 Plus with module for MDD with anxious distress will be used during screening. 
The semi-structured interview guide for the IDS-C30 will be used.
The HDSR17 and HAM-A will be done at screening, using the Structured Interview Guide for the HDRS17
(SIGH-D) and the Structured Interview Guide for the HAM-A (SIGH-A), respectively.
The SIGH-D and SIGH-A will be completed by the same rater from screening throughout the study for a 
given participant. Exceptions will need to be discussed with and approved by the sponsor. The sponsor can 
request a rater change based on quality concerns, identified during the independent data quality monitoring.
The structured Massachusetts General Hospital Antidepressant Treatment History Questionnaire 
(MGH-ATRQ) will be used retrospectively to determine a suboptimal response to the current standard oral 
antidepressant therapy. Determination of the number of failed antidepressant treatments in the current 
episode will be made retrospectively using medical/pharmacy/prescription records or a letter from a treating 
physician and documented on the MGH-ATRQ. IDS-C30 scores and MGH-ATRQ will be confirmed by 
the SAFER interview. 
The procedures scheduled during the screening visit may be divided over multiple days, according to 
operational and/or site/country-specific needs. In case the screening visit is conducted over multiple days, 
the following assessments must be performed first and on the same day: MINI 7.0 Plus, MGH-ATRQ, 
IDS-C30, HAM-A, SIGH-D and Colombia suicide severity rating scale (C-SSRS). These will be done by 
a qualified rater at the site. Only participants that fulfill the criteria for MINI 7.0 Plus, MGH-ATRQ, 
C-SSRS and IDS-C30 will continue the screening phase.
Once a participant has performed all screening assessments and has been confirmed eligible for all 
screening criteria, a SAFER interview will be performed by an independent rater, minimally 21 days 
following the screening visit and within 7 to 4 days of baseline.
During this SAFER interview the following items will be confirmed:

suboptimal response to current standard oral antidepressant therapy: improvement <50% according to 
the MGH-ATRQ

moderate to severe depression: IDS-C30 score ≥35 

somatic anxiety: score of ≥ 2 on either items 26 or 27 of the IDS-C30
If participants are confirmed to meet these criteria, they are eligible for the study.


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During the SAFER interview, the IDS-C30 will be performed again by the independent rater and the 
MGH-ATRQ performed by the site during the screening visit, will be reviewed and confirmed. Therefore, 
the MGH-ATRQ will be provide to the independent rater prior to the SAFER interview.
The semi-structured interview guide for IDS-C30 and the SIGH-D done by the qualified site raters will be 
recorded, as well as the SAFER interviews, to allow for independent data quality monitoring. If more time 
is needed to decide on the eligibility of a participant based on the outcome of the SAFER interview and/or 
independent data quality review, the screening phase may be extended beyond 28 days, upon discussion 
with and approval from the sponsor, without constituting a protocol deviation.
Double-blind treatment phase
Participants who successfully complete the screening phase will be randomized to receive either adjunctive 
placebo or adjunctive treatment with 135 mg of JNJ-61393215 (daily) in a 1:1 ratio for a 6-weeks treatment 
period. Participants will visit the clinical site at baseline (Week 0), weeks 2, 4 and 6. 
During clinic visits, assessments will be performed according to the SoA.
The SIGH-D done by the qualified site raters will be recorded at each visit, to allow for independent data 
quality monitoring.
Efficacy assessments include HDRS17, HAM-A, PHQ-9 and GAD-7. 
Safety assessments will include the monitoring of AEs, physical examinations, vital signs measurements, 
clinical laboratory tests (including liver enzymes and thyroid enzymes), 12-lead electrocardiograms 
(ECGs), and C-SSRS. 
In addition, samples for PK, biomarkers and pharmacogenomic samples (DNA and RNA) will be collected. 
Follow-Up Visit / End-of-Study Visit
Approximately 2 weeks (+/- 2 days) after last dosing, participants will return to the clinical unit for a follow-
up visit. Follow-up procedures will be performed as described in the SoA.
If a participant withdraws from the study before the end of the double-blind treatment phase, he or she will 
be advised to complete the end-of-study (follow-up) assessments.
DOSAGE AND ADMINISTRATION
JNJ-61393215 will be supplied for this study as 45-mg capsules. Placebo will be supplied as matching 
capsules. 
The dose for this study is 135 mg. All participants will take three 45-mg JNJ-61393215 capsules or three 
placebo capsules once daily (QD), either at the clinic, during visits, or at home, in between visits. As there 
is no effect of food on the absorption of JNJ-61393215, the study intervention can be administered 
irrespective of food intake (with or without a meal). Study intervention should be taken in the morning 
(before noon 12pm), at approximately the same time every day when feasible.
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed. 


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The participants will attend each study visit in a fasted state and are to bring their study intervention with 
them. The study intervention will be self-administered by the participant after the completion of pre-dose 
study assessments. Dosing will be witnessed by the study staff.
Where regulations allow, a study intervention adherence monitoring platform will be used to monitor study 
intervention intake by the participants. The platform uses artificial intelligence via an app on smartphones 
to visually confirm proper administration of study intervention and ingestion of the study intervention in 
real time without human intervention.  Video recordings of the study intervention intake are also recorded 
and stored to a secure server for further analysis to reconfirm proper intervention administration, to identify 
any usability issues or intentional non-adherence, and to check for duplicate enrollment. In addition, built-
in reminders and a communication system allow real-time intervention by study personnel in case of 
improper intervention administration or interruptions by the participant.
EFFICACY EVALUATIONS
Clinician rated measures for depression

Hamilton Depression Rating Scale (HDRS17) via Structured Interview Guide for HDRS17 (SIGH-D)
Clinician rated measures for anxiety

Hamilton Anxiety Scale (HAM-A) via Structured Interview Guide for HAM-A(SIGH-A)
Patient rated measures for depression

Patient Health Questionnaire (PHQ-9)
Patient rated measures for anxiety

Generalized Anxiety Disorder 7 (GAD-7) 
PHARMACOKINETIC EVALUATIONS
Venous blood samples for analysis of JNJ-61393215 plasma concentrations will be collected at the time 
points indicated in the SoA.
Blood samples for analysis of α-1-acid-glycoprotein (plasma) and plasma protein binding will also be 
collected.
BIOMARKER EVALUATIONS
Venous blood samples for the assessment of biomarkers related to HPA axis, growth factors, immune, and 
metabolic activity will be collected on each visit indicated in the Schedule of Activities during the double-
blind treatment phase. Biomarkers may be added or deleted based on scientific information or technical 
innovations under the condition that the total volume of blood collected will not be increased.
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.
To help with interpreting biomarker results, menstrual cycle in female participants will be tracked during 
the study per the SoA.


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PHARMACOGENOMIC (DNA and RNA) EVALUATIONS
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 allow for the identification of genetic (DNA) and/or transcription (RNA) factors that may 
influence the PK, efficacy, safety, or tolerability of JNJ-61393215 and to identify genetic factors associated 
with MDD. The RNA will be collected pre- and posttreatment to allow examination of changes in gene 
transcription related to administration of JNJ-61393215 and/or changes in other biomarkers collected 
during the study (eg, cortisol, cytokines, etc.). DNA genotyping may include, but is not limited to, 
interrogation of single nucleotide polymorphisms (SNPs) at discrete loci implicated in mood disorders or 
drug metabolism. DNA samples may be used to help address emerging issues and to enable the development 
of safer, more effective and ultimately individualized therapies in the future.
SAFETY EVALUATIONS
The collection of AEs and concomitant medications will start after the ICF has been signed and will 
continue until the final visit. 
The following safety assessments will be done: physical examination, body weight, vital signs (including 
temperature), 12-lead ECG, urine drug testing, alcohol testing, pregnancy testing (female participants only), 
clinical labs (hematology, chemistry panel, including liver enzymes, thyroid enzymes) and urinalysis. 
Serology and FSH (follicle stimulating hormone) (when applicable) at screening only.
Additional blood and urine samples may be taken or vital signs and ECGs recorded at the discretion of the 
investigators.   
Additionally, emergence of suicidal ideation will be assessed using the C-SSRS at screening, and during 
each study visit. 
STATISTICAL METHODS
Sample size determination
The estimated sample size of 218 participants (109 participants per group) was determined based on the 
assumption of an effect size of at least 0.4 for the HDRS17 total score (mean change from baseline to Week 6 
endpoint between the JNJ-61393215 and placebo groups of 3 units with SD=7.5). This is considered to be 
a clinically relevant difference in a population with suboptimal response to standard oral antidepressant 
therapy. The SD of 7.5 in the change in HDRS17 total score from baseline is a reasonable assumption based 
on previously conducted clinical trials in a similar patient population (40411813DAX2001 and 
42165279MDD2001). Power is set at 90%, with a 1-sided alpha of 0.10 and a 6-week drop-out rate of 10%.
It was also assumed that 15% of the randomized participants would be excluded from the primary efficacy 
analysis due to showing a screening response. The criteria for screening response will be defined in the 
Statistical Analysis Plan (SAP). Thus, the estimated participants to be included in the primary analysis is 
166.
Sample size may be re-adjusted if the observed screening response, the drop-out rate (including drop-outs 
due to the COVID-19 pandemic), or the standard deviation substantially deviate from the assumed value. 
Sample size can increase with maximal 25%. The potential maximal number of participants to be enrolled 
in this trial would be 272.


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Efficacy analysis
The intent-to-treat (ITT) analysis set will include all randomized participants who receive at least 1 dose of 
study drug and have both the baseline and at least 1 post-baseline measurement on a clinician rated 
assessment relevant for depression and anxiety.  The primary analysis set for efficacy will be the modified 
intent-to-treat (mITT) analysis set (enriched population) which consists of the ITT set excluding 
participants who showed a screening response.  The criteria for screening response that will be used for 
stratification within the IWRS will be blinded to the investigators.  The secondary analysis set for efficacy 
will be the ITT analysis set.
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined by the 
following 3 components:

Population: participants with MDD with anxious distress with suboptimal response to standard 
antidepressants

Endpoint: change from baseline to Week 6 in the HDRS17 total score 

Measure of Intervention: the effect of the initially randomized treatment that would have been 
observed had all participants remained on their treatment throughout the double-blind treatment phase. 
The JNJ-61393215 treatment group will be compared with the placebo group using the primary efficacy 
endpoint, change from baseline in HDRS17 total score, with the comparison performed by means of a 
mixed-effects model using repeated measures (MMRM), with time, treatment (placebo, JNJ-61393215), 
country, and time-by-treatment interaction as factors, baseline HDRS17 total score as a continuous covariate. 
An unstructured variance-covariance matrix will be used. 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) (first order autoregressive 
process) with separate subject random effect.  The comparison of JNJ-61393215 versus placebo will be 
performed using the appropriate contrast. In addition, a sensitivity analysis by excluding participants who 
were ongoing at the time of the trial suspension due to the COVID-19 pandemic and/or by excluding 
noncompliance participants will be conducted.
Analyses for secondary endpoints will be carried out in an enriched population using the same MMRM 
method that is aforementioned for the primary analysis.
In addition, the analyses for the efficacy endpoints will also be carried out in the full population using a 
MMRM, with time, treatment (placebo, JNJ-61393215), country, screening response status and 
time-by-treatment interaction as factors, and baseline HDRS17 total score as a continuous covariate. An 
unstructured variance-covariance matrix will be used. 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) (first order autoregressive 
process) with separate subject random effect.   
Pharmacokinetic Analysis
A population PK (pop PK) analysis using nonlinear mixed effects modeling (NONMEM) may be conducted 
to characterize the disposition characteristics of JNJ-61393215 using the data in the current study or 
combined data with other studies. Details will be given in a pop PK analysis plan, and results of the pop 
PK analysis will be presented in a separate technical report.


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Data will be listed for all participants with available plasma concentrations. 
Based on the individual concentration-time data, using the actual dose taken and the actual sampling times, 
PK parameters and exposure information of JNJ-61393215 may be derived using popPK modeling, 
including, but not limited to: AUC, Ctrough, and possibly Cmax. Other PK parameters may be determined if 
deemed useful to evaluate the PK of JNJ-61393215. Descriptive statistics, including arithmetic mean, SD, 
coefficient of variation, median, minimum, and maximum may be calculated for all derived PK parameters.
Special attention will be paid to the plasma concentrations and/or PK parameters of those participants who 
have discontinued the study for an AE, or who experienced an AE of severe intensity, or a serious adverse 
event (SAE).
Exposure-response Analysis
Relationships of JNJ-61393215 population-derived exposure parameters with some efficacy endpoints (e.g. 
HDRS17) or safety parameters may be explored, if deemed appropriate. Results will be presented in a 
separate report.
Biomarkers Analysis
The remaining exploratory biomarkers will be tabulated by treatment and summary statistics will be 
calculated. Posttreatment changes in exploratory biomarkers will be summarized by intervention group. 
Associations between baseline biomarker levels and clinical endpoints may be explored. Results may be 
presented in a separate biomarkers report.  
Pharmacogenomic analysis
Pharmacogenomic samples may be analyzed if needed. A composite genotype will be derived from the raw 
genotyping data for the analyzed genes, as appropriate. Specific analyses will include, but are not limited 
to, interrogation of SNPs in whole blood DNA at discrete loci implicated in mood. The relationship between 
genetic subgroups and JNJ-61393215 PK endpoints and/or PD markers may be examined through 
descriptive statistics or graphically. 
Due to the expected small sample size within genetic groups after stratification, analyses will be exploratory 
and are for hypothesis-generation purposes. No statistical tests will be performed.
Results may be presented in a separate report.
Safety Analyses
All participants receiving at least one dose of study drug will be included in the safety analysis.
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent adverse events are adverse events with onset during the treatment phase or that are a consequence 
of a pre-existing condition that has worsened since baseline. All reported AE’s will be included in the 
analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the given 
event will be summarized by treatment group. In addition, comparisons between treatment groups will be 
provided if appropriate. Summaries, listings, datasets, or participant narratives may be provided, as 
appropriate, for those participants who die, who discontinue treatment due to an adverse event, or who 
experience a severe or a serious adverse event.


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Laboratory data will be summarized by type of laboratory test. 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 at each scheduled time point. Changes from baseline 
results will be presented in pre- versus posttreatment cross-tabulations (with classes for below, within, and 
above normal ranges). 
Electrocardiogram data will be summarized by ECG parameters. Descriptive statistics will be calculated at 
baseline and for observed values and changes from baseline at each scheduled time point. Frequency 
tabulations of the abnormalities will be made. The ECG variables that will be analyzed are heart rate, PR 
interval, QRS interval, QT interval, and corrected QT (QTc) interval using [some or all of] the following 
correction methods: QT corrected according to Bazett's formula (QTcB) and QT corrected according to 
Fridericia's formula (QTcF). Descriptive statistics of QTc intervals and changes from baseline will be 
summarized at each scheduled time point. The percentage of participants with QTc interval >450 msec, 
>480 msec, or >500 msec will be summarized, as will the percentage of participants with QTc interval 
increases from baseline >30 msec or >60 msec. All significant abnormalities in ECG waveform that are 
changes from the baseline readings will be reported (e.g., changes in T-wave morphology or the occurrence 
of U-waves).
Descriptive statistics of temperature, pulse/heart rate, supine blood pressure (systolic and diastolic) values 
and changes from baseline will be summarized at each scheduled time point. The percentage of participants 
with values beyond clinically important limits will be summarized.
Abnormalities observed during the physical examination will be summarized and listed by treatment group 
at each scheduled time point. 
Results from the C-SSRS will be tabulated by treatment group for all participants receiving at least one 
dose of study drug in this study.
Interim Analysis
No formal interim analysis is foreseen. 
A blinded data review for purpose of sample size re-estimation may be performed. Sample size may be 
re-adjusted if the observed screening response, the drop-out rate (including drop-outs due to the COVID-19 
pandemic) or the standard deviation substantially deviate from the assumed value. Sample size can increase 
with maximal 25%.


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1.2.
Schema










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2.
INTRODUCTION
JNJ-61393215 is a novel, selective, high affinity/potent orexin-1 receptor (OX1R) antagonist and 
is a potential therapy for the treatment of panic, substance abuse, and different neuropsychiatric 
disorders including anxiety disorders, mood disorders, addictive behaviors, and major depressive 
disorder. 
Orexin neurons are “multi-tasking” neurons that regulate multiple physiological functions 
(circadian rhythm, reward, wakefulness, autonomic nervous system, endocrine system, energy 
balance, sleep, emotion). The role of OX1Rs in complex emotional behavior is emerging. There 
is evidence for the overactivation of the OX1R pathway in hyperarousal states (for example panic 
attacks), and consequently a selective OX1R antagonist might normalize overexcited networks 
without inducing sedation.
To date, 4 Phase 1 clinical studies have been conducted with JNJ-61393215: first-in-human [FIH] 
study 61393215EDI1001 and study 61393215EDI1002, to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-61393215 in healthy participants 
both for single dose and multiple dose respectively, study 61393215EDI1003 to evaluate the 
effects of a CYP3A4 inhibitor (ritonavir) on the single-dose PK of JNJ-61393215 in healthy 
participants and study 61393215EDI1004, to evaluate safety, tolerability, and PK of 
JNJ-61393215, administered at single and multiple doses higher than explored in the FIH study 
and to evaluate relative bioavailability of a solid formulation and the suspension as well as food 
effect. In the 61393215EDI1002 study, dosing of JNJ-61393215 (90 mg) and alprazolam (1 mg) 
was associated with a statistically significant reduction in fear and anxiety symptoms induced by 
CO2 inhalation according to the Panic Symptom List IV (PSL-IV) assessment. The observed 
anxiolytic effect of JNJ-61393215 provides the rationale for testing the efficacy of JNJ-61393215 
in participants with mood disorders and clinically significant mood and anxiety symptoms. The 
current study will be conducted to assess the efficacy, safety, tolerability, pharmacokinetics, and 
pharmacodynamics of JNJ-61393215 as adjunctive treatment in MDD participants with anxious 
distress.
For the most comprehensive nonclinical and clinical information regarding Orexin-1, refer to the 
latest version of the Investigator's Brochure (IB) for Orexin-1.10
The term “study intervention” throughout the protocol, refers to study drug.
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.
The term "participant" throughout the protocol refers to the common term "participant".
2.1.
Study Rationale
Non-clinical data suggest potential antidepressant-like effects of OX1R inhibitors1,21, although the 
role of OX1R in depressive-like behaviors has not been systematically investigated and the results 
from the limited number of studies published in the literature so far are not entirely consistent. 


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Overall, existing non-clinical data support a potential role of OX1R inhibitors as novel treatment 
strategies for different neuropsychiatric disorders, including anxiety disorders, addictive 
behaviors, and potentially depression. 
Comorbid anxiety occurs with significant frequency in patients with MDD and leads to greater 
refractoriness to treatment, more severe illness and higher risk for suicide.  Addressing anxiety 
symptoms in the context of depression may lead to improved outcomes for patients and more rapid 
relief of depression symptoms.
2.2.
Background
2.2.1.
Nonclinical Studies
Nonclinical Pharmacology
JNJ-61393215 is a high affinity/potent OX1R antagonist (human OX1R negative log of inhibition 
constant [pKi] = 8.17, negative log of the functional equilibrium dissociation constant [pKB] = 
7.76; rat OX1R pKi = 8.13, pKB = 7.72). JNJ-61393215 has an excellent selectivity profile (clean 
profile in a panel of over 50 different receptors including the orexin-2 receptor (OX2R) and various 
transporters tested up to 10 M). Ex vivo receptor occupancy studies demonstrated that 
JNJ-61393215 time- and dose-dependently occupied OX1R binding sites after oral (p.o.) 
administration. After acute p.o. administration of 10 mg/kg in rats, maximal OX1R occupancy was 
observed at 15 minutes (89 ± 6%) and the level of OX1R occupancy remained above 47% for the 
first 8 hours, before dropping to negligible occupancy. The plasma concentration associated with 
50% receptor occupancy (EC50) was 34 ng/mL and for 80% occupancy (EC80) it was estimated as 
136 ng/mL (4x EC50). Adjusting for differences in plasma protein binding (PPB) between human 
(fraction unbound [fu]=0.0183) and rat (fu=0.1265), the predicted human EC50, EC80, and EC90
are 239, 956, and 2,151 ng/mL, respectively.
The molecular weight of the drug substance is 460.42.
Previous studies have demonstrated that OX1R antagonists minimally affect sleep-wake states in 
baseline conditions but produce a disinhibition of rapid eye movement (REM) sleep in the presence 
of OX2R blockade. As expected, JNJ-61393215 (10 mg/kg, p.o.) did not alter spontaneous sleep 
in rats except for a moderate decrease in the latency to non-rapid eye movement (NREM) and 
REM. To establish an efficacy model for the OX1R antagonist, the effects of JNJ-61393215 on 
REM sleep were examined in mice lacking the OX2R (OX2R KO). In OX2R KO mice but not in 
wild type mice, administration of JNJ-61393215 (30 mg/kg, p.o.) resulted in a disruption of REM 
sleep (reduced REM latency and increased REM duration) demonstrating functional target 
engagement.
Emerging literature data indicate that a hyperactive orexin system is linked to anxiety- and panic-
vulnerability in rats and humans. Activation of the OX1R is a critical component of CO2-mediated 
anxiety and hypertension. JNJ-61393215 was tested in a rat model of CO2-induced panic. JNJ-
61393215 blocked CO2-induced anxiety behavior in the social interaction test at 10 and 30 mg/kg 


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(p.o.). Additionally, an attenuation of the bradycardia response was also observed at 30 mg/kg 
(p.o.).
JNJ-61393215 was evaluated in several models of drug addiction. JNJ-61393215 significantly 
reversed somatic signs of withdrawal in nicotine dependent mice at doses of 1-, 3-, 10-, and 
30-mg/kg intra gastric (i.g.). In addition, JNJ-61393215 significantly reversed hyperalgesia at 
3mg/kg and 10 mg/kg. JNJ-61393215 at any of the doses does not alter rates of responding during 
extinction of lever pressing in rats previously reinforced with food pellet delivery nor does it alter 
the ability of cocaine to facilitate lever pressing in rats reinforced by medial forebrain bundle 
stimulation. And finally, JNJ-61393215 was tested for its ability to reduce footshock-induced 
reinstatement of extinguished, cocaine-reinforced lever pressing in rats. JNJ-61393215 did not 
reduce footshock-induced reinstatement of lever pressing at any of the doses.
Safety Pharmacology
Single oral administration at 250 and 600 mg/kg to male rats caused dose-dependent decreases in 
respiratory rate and minute volume up to 6 hours postdose together with a dose-dependent increase 
in tidal volume up to 5 hours postdose. The no observed adverse effect level (NOAEL) for 
respiratory safety effects was set at 50 mg/kg (exposure at 6.5 hours postdose: 6,976 ng/mL).
JNJ-61393215 has intrinsic human ether-a-go-go-related gene (hERG)-blocking properties (half 
maximal inhibitory concentration (IC50) = 14.8 M), but did not prolong the QTc interval in vivo 
in anesthetized guinea pigs and dogs up to exposures of 13,000 ng/mL and 13,250 ng/mL, 
respectively, and in conscious dogs up to a single oral dose of 150 mg/kg (exposure at 4 hours 
postdose 9,458 ng/mL). Small and transient decreases in blood pressure were seen in conscious 
dogs at 150 mg/kg. Overall, JNJ-61393215 was considered not to pose a cardiovascular safety 
concern for humans.
In a single oral dose Irwin study in male rats, 50 mg/kg did not adversely affect neurofunctional 
integrity (highest plasma exposure at 3 hours postdose: 14,600 ng/mL). Administration of 
250 mg/kg and 600 mg/kg led to dose-related neurobehavioral observations associated with 
spontaneous activity, motor-affective and sensory-motor responses. Some neurological parameters 
involving muscle tone and equilibrium and gait were affected. Autonomic effects such as 
mydriasis, narrowing of the palpebral fissure, decreased respiratory rate and decreased body 
temperature were also recorded at these doses. At 600 mg/kg, catalepsy was recorded in 2 animals. 
Signs of general toxicity included crusty eyes and/or a crusty nose and decreased body weight and 
body weight gain at 600 mg/kg. On Day 7, absence of locomotor activity and of alertness was still 
evident at 600 mg/kg.
Pharmacokinetics and Product Metabolism in Animals
Absorption of JNJ-61393215 was rapid in all species (tmax ≤1 hour). Oral bioavailability was high 
in rats (83%) and low to moderate in other species, ranging between 6% (monkey) to 52% (dog), 
and predicted to be good in humans based on high permeability in a Caco-2 cell model of intestinal 
absorption. The volume of distribution of JNJ-61393215 at steady state (Vdss) was moderate in all 


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species (Vdss; ≤1.4 L/kg), and clearance was low to moderate, ranging between 13% (guinea pig) 
to 55% (rat) of hepatic blood flow following intravenous (IV) administration. Elimination after IV 
administration was rapid to moderate (t1/2=0.2 to 2.4 hours) and JNJ-61393215 was moderately 
to highly bound (64% to 99%) to animal and human plasma proteins at concentrations up to 25 µM. 
With the exception of the mouse, saturation of binding was observed across all species at 
concentrations of 6 to 10 µM. JNJ-61393215 binds to both human α1-acid glycoprotein and 
albumin, and has limited partitioning into red blood cells with blood-to-plasma ratios <1 for all 
species. Distribution of JNJ-61393215 over 24 hours was highest in liver and kidney and lowest 
in brain (tissue-to plasma AUC ratios of 5.4, 2.5, and 0.4, respectively). Following a single dose 
of [14C]JNJ-61393215 in rats, quantitative whole body autoradiography showed highest levels of 
total radioactivity in preputial gland, liver, and kidney cortex. Similar levels of total radioactivity 
in nonpigmented and pigmented skin suggest that JNJ-61393215 does not preferentially bind to 
melanin.
In vivo biotransformation and disposition of [14C]JNJ-61393215 were studied in rats and dogs 
given a single oral dose and in bile duct cannulated (BDC) rats given a single IV dose. The majority 
of the radioactive dose was recovered in feces of intact rats (83.4%) and dogs (59.2%), and in the 
bile of BDC rats (83.2%). Urinary excretion of total radioactivity accounted for 9.7%, 25.4%, and 
14.3% of the radioactive dose in intact rats and dogs and BDC rats, respectively. This is consistent 
with biliary-fecal elimination as the major excretory route of total radioactivity and with minor 
contribution of urinary excretion. Metabolic profiling for the intact rat and dog showed unchanged 
drug to be the major component of drug-derived radioactivity in plasma (36.9% and 46.7%, 
respectively). The major plasma metabolites were M5 (ring-opened amino alcohol) and M54 
(monooxy-UD) in both species, followed by M6 (ring-opened amino carboxy) and M7 (ringopened 
amino alcohol) in rats and dogs, respectively. Intact JNJ-61393215 recovered in rat and dog urine 
and feces, and rat bile was minimal (<0.5% of the dose). M5 and M6 were the predominant 
metabolites identified in urine in both species. M6, M40 (ring-opened amino alcohol-glucuronide) 
and M32 (monooxy--ring-opened amino carboxy) were the predominant drug-related entities in 
rat bile. In feces the predominant metabolites were M6 and M9 (ring-opened amino carboxy) in 
rat and dog, M31 (dioxy-ring-opened amino alcohol), M32, and M49/M50 (monooxy-ring-opened 
amino alcohol) in rat feces, and M5 and M52 (monooxy-ring-opened amino alcohol) in dog feces. 
All metabolites generated in human hepatocytes were also detected in at least one rat or dog matrix
sample from the in vivo metabolism studies. JNJ-61393215 was mainly metabolized by 
cytochrome P450 (CYP)3A4, with minor contributions from CYP3A5 and CYP2C19.
In human hepatocytes (fu = 0.75-0.88 in homogenized hepatocytes), JNJ-61393215 (10 µM) was 
a strong CYP3A4 inducer (up to 119% of rifampicin) and a weak CYP2B6 inducer (up to 43.5% 
of phenobarbital). JNJ-61393215 did not induce CYP1A2 appreciably. In liver microsomes, 
JNJ-61393215 was a moderate CYP3A4 reversible inhibitor with midazolam as the marker 
substrate (IC50 = 12 µM) and weakly inhibited CYP2C9 (against tolbutamide) and CYP2C19 with 
IC50 values of 90 µM and 60 µM, respectively. JNJ-61393215 was also a moderate time-dependent 
CYP3A4 inhibitor (apparent inactivation constant [KI] = 7 M; maximal inactivation rate constant 
[Kinact] = 0.015 min-1). Binding of JNJ-61393215 (1 to 7 µM) in human liver microsomes ranged 
from 9.94 to 25.72 % at protein concentrations of 0.15 to 1 mg/ml.


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JNJ-61393215 was not a P-glycoprotein (P-gp) inhibitor, but was a weak substrate in 
MDCKII-MDR1 transduced cells suggesting JNJ-61393215 will have limited interaction with 
P-gp at the human blood brain barrier. In human hepatocytes JNJ-61393215 uptake was weakly 
inhibited by known organic cation transporter (OCT) inhibitors, but not organic anion transporter 
polypeptide (OATP) inhibitors. JNJ-61393215 was not a substrate for OATP1A2, OATP1B1, 
OATP1B3, OATP2B1, or breast cancer resistance protein (BCRP) in cell lines stably transfected 
with these transporters. It was an inhibitor (IC50) of OATP1A2 (15.88 M), OATP1B1 
(38.64 , OATP1B3 (84.66 , multidrug and toxin extrusion protein (MATE) 1 (6.88 M), 
MATE-2K (36.88 , organic anion transporter (OAT) 3 (41.83 , OCT1 (72.41 , and 
OCT2 (23.07 ) but not OAT1, OATP2B1, or OCT3 in cell lines stably transfected with these 
transporters, and of BCRP (127.07 in stably transfected vesicles.
Toxicology
The potential toxicological effects of JNJ-61393215 have been evaluated in single- and repeated-
dose studies in rats and dogs for up to 3 months, in genotoxicity and reproductive and 
developmental toxicity studies, and in an in vitro phototoxicity study. 
A single dose of 1,000 mg/kg in male rats and 600 mg/kg in female rats was beyond the maximum 
tolerated dose (MTD). In the 1-month Good Laboratory Practice (GLP) study in rats, oral doses of 
50, 250, and 600 mg/kg/day were evaluated in male rats, and 20, 100, and 240 mg/kg/day in female 
rats. JNJ-61393215 was well tolerated and did not induce structural and/or numerical chromosome 
aberrations in bone marrow erythrocytes. Higher liver weights correlated with hepatocellular 
hypertrophy in males at ≥250 mg/kg/day and with hepatocellular hypertrophy in females at 
240 mg/kg/day. Focal subcapsular hepatocellular necrosis was noted in males (≥250 mg/kg/day). 
Higher thyroid weights in males (≥250 mg/kg/day) and in females (240 mg/kg/day) correlated with 
thyroid follicular cell hypertrophy. The NOAEL was 240 mg/kg/day for females and 50 mg/kg/day 
for males with corresponding lowest mean plasma AUC0-t values for females of 430,000 ng.h/mL 
and for males of 54,800 ng.h/mL. 
In the 3-month GLP study in rats, JNJ-61393215 was evaluated at doses of 25, 75 and 
250 mg/kg/day in male rats, and 75, 250 and 600/400 mg/kg/day in female rats. Test item-related 
mortality occurred in females after a single dose of 600 mg/kg on Day 1 and one female rat given 
250 mg/kg/day was euthanized pre-terminally due to poor condition. Adverse clinical signs, 
findings in the liver (necrosis, increased organ weights with increased liver enzymes) and thyroid 
(focal follicular cell hyperplasia in one rat) were observed in males at 250 mg/kg/day. In females, 
adverse clinical signs and findings in the liver (increased organ weights associated with increased 
liver enzymes) were noted at ≥250 mg/kg/day. Vacuolation of the ovary interstitial gland, related 
to an extended diestrus phase, was observed at the highest dose of 600/400 mg/kg/day. The ovary 
changes were fully reversed following a 1-month dosing-free period. No histopathological changes 
in the ovaries were observed up to 250 mg/kg/day, while a transient effect on the estrous cycle was 
noted at this dose level. Additional test-article related findings were found in the lung (females), 
adrenal gland, stomach, pancreas (males) and duodenum (females), and were considered adverse 
only in the duodenum of female rats at 600/400 mg/kg/day (based on severity of 


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erosion/ulceration, inflammation, and exudate). At the NOAEL of 75 mg/kg/day in both sexes, 
lowest mean AUC0-24h values were 43,500 ng.h/mL and 102,000 ng.h/mL for male and female rats, 
respectively, resulting in unbound AUC exposure ratios of 5.8-fold and 14-fold, respectively, 
relative to the human exposure at the 145 mg dose (or 0.6- and 1.3-fold, respectively, considering 
total exposure).
Across repeat-dose studies in rats, the liver and thyroid changes, together with the decreased 
plasma exposure upon repeated dosing and specific liver gene expression data are indicative of a 
known adaptive response to drug metabolic enzyme induction in rodents with little relevance to 
man. The hepatocellular hypertrophy and associated increase in liver weight was recovered in 
males and partially recovered in females after a 1-month recovery period following the 3-month 
study.
In the 1-month GLP study in male and female dogs, JNJ-61393215 was evaluated at doses 10, 50, 
and 150 mg/kg/day. Higher liver weights in both sexes at ≥50 mg/kg/day correlating with 
hepatocellular hypertrophy were non-adverse. The NOAEL was 150 mg/kg/day with 
corresponding lowest mean plasma AUC0-t values for males of 133,000 ng.h/mL and for females 
of 129,000 ng.h/mL. In male dogs, 300 mg/kg JNJ-61393215 qd for 7 days was the MTD, based 
on body weight loss accompanied with central nervous system (CNS) signs (Cmax: 51,800 ng/mL 
on Day 6). 100 and 150 mg/kg bid in male dogs resulted in severe CNS-related clinical signs 
including convulsions after the second dose (Cmax: 52,200 ng/mL at 150 mg/kg bid).
In a 3-month GLP toxicity study in male and female dogs, JNJ-61393215 was evaluated at doses 
30, 100, and 300 mg/kg/day. Hepatocellular hypertrophy at all dose levels was associated with 
higher liver weights and was partially reversed after the 1-month treatment-free period. The high 
dose of 300 mg/kg/day in males was considered adverse based on body weight losses in individual 
dogs, moderate increase in alkaline phosphatase (ALP) and minimal liver necrosis in a single dog. 
The NOAEL was 100 mg/kg/day in males and 300 mg/kg/day in females. At the NOAEL, mean 
AUC0-24h values were 200,000 ng∙h/mL for males and 168,000 ng∙h/mL for females, resulting in 
unbound AUC exposure ratios of 27- and 23-fold, respectively, relative to the human exposure at 
the 145 mg dose (or 2.5- and 2.1-fold, respectively, considering total exposure).
JNJ-61393215 did not show any genotoxic potential in a bacterial reverse mutation test, and in in 
vitro and in vivo micronucleus tests. JNJ-61393215 was not phototoxic in vitro.
Effects of JNJ-61393215 on male and female fertility have been evaluated in rats. No treatment-
related effects were seen on male fertility and the NOAEL for male reproductive performance was 
the high dose of 250 mg/kg/day. In female rats, there were reversible changes in estrous cycle 
(increased incidence of acyclic females or females with acyclic periods) at the high dose of 
200 mg/kg/day without any obvious effect on mating performance or fertility index. There was a 
small and non-adverse reduction in the mean number of corpora lutea and consequently 
implantations and live embryos were lower in the 200 mg/kg/day group, which was completely 
reversed after 3 dosing-free weeks. The NOAEL for female reproductive performance was set at 
the high dose of 200 mg/kg/day. 


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In an embryofetal development study in pregnant rats, maternal toxicity (clinical signs, lower body 
weight gain and food consumption) was seen from the low dose of 25 mg/kg/day onwards and the 
NOAEL for embryofetal development was 75 mg/kg/day (based on the lower mean fetal weight 
at the high dose of 200 mg/kg/day, considered the consequence of the severe maternal toxicity at 
this dose). In an embryofetal development study in pregnant rabbits, the NOAEL for maternal 
toxicity was 40 mg/kg/day (based on the reduction in body weight gain and food consumption at 
60 mg/kg/day) and the NOAEL for embryofetal development was the high dose of 60 mg/kg/day. 
2.2.2.
Clinical Studies
To date, JNJ-61393215 has been tested in 4 Phase 1 clinical studies (61393215EDI1001, 
61393215EDI1002, 61393215EDI1003, and 61393215EDI1004), evaluating the safety, 
tolerability, PK, and PD of JNJ-61393215 in healthy participants. Three studies 
(61393215EDI1001, 61393215EDI1002, and 61393215EDI1003) have been completed. For one 
Phase 1 clinical study (Study 61393215EDI1004) reporting is ongoing with JNJ-61393215. The 
results of these 4 clinical studies are summarized below. Details of the study design, objectives, 
and enrollment of clinical studies of JNJ-61393215 are summarized in Table 1.
Table 1:
Summary of Clinical Studies With JNJ-61393215
Study Number
(Status)
Brief Objective
Brief Study Design/Enrollment
61393215EDI1001
(Completed)
Safety, tolerability, PK, PD, and 
food-effect of JNJ-61393215 in 
healthy participants after single 
doses
First-in-human randomized, double-blind, placebo-controlled, 
single ascending dose study.
Part 1 (double-blind, single ascending dose cohorts in young 
healthy men): JNJ-61393215 (1-, 2-, 6-, 15-, 30-, 45-, 60-, 90-
mg) or matching placebo under fasted conditions.
Participants Enrolled/Completed: 64/63
Treated with JNJ-61393215: 48
Part 2 (open-label, single oral dose in healthy elderly men and 
women): 15 mg JNJ-61393215 under fasted conditions.
Participants Enrolled/Completed: 8/8
Treated with JNJ-61393215: 8
Part 3 (double-blind, food-effect cohort, single oral dose, in 
young healthy men): 30 mg JNJ-61393215 or placebo under fed 
conditions.
Participants Enrolled/Completed: 8/8
Treated with JNJ-61393215: 6
Overall, Participants Enrolled/Completed: 80/79
Treated with JNJ-61393215: 62


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Table 1:
Summary of Clinical Studies With JNJ-61393215
Study Number
(Status)
Brief Objective
Brief Study Design/Enrollment
61393215EDI1002
(Completed)
Safety, tolerability, PK and PD of 
JNJ-61393215 in healthy 
participants after multiple 
ascending doses
Randomized, double-blind study consisting of 2 parts:
Part 1: Placebo-controlled, multiple ascending dose part to 
assess safety, tolerability, and PK of JNJ-61393215.
4 cohorts with 8 participants each randomly assigned to 1 of 2 
treatment groups at ratio of 3:1 (6 participants on JNJ-61393215 
and 2 participants on placebo) at the doses of 5-, 15-, 45-, and 
90-mg qd
Participants Enrolled/Completed: 32/31
Treated with JNJ-61393215: 24
Part 2: Double-dummy blind, placebo- and active comparator-
controlled, 4-treatment, 3-arm 2x2 crossover part consisting of a 
single cohort of 36 participants to establish the anxiolytic PD 
properties of JNJ-61393215 after the administration of multiple 
doses. Participants were assigned to 1 of 6 treatment sequences.
The doses of JNJ-61393215 selected for part 2 were 25 mg qd 
and 90 mg qd; alprazolam (1 mg bid) was used as active 
comparator.
Participants Enrolled/Completed: 39/35
Treated with JNJ-61393215: 24
61393215EDI1003
(Completed)
Safety, tolerability, and PK of 
JNJ-61393215 in healthy 
participants after a single-dose of 
JNJ-61393215 administered 
alone and in combination with 
ritonavir
A single-center, open-label, and fixed-sequence study. 
Enrolled participants received 2 oral administrations of a 
single-dose of 2 mg JNJ-61393215 and/or 100 mg of 
ritonavir bid in the sequential order mentioned ahead-
2 mg JNJ-61393215 (On Day 1 – Morning Dose), 100 mg 
ritonavir (On Day 4 – Morning and Evening Dose), 2 mg 
JNJ-61393215 + 100 mg ritonavir (On Day 5 – Morning 
Dose), 100 mg ritonavir (On Day 5 – Evening Dose), and 
100 mg ritonavir (On Day 6 to 14 – Morning and Evening 
Dose). Morning dose administration on Day 1 
(JNJ-61393215) and on Day 5 (JNJ-61393215 and 
ritonavir) were done in fasting condition. All other dose 
administrations (ritonavir) were done in fed conditions.
Participants Enrolled/Completed: 12/12
Treated with JNJ-61393215: 12
61393215EDI1004
(completed)
Safety, tolerability, and PK of 
single and multiple ascending 
doses of JNJ-61393215 
(suspension) and Safety, 
tolerability, relative bioavailability 
and food-effect of a new solid 
formulation (capsules [G005]) 
of JNJ-6139321215 in healthy 
participants
This Phase 1 study will consist of 3 parts.
Part 1:
Participants Enrolled/Completed: 16/16
Treated with JNJ-61393215: 12
Part 2:
Participants Enrolled/Completed: 24/23
Treated with JNJ-61393215: 24
Part3:
Participants Enrolled/Completed: 16/15
Treated with JNJ-61393215: 12
Key: b.i.d. = twice daily, NA = not available, PK = pharmacokinetics, PD = pharmacodynamics, qd = once daily
Pharmacokinetics and Product Metabolism
After administration of a single dose of JNJ-61393215, Cmax and AUC∞increased in a 
dose-proportional manner up to 30 mg, and in a less than dose-proportional manner at doses above 


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30 mg. Between 1 mg and 250 mg, Cmax and AUC∞increased from 97.4 to 6,297 ng/mL and from 
2,148 to 124,351 ng.h/mL, respectively. However, in terms of unbound Cmax and AUC, the 
increase was less deviating from dose-proportionality. JNJ-61393215 was found to be a 
low-clearance drug with mean CL/F ranging from 0.419 to 2.08 L/h with fu ranging from 1.4% at 
a concentration of <100 ng/mL to 5% at approximately 5,720 ng/mL (2.5 hour postdose). The 
mean t1/2term ranged from 13.6 to 24.6 hours across cohorts. After a single oral dose of 30 mg 
JNJ-61393215 renal clearance was low (0.753 mL/h) and contributed minimally (<1% of dose) to 
the total clearance.
After single oral dose administration of 15 mg JNJ-61393215 to elderly healthy men and women, 
under fasted conditions, JNJ-61393215 cerebrospinal fluid (CSF) concentrations were lower than 
the corresponding unbound JNJ-61393215 plasma concentrations. After reaching tmax, the 
CSF/unbound plasma concentration ratios of JNJ-61393215 ranged from 0.420 at 1.5 hours after 
dosing to 0.752 at 12 hours postdose.
The amount of JNJ-61393215 excreted unchanged in urine was low. The mean percentage of dose 
excreted in urine was less than 0.3% in the 45 and 90 mg dose groups.
After administration of a single oral dose of JNJ-61393215 as a solid formulation (capsule) under 
fasted conditions, both at 30 mg and 145 mg, Cmax, AUClast and AUC∞were similar (all within 
15% based on GMR) to the corresponding values for a suspension.
After administration of a single oral dose of JNJ-61393215 as a solid formulation with a 
high-fat/high-calorie breakfast, Cmax, AUClast, and AUC∞(all within 20% based on geometric mean 
ratio [GMR]) were comparable to the values obtained after administration under fasted conditions, 
both at 30 and 145 mg.
With multiple doses of JNJ-61393215, mean Cmax and AUC24h increased with increasing doses on 
both Day 1 and Day 7. Mean values for the dose normalized PK parameters on Day 1 and Day 7 
slightly decreased with increasing doses, suggesting a less than dose proportional increase over 
the dose range of 5- to 245-mg qd JNJ-61393215. The fraction unbound (fu) of JNJ-61393215 
increased with increasing JNJ-61393215 plasma concentrations and decreased with increasing 
alpha-1 acid glycoprotein concentrations.
Median tmax of JNJ-61393215 on Day 7 was 1.25 hours postdose for the 5 mg dose and 1.50 to 
2.50 hours postdose for all other doses of JNJ-61393215. Mean t1/2term was similar for the 4 
JNJ-61393215 dose groups of 17.1 h (5 mg), 14.3 h (15 mg), 17.5 h (45 mg), 13.4 h (90 mg), 16.6 
h (145 mg), and 13.0 h (245 mg). Mean CL/F and Vd/F values increased with increasing dose. 
Individual mean Vd/F values at each JNJ-61393215 dose was 16.3 L (5 mg), 17.4 L (15 mg), 24.5 
L (45 mg), 27.0 L (90 mg), 43.0 L (145 mg) and 54.3 L (245 mg). Individual mean CL/F values at 
each JNJ-61393215 dose was 0.789 L/h (5 mg), 0.878 L/h (15 mg), 1.02 L/h (45 mg), 1.45 L/h 
(90 mg), 1.96 (145 mg) and 3.04 (245 mg). Accumulation ratios for Cmax and AUC24h were low 
and similar across dose levels. Mean ARCmax at each JNJ-61393215 dose were 147.48% (5 mg),
117.96% (15 mg), 114.95% (45 mg), 107.08% (90 mg), 100.38% (145 mg) and 91.59% (245 mg); 


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mean ARAUC values were 136.37% (5 mg), 126.87% (15 mg), 114.17% (45 mg) and 103.37% 
(90 mg), 111.71% (145 mg) and 99.01% (245 mg).
The mean P/T ratio and fluctuation index (FI) was similar for the 4 dose groups, with mean values 
ranging from 3.48 to 4.67 for the P/T ratio, and from 117% to 151% for the FI. 
When co-administering a single-dose of 2 mg JNJ-61393215 with 100 mg bid ritonavir (test), 
JNJ-61393215 Cmax was similar (ratio: 1.09) and AUC∞increased 3.74-fold compared to a 
single-dose of 2 mg JNJ-61393215 alone.
Pharmacodynamics
No clear PD effects were observed in the FIH Study 61393215EDI1001 and no trends were noted 
in analysis of NeuroCart parameters (including Visual Analogue Scale [VAS] Alertness, VAS 
Mood, VAS Calmness, VAS External and VAS Internal, VAS Feeling High, FACIT-F subscale, 
Swiss Nacrolepsy, Word Recall, Delayed Word Recall, electroencephalogram [EEG] analysis, 
Smooth Pursuit, Body Swaying, Adaptive Tracking, Saccadic Inaccuracy, Saccadic Peak Velocity, 
and Saccadic Reaction Time).
In Study 61393215EDI1002, there was a statistically significant reduction in CO2-induced fear 
and anxiety symptoms as measured by the Panic Symptoms List IV (PSL-IV). JNJ-61393215 
(90 mg) and alprazolam (1 mg) reduced the PSL-IV total score versus placebo with a one-sided 
p-value <0.1, supporting a potential anxiolytic effect of 90 mg JNJ-61393215.
Treatment with 1 mg alprazolam bid (active comparator) was associated with a statistically 
significant reduction of fear potentiated startle (FPS), while 25-mg and 90-mg doses of 
JNJ-61393215 were ineffective, as observed with another OX1R antagonist.
Safety and Tolerability
No significant safety findings were observed in Phase 1 clinical studies completed to date.
Of the 62 participants dosed with JNJ-61393215 in the FIH Study 61393215EDI1001, the most 
common treatment-emergent adverse events (TEAEs) for all doses of JNJ-61393215 in all parts 
of the study were somnolence (n=9), headache (n=8), and nasopharyngitis (n=4). Most of the 
TEAEs were considered by the investigator as ‘not related’ or ‘doubtful’ in participants dosed with 
JNJ-61393215. Somnolence was considered by the investigator to be ‘possibly’ or ‘very likely’ 
related to JNJ-61393215 in 4 participants from Part 1 and headache was considered as ‘possibly’ 
related to JNJ-61393215 in 1 participant in the Part 3 cohort.
All but one TEAEs were mild in severity. Two participants dosed with 15 mg JNJ-61393215, who 
underwent a CSF sampling procedure during Part 2, were reported with post lumbar puncture 
syndrome. These were considered as moderate in severity and not related to JNJ-61393215. There 
were no deaths, any serious adverse events (SAEs) or any TEAEs leading to discontinuation during 
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The most common TEAEs (reported by ≥10% of participants) in participants treated with 5-, 15-, 
45-, or 90 mg JNJ-61393215 qd in Part 1 of Study 61393215EDI1002 were headache (33.3%), 
somnolence (29.2%), nausea (16.7%), nasopharyngitis (16.7%), dysgeusia (12.5%), and epistaxis 
(8.3%). The most common TEAEs in the placebo group were headache (37.5%), somnolence 
(37.5%), dysgeusia (25.0%), and abdominal pain upper (25.0%). None of the TEAEs were 
considered severe. The most common TEAEs (reported by ≥10% of participants) in participants 
treated with 25- or 90-mg JNJ-61393215 qd in Part 2 of Study 61393215EDI1002 were 
somnolence (48.0%), headache (12.0%), and abdominal pain upper (12.0%). The most common 
TEAEs in the alprazolam group were somnolence (69.2%), and dizziness postural (23.1%). The 
most common TEAEs in the placebo group were somnolence (44.7%), headache (28.9%), and 
nasopharyngitis (10.5%). None of the TEAEs were considered severe.
In Study 61393215EDI1003, the most common TEAE in participants dosed with JNJ-61393215 
was bowel movement irregularity (1 [8.3%] of 12 participants). The most common TEAEs in the 
ritonavir total group were abdominal discomfort, leukopenia, photophobia, nasopharyngitis, upper 
respiratory tract infection, alanine aminotransferase increased, hyperuricaemia, somnolence, 
cough, and hyperhidrosis (1 [8.3%] of 12 participants each) and headache (2 [16.7 %] of 
12 participants).
In Part 1 of Study 61393215EDI1004, the most common TEAEs following a single dose 
administration with JNJ-61393215 were nausea, fatigue, headache, and hot flush (1 [8.3%] of 
12 participants). In Part 2 of Study 61393215EDI1004, the most common TEAEs (reported by 
≥10% of participants) were fatigue (8 [33.3%] of 24 participants), headache (7 [29.2%] of 
24 participants), and somnolence (3 [12.5%] of 24 participants). In Part 3 of Study 
61393215EDI1004, the most common TEAEs (reported by ≥10% of participants) following a 
multiple ascending dose administration in a fasted state with JNJ-61393215 were fatigue 
(6 [50.0%] of 12 participants) and headache (2 [16.7%] of 12 participants).
In study 61393215EDI1001 none of the participants had a QTc increase >60 msec or absolute 
QTc ≥470 msec. Four participants had a change in QTc >30 msec from baseline following a single 
oral dose of 2-, 30-, 60-, and 15-mg JNJ-61393215, however, no clear dose-response relationship 
nor a clear relationship with a specific timing after dosing were observed. Those findings were not 
confirmed in the multiple ascending dose (MAD) study 61393215EDI1002.
In Study 61393215EDI1004, three participants had a change in QTc >30 msec from baseline 
following a single oral dose of 30- and 145-mg JNJ-61393215 in Part 1 and Part 2 of the study. 
There was no clear relationship with exposure or a specific time after dosing. None of the 
participants dosed in the MAD part of the study (Part 3) had a change in QT interval corrected 
according to Bazett’s formula (QTcB)/ QT interval corrected according to Fridericia’s formula
(QTcF) >30 msec from baseline following administration of JNJ-61393215. None of the 
participants had a QTcB/QTcF increase >60 msec or absolute QTcB/QTcF >480 msec. None of 
the electrocardiogram (ECG) abnormalities were reported as TEAEs.
There were no consistent treatment-related effects in clinical laboratory parameters (hematology, 
biochemistry, coagulation profile and urinalysis), vital signs, or electrocardiogram (ECG) 


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measurements, and no abnormalities were observed during physical examination in the Phase 1 
studies.
JNJ-61393215 is generally safe and well tolerated.
Refer to IB for additional details (IB Edition 4, 2019)10.
2.3.
Benefit-Risk Assessment
In total, 170 healthy participants have been exposed to single or multiple doses of JNJ-61393215
in the 4 completed clinical studies. No significant safety concerns were encountered after 
single-dose administration of JNJ-61393215 up to 250 mg and after multiple-dose administration 
of JNJ-61393215 up to 245 mg. 
The primary objective of this study is to investigate the efficacy of JNJ-61393215 as an adjunctive 
therapy in participants with MDD with anxious distress. Participants will receive active study 
intervention (JNJ-61393215) or placebo for 6 weeks. Participants may not benefit from the study 
in terms of long-term improvement of their symptoms. However, participants with poor response 
to their current treatment may benefit from the extensive medical review and disease follow-up 
during the study. 
Additionally, the safety and tolerability data so far accumulated for JNJ-61393215 in healthy 
participants were generally acceptable based on a thorough review of the safety information from 
completed clinical studies. No death or SAEs have been reported after participants received 
JNJ-61393215. The most commonly reported treatment-emergent adverse events (TEAEs) in 
JNJ-61393215-treated participants were somnolence and headache.
To ensure safe use of the study drug, besides routine safety monitoring and participant
management, this protocol also includes specific risk mitigation strategies such as reducing 
suicidality risk inherent in the underlying depression by excluding high risk participants and 
performing the Colombia suicide severity rating scale (C-SSRS) at every site visit. 
More detailed information about the known and expected benefits and risks of Orexin-1 may be 
found in the IB.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Primary
The primary objective of this study is to evaluate the efficacy of JNJ-61393215 as adjunctive 
treatment compared to adjunctive placebo, as assessed by the change from baseline to week 6 on 
a 17-item Hamilton Depression Rating Scale (HDRS17) in participants with MDD with anxious 
distress with a score ≥2 on item 26 or 27 of the Inventory of Depressive Symptomatology, 
Clinician Rating -30 (IDS-C30), who have a suboptimal response to current treatment with a 
standard antidepressant.


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3.2.
Secondary
The key secondary objective is to evaluate the impact of adjunctive treatment with JNJ-61393215 
compared to adjunctive placebo on the severity of anxiety as measured by the change in the 
Hamilton Anxiety Rating scale (HAM-A) from baseline to Week 6.
Other secondary objectives are:

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive 
placebo on the severity of anxiety as measured by the change in HAM-A from baseline to 
weeks 2 and 4.

To evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive 
placebo, as assessed by the change from baseline to Week 6 on the HDRS17 in participants 
with a baseline HAM-A score ≥20.

To evaluate the efficacy of JNJ-61393215 as adjunctive treatment compared to adjunctive 
placebo, as assessed by the change from baseline to Week 6 on the HAM-A in participants 
with a baseline HAM-A score ≥20.

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive 
placebo on participant-reported severity of anxiety as measured by the change in the General 
Anxiety Disorder-7 scale (GAD-7) from baseline to Week 6.

To evaluate the impact of adjunctive treatment with JNJ-61393215 compared to adjunctive 
placebo on participant-reported severity of symptoms of MDD, as measured by the change in 
the Patient Health Questionnaire (PHQ-9) from baseline to weeks 2, 4 and 6.

To evaluate the change in HDRS17 from baseline to weeks 2 and 4. 

To investigate the overall safety and tolerability of adjunctive treatment with JNJ-61393215 
in participants with MDD with anxious distress.

To evaluate pharmacokinetics of JNJ-61393215 in participants with MDD with anxious 
distress.

To evaluate directly and/or indirectly the impact of plasma protein binding on the PK of 
JNJ-61393215 in participants with MDD with anxious distress. 
3.3.
Exploratory
The exploratory objectives are:

To explore the relationship between JNJ-61393215 pharmacokinetics and selected efficacy 
endpoints (e.g. HDRS17) or safety parameters after repeated dosing of JNJ-61393215, if 
deemed appropriate.

To explore the relationship between biomarkers of HPA axis, metabolic, and immune system 
function, and the clinical response of depression/anxiety symptoms upon adjunctive treatment 
with JNJ-61393215, if deemed appropriate.

To explore the effect of JNJ-61393215 versus placebo on biomakers of the hypothalamic–
pituitary–adrenal (HPA) axis, if deemed appropriate


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HYPOTHESIS
The primary hypothesis of this study is that treatment with JNJ-61393215 will lead to significant 
improvement in depressive symptoms from baseline compared to placebo when administered as 
an adjunctive treatment to a standard antidepressant in the treatment of MDD patients with anxious 
distress with a score ≥2 on item 26 or 27 of the IDS-C30 who have a suboptimal response to 
current standard treatment. Significant improvement will be demonstrated by improvement in 
depressive symptoms from baseline to the 6-week endpoint in the HDRS17 total score.
4.
STUDY DESIGN
4.1.
Overall Design
This is a double-blind, placebo-controlled, randomized, parallel-group, multicenter study. An 
estimated target of approximately 218 participants will be randomly assigned in this study with 
109 participants planned per treatment group.
Sample size may be re-adjusted if the observed screening response rate, the drop-out rate 
(including drop-outs due to the COVID-19 pandemic), or the standard deviation substantially 
deviate from the assumed value (see Section 9.1 and 9.3). Overall sample size can increase with 
maximal 25%. The potential maximal number of participants to be enrolled in this trial would be 
272.
Study population
The target study population includes male and female participants, between 18 and 64 years of age 
inclusive, with a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 
diagnosis of MDD with anxious distress, confirmed by the Mini International Neuropsychiatric 
Inventory (MINI) Plus with module for MDD with anxious distress2,13,23,24. Participants also need 
to:

have moderate to severe depression (IDS-C30 total score ≥35)

have symptoms of somatic anxiety (score ≥2 on item 26 or 27 of the IDS-C30) 

have a suboptimal response to at least one antidepressant in their current treatment
(improvement <50%)

have failed no more than 3 antidepressants (of adequate dose and duration), including their 
current treatment, in the current major depressive episode.
Participants will continue to take their standard treatment at an adequate and tolerated stable dose 
throughout the study. No antidepressant dose changes are permitted from screening through the 
end of the study, including the post-treatment phase.
The study will consist of 3 phases: a screening phase of up to 4 weeks, a double-blind treatment 
phase of 6 weeks, and a posttreatment follow-up phase of 2 weeks, as shown in Figure 1. The total 
duration of participant participation will be approximately 12 weeks. The end of study is defined 
as the date of the last visit of the last participant in the study.


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Figure 1:
Schematic study overview
Screening
No trial specific screening procedures will be undertaken prior to finalization of the informed 
consent form (ICF) procedures and the provision of written informed consent by the participant. 
After giving written informed consent, participants will be screened between 28 days and 4 days 
prior to baseline to ascertain their eligibility for the study according to the inclusion and exclusion 
criteria. Screening will include assessment of study inclusion and exclusion criteria, medical 
history and demographics, physical examination, psychiatric and safety evaluations and standard 
lab tests. Upon completion of all ICF procedures, recording of AEs and concomitant medication 
will start.
During the screening phase, assessments will be done as described in the Schedule of Activities 
(SoA).
The screening phase will consist of:
1) a screening visit and 
2) a SAFER interview by phone, with an independent rater. [SAFER is an acronym for: State 
versus trait; Assessability; Face validity; Ecological validity; and Rule of three Ps (pervasive, 
persistent, and pathological)]


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To define a diagnosis of MDD with anxious distress according to DSM-5 and exclude comorbid 
psychiatric disorders, the MINI 7.0 Plus with module for MDD with anxious distress will be used 
during screening. In addition, the severity of depression and the symptoms of somatic anxiety will 
be assessed by the IDS-C30, using the semi-structured interview guide for the IDS-C30. 
The HDSR17 and HAM-A will be done at screening, using the Structured Interview Guide for the 
HDRS17 (SIGH-D) and the Structured Interview Guide for the HAM-A (SIGH-A), respectively.
The SIGH-D and HAM-A will be completed by the same rater from screening throughout the 
study for a given participant. Exceptions will need to be discussed with and approved by the 
sponsor. The sponsor can request a rater change based on quality concerns, identified during the 
independent data quality monitoring.
The clinician-rated IDS-C30 is a 30-item, depression-specific symptom severity rating scale17. The 
IDS-C30 is designed to measure the specific signs and symptoms of depression, including 
melancholic, atypical and anxious features. Total scores range from 0 to 84 with higher scores 
representing greater severity of depressive symptoms. The inter-rater reliability and internal 
consistency coefficients are high18.  The IDS-C30 and the IDS-self report have reasonable 
construct validity, and a concurrent validity index above 0.90, correlating well with the HDRS17 
and the Beck Depressive Inventory18. A semi-structured interview guide for the IDS-C30 is 
available and provides a set of standardized introductory questions and follow-up prompts that are 
helpful in standardizing test administration. For this reason, the semi-structured interview guide 
version of the IDS-C30 will be used in the current study to facilitate and standardize gathering 
clinical information from the participant.
The structured Massachusetts General Hospital Antidepressant Treatment History Questionnaire 
(MGH-ATRQ) will be used retrospectively to determine a suboptimal response to the current 
standard oral antidepressant therapy. Determination of the number of failed antidepressant 
treatments 
in 
the 
current 
episode 
will 
be 
made 
retrospectively 
using 
medical/pharmacy/prescription records or a letter from a treating physician and documented on 
the MGH-ATRQ. IDS-C30 scores and MGH-ATRQ will be confirmed by the SAFER interview.
The procedures scheduled during the screening visit may be divided over multiple days, according 
to operational and/or site/country-specific needs. If the screening visit is conducted over multiple 
days, the following assessments must be performed first and on the same day: MINI 7.0 Plus, 
MGH-ATRQ, IDS-C30, HAM-A, SIGH-D and C-SSRS. These will be done by a qualified rater 
at the site. Only participants that fulfill the criteria for MINI 7.0 Plus, MGH-ATRQ, C-SSRS and 
IDS-C30 will continue the screening phase.
Once a participant has performed all screening assessments and has been confirmed eligible for all 
screening criteria, a SAFER interview will be performed by an independent rater, minimally 21
days following the screening visit (first day if split over multiple days) and within 7 to 4 days of 
baseline.


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During this SAFER interview the following items will be confirmed:

MDD diagnosis: according to SAFER Criteria Inventory

suboptimal response to current standard oral antidepressant therapy: improvement <50% 
according to the MGH-ATRQ

moderate to severe depression: IDS-C30 score ≥35 

somatic anxiety: score of ≥ 2 on either items 26 or 27 of the IDS-C30
If participants are confirmed to meet these criteria, they are eligible for the study.
During the SAFER interview, the IDS-C30 will be performed again by the independent rater and 
the MGH-ATRQ performed by the site during the screening visit, will be reviewed and confirmed.
Therefore, the MGH-ATRQ will be provide to the independent rater prior to the SAFER interview.
The semi-structured interview guide for IDS-C30 and SIGH-D done by the qualified site raters 
will be audio-recorded, as well as the SAFER interviews, to allow for independent data quality 
monitoring. If more time is needed to discuss the outcome of the site rater, of the SAFER interview 
and of the independent data quality monitoring, the screening phase may be extended beyond 28 
days, upon discussion with and approval from the sponsor, without constituting a protocol 
deviation.
If quality concerns for the SAFER interview are raised during the independent data quality 
monitoring, the SAFER interview will be repeated with a different rater, and the screening window 
can be extended until the repeat SAFER interview is done, without constituting a protocol 
deviation.
Double-blind treatment phase
Participants who successfully complete the screening phase will be randomized to receive either 
adjunctive placebo or adjunctive treatment with 135 mg of JNJ-61393215 in a 1:1 ratio for a 
6-weeks treatment period. Participants will visit the clinical site at baseline (Week 0), Weeks 2, 4 
and 6. During clinic visits, assessments will be performed according to the SoA. 
Efficacy assessments include HDRS17, HAM-A, PHQ-9 and GAD-7. 
During the treatment period, the severity of depression will be assessed using the HDRS17. 
Safety assessments will include the monitoring of adverse events, physical examinations, vital 
signs measurements, clinical laboratory tests (including liver enzymes and thyroid enzymes), 
12-lead ECGs, and C-SSRS. 
In addition, samples for PK and biomarkers (including DNA and RNA samples) will be collected. 
Follow-Up Visit / End-of-Study Visit
Approximately 2 weeks after last dosing, participants will return to the clinical unit for a follow-up 
visit. Follow-up procedures will be performed as described in the SoA.


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If a participant withdraws from the study before the end of the double-blind treatment phase, he or 
she will be advised to complete the end-of-study (follow-up) assessments.
4.2.
Scientific Rationale for Study Design
Randomization, Blinding, Control, Study Phase/Periods, Treatment Groups
This will be a multi-center, double-blind, randomized, placebo-controlled study in participants with 
MDD with anxious distress. 
Randomization will be used to avoid bias in the assignment of participants to intervention groups, 
to increase the likelihood that known and unknown participant attributes (e.g., demographic and 
baseline characteristics) are evenly balanced across intervention groups, and to enhance the 
validity of comparisons across intervention groups. Blinded intervention will be used to reduce 
potential bias during data collection and evaluation of clinical endpoints. 
A placebo control is used to establish the frequency and magnitude of changes in clinical endpoints 
that may occur in the absence of active intervention. During the study, the participant, investigator 
and sponsor will be blinded to intervention allocation up to completion of the study.
Population 
Comorbid anxiety occurs with significant frequency in patients with MDD and leads to greater 
refractoriness to treatment, more severe illness and higher risk for suicide.  Addressing anxiety 
symptoms in the context of depression may lead to improved outcomes for patients and more rapid 
relief of depression symptoms.
Treatment duration
A treatment duration of 6 weeks is considered appropriate to detect efficacy of antidepressant 
medications as compared to placebo19,28.
Clinical assessments
Depression
Hamilton Depression Rating Scale-17 (HDRS17)
The HDRS17 is a Clinician-Administered rating scale designed to assess the severity of symptoms 
in participants diagnosed with depression6 with a score range of 0 to 52. It is the most widely used 
symptom severity measure for depression. Each of the 17 items is rated by the clinician on either 
a 3- or a 5-point scale. The recall period is one week. The HDRS has an inter-rater reliability 
correlation of r = 0.90 and the internal consistency of the measure is reported to be high with a 
coefficient alpha of 0.88. Criterion-related validity for this measure is high; Knesevich et al. found 
a high correlation between the Hamilton score and a psychiatrist’s global rating (r = 0.89, and 
between the change in these ratings during treatment (r = 0.68)11. The structured interview guide 
for the Hamilton depression scale (SIGH-D) is based on the HDRS17 and will be used in this study 
to take the HDRS1729. 


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Patient Health Questionnaire (PHQ-9)
The PHQ-9 will be used as a patient-reported measure of depressive symptomatology25. The 
PHQ-9 is a 9-item scale, where each item is rated on a 4-point scale (0=Not at all, 1=Several Days, 
2=More than half the days, and 3=Nearly every day), with a total score range of 0 to 27. The recall 
period is 2 weeks.
Anxiety
Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A)
This original HAM-A scale assesses the severity of different anxiety-related symptoms7,8 with a 
score range of 0 to 56. It is the most widely used symptom severity measure for anxiety. Each of 
the 14 items is rated by the clinician on a 5-point scale ranging from 0 (not present) to 4 (maximum 
degree). The HAM-A has an inter-rater reliability correlation of r = .7415 and the internal 
consistency of the measure is reported to be high with a coefficient alpha of .864.  The symptoms 
can be grouped into two clusters: psychic anxiety and somatic anxiety.
As the original HAM-A lacks instructions for administration and clear anchor points for the 
assignment of severity ratings, the structured interview guide version will be used in the current 
study (Shear 2001).  The SIGH-A has been shown to have high inter-rater and test-retest reliability 
and produced similar but consistently higher (+ 4.2) scores compared to the original HAM-A. 
Correlation with a self-report measure of overall anxiety has also been shown to be high22. 
Subscales, such as the HAM-A6 which focuses on psychic anxiety and may be more sensitive to 
certain treatments, can be derived from the SIGH-A.
Generalized Anxiety Disorder 7 (GAD-7) 
The GAD-7 is a self-reported questionnaire for screening and severity measuring of generalized 
anxiety disorder (GAD)26. GAD-7 has seven items, which measure severity of various signs of 
GAD according to reported response categories with assigned points (see below). Assessment is 
indicated by the total score, which made up by adding together the scores for the scale all seven 
items27.
GAD-7 is a sensitive self-administrated test to assess generalized anxiety disorder12 normally used 
in outpatient and primary care settings for referral to psychiatrist pending outcome14. However, it 
cannot be used as replacement for clinical assessment and additional evaluation should be used to 
confirm a diagnosis of GAD. 
The scale uses a normative system of scoring as shown below, with question at the end 
qualitatively describing severity of the patient's anxiety over the past 2 weeks14. 

Not at all (0 points)

Several days (1 point)

More than half the days (2 points)

Nearly every day (3 points)


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Safety assessments
Standard safety assessments including physical examination, vital signs, 12-lead ECG, clinical 
chemistry (including liver enzymes and thyroid hormones), hematology, and urinalysis will be 
performed. 
Additionally, emergence of suicidal ideation will be assessed using the C-SSRS16. The C-SSRS 
has been used frequently in clinical studies and is a standard measure for suicidal ideation 
assessment according to FDA guidance (US FDA 2012).  
DNA, RNA 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 allow for the identification 
of genetic (DNA) and/or transcription (RNA) factors that may influence the PK, efficacy, safety, 
or tolerability of JNJ-61393215 and to identify genetic factors associated with MDD. The RNA 
will be collected pre- and posttreatment to allow examination of changes in gene transcription 
related to administration of JNJ-61393215 and/or changes in other biomarkers collected during the 
study (eg, cortisol, cytokines, etc.). DNA genotyping may include, but is not limited to, 
interrogation of single nucleotide polymorphisms (SNPs) at discrete loci implicated in mood 
disorders. DNA samples may be used to help address emerging issues and to enable the 
development of safer, more effective and ultimately individualized therapies in the future.
Blood samples will be collected to explore biomarkers related to endocrine, metabolic, and 
immune system activity [including but not limited to cortisol, adrenocorticotropic hormone 
(ACTH), growth factors, inflammation, or metabolic markers]. Many of these factors may be 
influenced by stage of menstrual cycle in women; therefore, the menstrual cycle will be tracked in 
premenopausal women during the study, by the participant’s verbal report. Biomarker samples 
may help to explain interindividual variability in clinical outcomes or identify population 
subgroups that respond differently to JNJ 61393215.
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during 
the study, participants will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only participants who are fully able to understand the risks, 
benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Although some of the participants with MDD in this study may benefit from the 6-week treatment 
period, participants will not be allowed to continue the treatment after completion of the study. 
This is explained by the limited experience with long term treatment with JNJ-61393215. So no 
long-term benefit is to be expected in this study. Participants might benefit from the clinical 


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evaluations and the information collected as part of this study. The results of the investigation of 
JNJ-61393215 may help future patients.
The primary ethical concern is the use of a placebo arm. A placebo arm is warranted and necessary 
to establish the frequency and magnitude of changes in clinical endpoints that may occur in the 
absence of active treatment. Treatment with placebo dosing is not equivalent to nontreatment; 
study intervention will be administered adjunctively to standard antidepressant therapy. All 
medication treatment will occur within the context of carefully supervised and supportive care. 
Only investigators experienced in the treatment of MDD will participate in the trial and can provide 
expert guidance on the alternatives for treatment if participants elect to discontinue the study prior 
to the last visit or after the completion of the study. Participants will be monitored for the severity 
of their major depressive episode including assessment of suicidality to ensure the safety of 
participants and confirm whether continuation in the study is in their best interest.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of a Red 
Cross blood donation.
4.3.
Justification for Dose
In this proof-of-concept study, the efficacy of JNJ-61393215 will be evaluated at a single dose that 
is anticipated to provide maximum probability of success whilst being well tolerated.
JNJ-61393215 dose selection considers the previously clinically observed safety and tolerability 
profile, signs of PD activity, exposure ratios relative to those at NOAEL in 3-month GLP 
toxicology studies and the PK data to date. 
In clinical studies 61393215EDI1001 and 61393215EDI1004, a single dose up to 250 mg and 
repeated QD dosing for 1 week at doses up to 245 mg QD were well tolerated.
At the selected 135 mg QD regimen, the anticipated safety margin (versus 75 mg/kg/day NOAEL 
in 3-month GLP TOX study in rat) (considering the differences in plasma protein binding in rat 
and man) is approximately 5, considering unbound exposure, and approximately 0.6-fold, 
considering total exposure.
JNJ-61393215 was tested in a rat model of CO2-induced panic (Study DD17205), using oral doses 
of 3-, 10-, and 30-mg/kg administered 30 to 50 minutes prior to the CO2 challenge. JNJ-61393215 
had no effect on baseline cardiovascular, temperature or locomotor activity, and blocked 
CO2-induced anxiety behavior in the social interaction test at 10 mg/kg and 30 mg/kg, i.e., 
maximum effect was observed at the highest doses, suggesting larger effects at highest OX1R
occupancy instead of a U-shaped dose-response curve.
The potential of JNJ-61393215 as anxiolytic was also evaluated in study 61393215EDI1002 by 
estimating the reduction in panic symptoms induced by a CO2 challenge in healthy participants. 
The study was placebo-controlled; the active control (alprazolam) and a 90 mg JNJ-61393215 QD
regimen were positive (statistically significant reduction in fear and anxiety symptoms in the Panic 
Symptoms List IV [PSL-IV] assessment); the 25 mg JNJ-61393215 QD regimen did not 


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demonstrate a statistically significant effect. These data, in line with non-clinical data suggest 
larger effects at highest OX1R occupancy. 
Given the steep dose-response in the 25 to 90 mg QD dose range, a 90 mg QD regimen may not 
provide maximal response yet. Therefore, the safety/tolerability of doses higher than 90 mg QD 
(145 and 245 mg QD) was confirmed in study 61393215EDI1004. Given that no substantial 
exposure increase was reached beyond 145 mg QD, the 245 mg QD regimen was not considered 
for this study. In order to minimize the burden for the patient, a 135 mg QD regimen (3 capsules
per day) was selected instead of the 145 mg QD regimen.
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as the last visit for the last participant in the study. The final data 
from the study site will be sent to the sponsor (or designee) after completion of the final participant 
visit at that study site, in the time frame specified in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed 
assessments at Week 6 of the double-blind phase.
Participants who prematurely discontinue study intervention for any reason before completion of 
the double-blind phase will not be considered to have completed the study.
5.
STUDY POPULATION
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study.  Waivers are not 
allowed. 
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Male and female participants between 18 and 64 years of age, inclusive.
2. Participants must have a body mass index (BMI) between 18 and 36 kg/m2, inclusive 
(BMI = weight/height2).
3. Participants must have a primary DSM-5 diagnosis of MDD with anxious distress, as assessed 
by the MINI 7.0. Plus (with module for MDD with anxious distress). Participants with a 
diagnosis of comorbid Generalized Anxiety Disorder (GAD), Post-Traumatic Stress Disorder, 
Persistent Depressive Disorder, Attention Deficit Hyperactivity Disorder (ADHD), Social 
Anxiety Disorder or Nicotine/Caffeine Dependence may be included, if the investigator 
considers MDD to be the primary diagnosis. Participants with Panic Disorder with or without 
agoraphobia may be included if the Panic Disorder diagnosis is primary.


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4. Participants must have an IDS-C30 total score ≥35 (moderate to severe depression) at 
screening, as confirmed by the SAFER independent rater.
5. Participant must have an IDS-C30 score for item 26 or 27 (symptoms of somatic anxiety) ≥2 
at screening, as confirmed by the SAFER independent rater.
6. Participant must not have received more than 3 failed antidepressant treatments (of adequate 
dose and duration), including their current treatment, in the current episode of depression, as 
documented by the MGH-ATRQ.
7. Participant must be currently receiving 1 of the following antidepressants for at least 6 weeks 
duration at screening, at an adequate therapeutic dose, as determined by the MGH-ATRQ and 
should remain on a stable dose throughout the study: bupropion, citalopram, escitalopram, 
sertraline, paroxetine, venlafaxine, desvenlafaxine, duloxetine, fluoxetine, vilazodone, 
vortioxetine, mirtazapine, agomelatine, nortriptyline, imipramine, amitriptyline and 
levomilnacipran. Fluvoxamine is not allowed as it is a moderate CYP3A4 inhibitor and JNJ-
61393215 is mainly metabolized by CYP3A4.
8. Participants must have a suboptimal response (improvement <50%) to the antidepressant used 
as their current treatment, as measured by the MGH-ATRQ. 
9. Participants must be healthy for their age group or medically stable with or without medication 
on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed 
at screening or at baseline. If there are abnormalities, they must be consistent with the 
underlying illness in the study population with written concurrence with the JRD responsible 
safety physician.
10. For participants with hypothyroidism who are on stable treatment for 3 months prior to 
screening: if the TSH value is out of range, but FT4 is normal, such cases should be discussed 
directly with the JRD responsible safety physician before the participant is enrolled. If the FT4 
value is out of range, the participant is not eligible.
11. Men who are sexually active with a woman of childbearing potential and have not had a 
vasectomy must agree to use a barrier method of birth control e.g., either condom or partner 
with 
occlusive
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository for the duration of the study plus 3 months after receiving the 
last dose of study drug. In addition, their female partners should also use an additional method 
of birth control (which may include a hormonal method, an intrauterine device [IUD] or an 
intrauterine system [IUS]) for at least the same duration.
12. Men must not donate sperm during the study and for 3 months after receiving the last dose of 
study drug.
13. Men should use a condom if their partner is pregnant.
14. Before randomization, a woman must be either:


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a.
Not of childbearing potential: postmenopausal (>50 years of age with amenorrhea for 
at least 12 months, or any age with amenorrhea for at least 6 months and a serum follicle 
stimulating hormone (FSH) level at screening >40 IU/L without hormonal replacement 
therapy); permanently sterilized [e.g., tubal occlusion (tubal cauterization and other 
comparable methods), hysterectomy, bilateral salpingectomy]; or otherwise be 
incapable of pregnancy.
b. Of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for 
participants participating in clinical studies (i.e. one that results in a less than 1% per 
year failure rate when used consistently and correctly). This may include:
i. Established and ongoing use of oral hormonal methods of contraception in 
combination with barrier methods.
ii. Established and ongoing use of patch, injected or implanted hormonal methods 
of contraception in combination with barrier methods.
iii. Placement of an IUD or IUS in combination with barrier methods. 
Accepted barrier methods as indicated above include:
1. condom with spermicidal foam/gel/film/cream/suppository 
2. occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository.
Note that a barrier method on its own is not sufficient.
iv. Male partner sterilization (the vasectomized partner should be the sole partner 
for that participant). 
v. True abstinence from heterosexual intercourse (when this is in line with the 
preferred and usual lifestyle of the participant). 
Women must agree to continue using these methods of contraception throughout the study 
and for at least 3 months after receiving the last dose of study intervention.
Note: If a woman of childbearing potential who is not heterosexually active becomes active 
after the start of the study, she must begin a highly effective method of birth control, as 
described above.
15. A woman of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test before the first dose. 
16. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for at least 3 months after receiving the last dose of study 
drug.
17. Participant must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol.
18. Participant must be able to read, understand and complete study questionnaires.


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19. Each participant must sign an informed consent form (ICF) indicating that he or she 
understands the purpose of and procedures required for the study and is willing to participate 
in the study.
Note:
The participant’s major depressive episode, severity of depression, somatic anxiety symptoms, 
treatment response and failed treatment must be deemed "valid" using the SAFER criteria 
interview (which includes the IDS-C30, a review of the MGH-ATRQ, and the SAFER Criteria 
Inventory) administered by the SAFER independent rater.
5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1. Participant has any other current Axis I psychiatric condition, including, but not limited to, 
MDD with current psychotic features, bipolar disorder (including lifetime diagnosis), 
obsessive-compulsive disorder, borderline personality disorder, eating disorder (e.g., bulimia, 
anorexia nervosa), or schizophrenia (lifetime). As noted above, participants with a diagnosis 
of comorbid GAD, Post-Traumatic Stress Disorder, Persistent Depressive Disorder, ADHD,
Social Anxiety Disorder, or Nicotine/Caffeine Dependence may be included, if the investigator 
considers MDD to be the primary diagnosis. Participants with Panic Disorder with or without 
agoraphobia may be included if the Panic Disorder diagnosis is primary.
2. Participant has an age of onset of depression after 55 years of age.
3. Participant has a history of alcohol or substance use disorder (abuse/dependence) within 
6 months prior to screening (nicotine and caffeine dependence are not exclusionary).
4. Participant has a current or recent (within the past year) history of clinically significant suicidal 
ideation (corresponding to a score of ≥ 3 for ideation) or any suicidal behavior within the past 
year, as validated on the C-SSRS at screening or baseline. Participants with a prior suicide 
attempt of any sort, or history of prior serious suicidal ideation/plan should be carefully 
screened for current suicidal ideation and only included at the discretion of the investigator. 
5. Length of current major depressive episode > 60 months.
6. Participant has organic brain disease or dementia.
7. Participant has known or suspected intellectual developmental disorder.
8. Participant has been treated with at least one of the following treatments:
-
electroconvulsive therapy in the current episode 
-
deep brain stimulation (lifetime) 
-
repetitive transcranial magnetic stimulation within 4 weeks prior to baseline visit.


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9. Participant has any clinically relevant medical condition that could potentially alter the 
absorption, metabolism, or excretion of the study intervention, such as liver disease or renal 
disease.
10. Criterion modified per Amendment 2
10.1 Participant has a relevant history of any significant and/or unstable cardiovascular, 
respiratory, neurological (including seizures - uncomplicated childhood febrile seizures 
with no sequelae are not exclusionary) or significant cerebrovascular, renal, hepatic, 
dermatologic, hematologic, gastrointestinal or endocrine diseases. Hospitalization for a 
cardiovascular event (myocardial infarction, unstable angina, stroke, transient ischemic 
attack) within 3 months prior to the first administration of study drug is exclusionary. 
Diabetes mellitus (DM) may be allowed when the participant is stable (HbA1c less than 
7.5% or 58 mmol/mol).
11. Participant has any known malignancy or has a history of malignancy within the previous 5 
years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence 
of recurrence for at least 3 months before the first study drug administration or cervical 
intraepithelial neoplasia with surgical cure).
12. Female participants who are pregnant or breastfeeding.
13. Participant has uncontrolled hypertension – hypertension must be controlled for at least 
3 months prior to screening; the dosage of any antihypertensive medication must have been 
stable for the past 3 months. Participants with a supine systolic blood pressure >150 mmHg or 
a supine diastolic blood pressure >95 mmHg at screening or baseline will be excluded.
14. Criterion modified per Amendment 2
14.1 Participant has a history of human immunodeficiency virus (HIV) antibody positive, 
or tests positive for HIV at screening. If participants have been successfully treated for HIV 
infection and are HIV RNA negative, they will be allowed in the study.
15. Criterion modified per Amendment 2
15.1 Participant has a history of hepatitis B surface antigen (HBsAg) or hepatitis C antibody 
(anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or 
anti-HCV at screening. If participants have been successfully treated for HCV infection or 
have spontaneously recovered from HCV and are HCV RNA negative, they will be allowed 
in the study.
16. Participant has a positive urine drug screen for amphetamines/methamphetamines, MDMA, 
oxycodone, barbiturates, benzodiazepines, cocaine, opiates, cannabinoids, methadone, and 
phencyclidines or positive alcohol screen at screening. In the case of a participant having a 
positive drug screen for cannabinoids, barbiturates or opiates, a one-time repeat urine drug 


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screen may be performed at the discretion of the investigator, provided the participant is willing 
to abstain from cannabinoids and other prohibited substances during the study.
17. Criterion modified per Amendment 2
17.1 Participant has a clinically significant abnormal physical examination, vital signs or 
12-lead ECG at screening or baseline. Minor deviations in ECG, which are not considered 
to be of clinical significance to the investigator, are acceptable. If at screening visit QTcB 
or QTcF interval ≥450 ms for males or ≥470 ms for females, or >480 ms if bundle branch 
block and prolongation of the QTc interval are present, participant is excluded.
18. Criterion modified per Amendment 2
18.1 Participant has a diagnosis of congestive heart failure Class III or IV or has a history 
of untreated second- or third-degree heart block.
19. Participant has a history of known demyelinating diseases such as multiple sclerosis or optic 
neuritis.
20. Participant used monoamine-oxidase inhibitors (MAOI) within 4 weeks before screening.
21. Criterion modified per Amendment 2
21.1 Participant used benzodiazepines or other anxiolytics within 1 week before screening 
(refer to Section 6.5) or during screening.
22. Participant used suvorexant within 1 week before screening (refer to Section 6.5) or during 
screening.
23. Participant uses
sleep medication (eg, zolpidem, zaleplon, zoplicone, eszopliclone, 
diphenhydramine, and ramelteon), that is not on a fixed daily dose for at least 2 weeks prior to 
screening.
24. Participant used mood stabilizers (e.g. anticonvulsants and/or lithium) or antipsychotics within 
2 weeks before screening. 
25. Participant used esketamine within 1 week prior to screening.
26. Participant has known allergies, hypersensitivity, or intolerance to JNJ-61393215 or its 
excipients.
27. Participant is on treatment with moderate/strong CYP3A4 inhibitors and/or inducers (see 
Section 10.7).
28. Participant has major surgery, (eg, requiring general anesthesia) within 8 weeks before 
screening, or has not fully recovered from surgery, or has planned major surgery during the 
time the participant is expected to participate in the study. 


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Note: participants with planned surgical procedures to be conducted under local anesthesia 
may participate.
29. Participant has been exposed to an experimental drug or experimental medical device within 
90 days before screening.
30. Participant has been involuntarily committed to psychiatric hospitalization in the current 
episode.
31. Participant is a vulnerable participant (e.g. a participant kept in detention).
32. Participant has any condition that, in the opinion of the investigator, would compromise the 
well-being of the participant or the study or that could prevent, limit or confound the protocol-
specified assessments.
33. Participant used any other antidepressant therapy than described in Section 6.5, Concomitant 
Therapy, within 2 weeks prior to screening, for symptoms or other indications than MDD also 
if taken at subtherapeutic dose.
NOTE: Investigators should ensure that all study enrollment criteria have been met at 
screening. If a participant's status changes (including 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 participant should be 
excluded from participation in the study.
5.3.
Lifestyle Considerations
Potential participants 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. Participants may not consume food containing poppy seeds for 72 hours before the screening 
visit.
2. Participants should abstain from using illegal drugs at any time during the study. 
3. Alcohol consumption should be limited to maximum 3 alcoholic beverages during the week 
prior to Day 1 and maximum 3 alcoholic beverages weekly throughout study. 
4. Participants must avoid donating blood for at least 90 days after completion (i.e., final 
follow-up visit) of the study.
5. Participants should not take any prohibited medication or food supplements as indicated in the 
Section 6.5, ‘Concomitant Therapy’.
6. Participants should not consume grapefruit/grapefruit juice from 14 days prior to study 
intervention administration until the last study visit.


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7. Strenuous exercise may affect study specified assessments and laboratory safety results; for 
this reason, strenuous exercise should be avoided within 24 hours before all planned study 
visits.
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
Retesting of abnormal screening values (including laboratory values), at the discretion of the 
Investigator, that may lead to exclusion of a participant are allowed only once using an 
unscheduled visit during the screening phase. Retesting will take place during an unscheduled visit 
in the screening phase.
Participants who were screened but not randomized due to the COVID-19 measures, may be 
rescreened once. Rescreened participants should be assigned a different participant number as for 
the initial screening.
6.
STUDY INTERVENTION
6.1.
Study Intervention(s) Administered
Eligible participants will be randomized to 135 mg JNJ-61393215 or placebo at a 1:1 ratio.
JNJ-61393215 will be supplied for this study as 45-mg capsules. Placebo will be supplied as 
matching capsules. 
All participants will take three 45-mg capsules or three capsules of placebo once daily, either at 
the clinic, during visits, or at home, in between visits. As there is no effect of food on the absorption 
of JNJ-61393215, the study intervention can be administered irrespective of food intake (with or 
without a meal). Study intervention should be taken in the morning (before 12pm noon) at 
approximately the same time every day when feasible.
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed. 
The participants will attend each study visit in a fasted state and are to bring their study intervention 
with them. The study intervention will be self-administered by the participant after the completion 
of pre-dose study assessments and blood collections. Dosing will be witnessed by the study staff.


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On the days the participant attends the clinic, the date and time of study intervention administration 
must be captured in the source documents and the case report form (CRF). Study-site personnel 
will instruct participants on how to store study intervention for at-home use as indicated for this 
protocol. 
Orexin-1 will be manufactured and provided under the responsibility of the sponsor. Refer to the 
IB for a list of excipients.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention will be stored in a secure area with restricted access. Capsules must be stored 
at controlled room temperatures as indicated on the product specific labeling.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The dispensing of study intervention to the 
participant, and the return of study intervention from the participant (if applicable), must be 
documented on the intervention accountability form. Participants must be instructed to return all 
original containers, whether empty or containing study intervention. All study intervention will be 
stored and disposed of according to the sponsor's instructions. Study-site personnel must not 
combine contents of the study intervention containers.
Study intervention 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 intervention, and study intervention returned by the 
participant, must be available for verification by the sponsor's study site monitor during on-site 
monitoring visits. The return to the sponsor of unused study intervention, or used returned study 
intervention for destruction, will be documented on the intervention return form. When the study 
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this 
must also be documented on the intervention return form.
Study intervention 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 intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant. Study intervention may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor. 


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6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be stratified 
by country and screening response status. The criteria for screening response will be blinded for 
the investigator. The interactive web response system (IWRS) will assign a unique intervention
code, which will dictate the intervention assignment and matching study intervention kit for the 
participant. The requestor must use his or her own user identification and personal identification 
number when contacting the IWRS and will then give the relevant participant details to uniquely 
identify the participant.
Blinding
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 participant.
Data that may potentially unblind the intervention assignment (i.e. study intervention plasma 
concentrations, plasma biomarkers) will be handled with special care to ensure that the integrity 
of the blind is maintained and the potential for bias is minimized. This can include making special 
provisions, such as segregating the data in question from view by the investigators, clinical team, 
or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the intervention by contacting the IWRS. While the responsibility to break the 
intervention code in emergency situations resides solely with the investigator, it is recommended 
that the investigator contact the sponsor or its designee if possible, to discuss the particular 
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be 
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date, time and reason for the unblinding must be documented in 
the appropriate section of the case report form (CRF) and in the source document. The 
documentation received from the IWRS indicating the code break must be retained with the 
participant's source documents in a secure manner.
Participants who have had their intervention assignment unblinded should continue to return for 
required follow-up evaluations.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, if an interim data review by an unblinded reviewer is 
specified (see Section 9.4), the randomization codes and, if required, the translation of 


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randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those participants included in the interim review.
6.4.
Study Intervention Compliance
Study intervention will be taken either at the clinic, during visits, or at home, in between visits. 
The capsules must be swallowed whole and not chewed, divided, dissolved or crushed. 
When in the clinic, study intervention will be self-administered on site as outlined in Section 6.1. 
The administration of study intervention will be witnessed by the investigator or a properly trained 
designee. Study site personnel will examine each participant’s mouth to ensure that the study 
intervention was ingested. The exact date and time of drug administration will be recorded in the 
source documents and the eCRF.
When participants self-administer study intervention at home, compliance with study intervention 
will be assessed, using a study intervention adherence monitoring platform (AiCure®-app) to 
monitor study intervention intake by the participants (where regulations allow). The platform uses 
artificial intelligence on smartphones to visually confirm proper study intervention administration 
and ingestion of the study intervention in real time without human intervention.  Video recordings 
of the study intervention intake are also recorded and stored to a secure server for further analysis 
to reconfirm proper study intervention administration, to identify any usability issues or intentional 
non-adherence, and to check for duplicate enrollment. In addition, built-in reminders and a 
communication system allow real-time intervention by study personnel in case of improper drug 
administration or interruptions by the participant.
The investigator or designated study personnel will maintain a log of all study drug dispensed and 
returned. Drug supplies will be inventoried and accounted for throughout the study. 
If appropriate, additional details may be provided in a pharmacy manual/study site investigational 
product manual that is provided separately and noted in Section 8, Study-Specific Materials.
6.5.
Concomitant Therapy
Prestudy oral antidepressant therapies and allowed sleep medication must be recorded at screening.
All prestudy therapies administered up to 30 days before screening must be recorded at screening.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the eCRF, throughout 
the study beginning with start of the first dose of study drug until last follow-up visit. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication.
Current antidepressant therapy 
Participant’s baseline oral antidepressants (bupropion, citalopram, escitalopram, sertraline, 
paroxetine, venlafaxine, desvenlafaxine, duloxetine, fluoxetine, vilazodone, vortioxetine, 


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mirtazapine, agomelatine, nortriptyline imipramine, amitriptyline and levomilnacipran) will be 
taken as prescribed (without dose change) throughout the screening and double-blind phase of the 
study. Adherence to participant’s baseline oral antidepressants will be checked at each visit to the 
site.
Disallowed concomitant therapy
Participants must agree not to use any of the following medications with psychotropic properties, 
including but not limited to:

Psychiatric medications, including mood stabilizers, antipsychotics (typical and atypical), 
psychostimulants and antidepressants other than their baseline standard antidepressant(s) 
(e.g., MAOIs and milnacipran are prohibited).

Any other antidepressant therapy than the ones described in the current antidepressant therapy 
section above, within 2 weeks prior to screening, This includes antidepressants prescribed for 
other indications than MDD also at subtherapeutic doses.

Benzodiazepines and any other non-benzodiazepine anxiolytic (e.g. buspirone, hydroxyzine)
Other prohibited medications include:

S-adenosyl methionine (SAMe), St. John’s wort, ephedra, ginkgo, ginseng, or kava kava

Opiates

Anticonvulsants

Esketamine

Sleep aids such as chloral hydrate, sedating antipsychotics and melatonine

Suvorexant
JNJ-61393215 is primarily metabolized by CYP3A4. Participants should not use medications that 
are moderate or strong CYP3A4 inhibitors from 14 days or at least 5-times the drug’s half-life 
(whichever is longer) prior to study drug administration until the last study visit. In addition, 
participants should not use medications that are moderate or strong CYP3A4 inducers from 
14 days or at least 5-times the drug’s half-life (whichever is longer) prior to study drug 
administration until the last study visit. See Section 10.7 for a list of prohibited CYP3A4 inhibitors. 
Allowed concomitant therapy
Allowable 
sleep 
medications
include:
zolpidem, 
zaleplon, 
zoplicone, 
eszopliclone, 
diphenhydramine, and ramelteon, only if the participant has been taking a fixed daily dose of the
sleep medication for at least 2 weeks prior to screening. As required (PRN) use of sleep medication 
is not allowed.
A dosage of trazodone not exceeding 150 mg/day given as a sleep aid or for sexual dysfunction is 
allowed, if the participant has been taking a fixed daily dose for at least 2 weeks prior to screening.


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Allowed treatments
Participants receiving psychotherapy can continue receiving psychotherapy provided this therapy 
has been stable in terms of frequency for the last 3 months prior to screening and will remain 
unchanged throughout study treatment. 
Cognitive behavioral therapy for ADHD is allowed (use of psychostimulants is not allowed).
Disallowed treatments

electroconvulsive therapy in the current episode

deep brain stimulation (lifetime)

repetitive transcranial magnetic stimulation within 4 weeks prior to baseline visit
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.6.
Intervention After the End of the Study
Investigators may recontact the participant to obtain long-term follow-up information regarding 
the participant's safety if there are any safety concerns at the last study visit.
Participants will be instructed that study intervention will not be made available to them after they 
have completed/discontinued study intervention and that they should return to their primary 
physician to determine standard of care.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention or withdraws from the study before the end of the 
double-blind phase, the early withdrawal assessments should be obtained.
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the participant to discontinue study intervention

The participant becomes pregnant 

A participant who shows signals of clinically meaningful acute suicidal ideation at any time 
during the study should be withdrawn from the study intervention and referred for appropriate 
medical/psychiatric care.

A participant will be discontinued from the study intervention if the liver function tests exceed 
the values as presented in Section 10.6.

If a participant discontinues study intervention for any reason before the end of the double-
blind phase, then the follow-up assessments should be obtained. Study intervention assigned 
to the participant who discontinued study intervention may not be assigned to another 
participant. Additional participants will not be entered.


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7.2.
Participant Discontinuation/Withdrawal from the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the CRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply (eg, consult with family members, contacting the participant’s other physicians, 
medical records, database searches, use of locator agencies at study completion,) as local 
regulations permit.
7.2.1.
Withdrawal from the Use of Research Samples
Withdrawal from the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Section 10.3, Regulatory, Ethical, and 
Study Oversight Considerations). In such a case, samples will be destroyed after they are no longer 
needed for the clinical study. Details of the sample retention for research are presented in the main 
ICF.
7.3.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed 
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the 
participant are deemed futile. The following actions must be taken if a participant fails to return to 
the study site for a required study visit:

The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 


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e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods. These contact attempts should be documented in the participant’s 
medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The SoA summarizes the frequency and timing of efficacy, PK, biomarker, pharmacogenomic and 
safety measurements applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: scales, 12-lead ECG, vital signs, PK, biomarker samples, 
safety labs. Other measurements may be done earlier than specified timepoints if needed. Actual 
dates and times of assessments will be recorded in the source documentation and CRF.
It is recommended that the clinician and patient reported scales are performed in the following 
sequence: SIGH-D, SIGH-A, GAD-7, PHQ-9 and C-SSRS. The SIGH-D however must be 
performed first.
Vital signs, temperature, blood samples for JNJ-61393215, biomarker samples and safety labs have 
to performed prior to study intervention intake. At weeks 2, 4 and 6 there are predose and postdose 
blood collections for JNJ-61393215 (refer to SoA).
The clinician and patient reported scales are preferably performed prior to study intervention intake 
but can be performed after the study intervention intake for logistical reasons; however, scales
have to start within the hour of the participant’s arrival to the clinical site. 
The SIGH-D done by the qualified site raters will be audio-recorded at each visit to allow for 
independent data quality monitoring.
The time points for PK and biomarker samples, SIGH-D, SIGH-A, GAD-7, PHQ-9, C-SSRS, 
12-lead ECG, vital signs, and safety labs may be changed (with or without affecting the overall 
frequency of these investigations) prior to and during the study based on newly obtained data to 
allow for optimal fit to the actual PK and PK/PD profile of the study drug. This modification may 
result in a change in the overall frequency of these assessments, however the maximal total blood 
volume collected per participant will not be exceeded. Such modifications, where performed only 
to allow optimal fit to the actual PK or PK/PD profile of the study drug, will not require a 
(substantial) amendment to the protocol.


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Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study.
For each participant, the maximum amount of blood drawn from each participant in this study will 
not exceed 450 mL. The volume of blood collected per sample and per participant will be detailed 
in a separate lab manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form. 
Refer to the SoA for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual. Any changes to the lab manual will not result in a protocol amendment.
Study-Specific Materials
The investigator will be provided with the following supplies:

IB for JNJ-61393215

Pharmacy manual/study site investigational product manual or equivalent document e.g., 
Investigational Product Preparation Instructions

Laboratory manual, tubes and labels

Electronic systems or paper documents for the completion of MINI 7.0 Plus, MGH-ATRQ, 
C-SSRS, SIGH-D, SIGH-A, IDS-C30, GAD-7 and PHQ-9.

Manuals for investigator and participant for the AiCure-app to assess treatment compliance 
by video recording the drug intake. The AiCure-app will be downloaded on the participants’ 
own smartphone, or a smartphone with the app included will be provided to the participant.

Sample ICF

IWRS Manual 

Electronic data capture (eDC) Manual.
8.1.
Efficacy Assessments
The study will include the following efficacy evaluations according to the time points provided in 
the SoA:


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Hamilton Depression Rating Scale (HDRS17)
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in participants diagnosed with depression6 with a total score range of 0 to 52, with higher scores 
indicting greater severity of depressive symptoms. It is the most widely used symptom severity 
measure for depression. Each of the 17 items is rated by the clinician on either a 3- or a 5-point 
scale. The HDRS17 has an inter-rater reliability correlation of r = .90 and the internal consistency 
of the measure is reported to be high with a coefficient alpha of 0.88. Criterion-related validity for 
this measure is high11. The original HDRS17 scale lacks instructions for administration and clear 
anchor points for the assignment of severity ratings. For this reason, the SIGH-D, the structured 
interview guide version of the HDRS17, will be used in the current study to facilitate and 
standardize gathering clinical information from the participant.
Hamilton Anxiety Scale (HAM-A)
The HAM-A measures the severity of a patient's anxiety, based on 14 parameters, including 
anxious mood, tension, fears, insomnia, somatic complaints and behavior at the interview8. It 
covers many of the features of GAD and can be helpful also in assessing its severity. The major 
value of HAM-A is to document the results of pharmaco- or psychotherapy, rather than as a 
diagnostic or screening tool. It takes 15-20 minutes to complete the interview and scoring. Each 
item is simply given a 5-point score - 0 (not present) to 4 (severe). In this study, the Structured 
Interview Guide version of the HAM-A (SIGH-A) will be used.
Patient Health Questionnaire (PHQ-9)
The PHQ-9 will be used as a participant-reported measure of depressive symptomatology25. The 
PHQ-9 is a 9-item scale, where each item is rated on a 4-point scale (0=Not at all, 1=Several Days, 
2=More than half the days, and 3=Nearly every day), with a total score range of 0 to 27. The recall 
period is 2 weeks.
Generalized Anxiety Disorder 7 (GAD-7) 
The GAD-7 is a self-reported questionnaire for screening and severity measuring of generalized 
anxiety disorder (GAD)26. GAD-7 has seven items, which measure severity of various signs of 
GAD according to reported response categories with assigned points (see below). Assessment is 
indicated by the total score, which made up by adding together the scores for the scale all seven 
items27. GAD-7 is a sensitive self-administrated test to assess generalized anxiety disorder12
normally used in outpatient and primary care settings for referral to psychiatrist pending 
outcome14. However, it cannot be used as replacement for clinical assessment and additional 
evaluation should be used to confirm a diagnosis of GAD. The scale uses a normative system of 
scoring as shown below, with question at the end qualitatively describing severity of the patient's 
anxiety over the past 2 weeks8. 

Not at all (0 points)

Several days (1 point)

More than half the days (2 points)

Nearly every day (3 points)


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Every effort should be made to ensure that all clinician administered assessments are completed 
by the same rater who made the initial baseline determinations. 
8.2.
Safety Assessments 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
Adverse Events
Adverse events will be reported by the participant from obtaining informed consent throughout the 
duration of the study. Adverse events will be reported and followed by the investigator as specified 
in Section 8.3, Adverse Events and Serious Adverse Events and Appendix 4, Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting. 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 condition is reached.
Any clinically relevant changes occurring during the study must be recorded on the AE section of 
the CRF.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology, thyroid hormones, FSH and pregnancy test 
(if applicable) and a random urine sample for urinalysis will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the eCRF. 
The following tests will be performed by the central laboratory:
Hematology Panel:
- hemoglobin
- platelet count
- hematocrit
- mean corpuscular volume
- red blood cell (RBC) count
- mean corpuscular hemoglobin
- white blood cell (WBC) count with differential
- mean corpuscular hemoglobin 
concentration.
Serum Chemistry Panel: 
- sodium
- potassium
- creatine phosphokinase (CPK)
- chloride
- lactic acid dehydrogenase (LDH)
- bicarbonate
- uric acid
- blood urea nitrogen (BUN)
- calcium
- creatinine
- phosphate
- glucose
- albumin
- aspartate aminotransferase (AST)
- total protein
- alanine aminotransferase (ALT)
- cholesterol
- gamma-glutamyltransferase (GGT)
- triglycerides
- alkaline phosphatase (ALP)
- high-density lipid proteins
- total bilirubin
- low-density lipid proteins


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- conjugated bilirubin if elevated total    
bilirubin
Estimated Glomerular Filtration Rate (eGFR) (at screening only)
Serology (at screening only):

HIV antibody

HBsAg

HCV antibody
Thyroid function:

Thyroid stimulating hormone (TSH) and free thyroxine (FT4) 
Pregnancy test (for women of childbearing potential [WOCBP] only):
Serum pregnancy test at screening and urine pregnancy test during the treatment phase and 
follow-up visit.
HbA1c at screening in diabetic participants only
Follicle Stimulating Hormone (at screening only): 
For women of any age with amenorrhea for at least 6 months without hormonal replacement 
therapy and for women > 50 years of age and with amenorrhea for less than 12 months. 
Urinalysis: 
Dipstick
Sediment
-specific gravity
-crystals
-pH
-casts
-glucose
-bacteria
-protein
-blood
-ketones
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
If dipstick result is abnormal, microscopy will be used to measure sediment.
Urine Drug Screen (at screening only):

Amphetamines/methamphetamines

MDMA

Oxycodone

Barbiturates

Benzodiazepines


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
Cocaine

Opiates (including methadone)

Cannabinoids

Phencyclidines

Methadone
Alcohol Breath Test (at screening only)
Electrocardiogram (ECG)
Twelve-lead ECGs, intended for safety monitoring, will be recorded in supine position (following 
5 minutes of rest) so that the different ECG intervals (heart rate [BPM], PR [msec], QRS duration 
[msec], QT interval, QTc [msec], QtcF [msec] and QTcB [msec]) can be measured at multiple 
time points at screening and during the study. The ECG will be recorded until 3 regular consecutive 
complexes are available in good readable quality. 
Single ECG’s will be recorded at all visits.
Hot and cold drinks and food should be avoided 30 minutes before an ECG measurement whenever 
possible.
During the collection of 12-lead ECGs, participants should be in a quiet setting without distractions 
(eg, television, cell phones). If blood sampling or vital sign measurement is scheduled for the same 
time point as 12-lead ECG recording, the procedures should be performed in the following order: 
ECG(s), vital signs, blood sampling. 
Clinically relevant abnormalities occurring during the study should be recorded in the Adverse 
Event Section of the eCRF.
Vital Signs (oral or tympanic temperature, pulse/heart rate, blood pressure)
Blood pressure and pulse/heart rate measurements will be assessed after being in supine position 
for at least 5 minutes with a completely automated device, at the timepoints indicated in the SoA. 
Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest 
in a quiet setting without distractions (e.g., television, cell phones).
Temperature (oral or tympanic) will be recorded at the time points indicated in SoA.
Physical Examination
The study investigator, or other authorized and appropriately qualified designee, will perform the 
physical examinations.
Height and weight will be measured as indicated in the SoA.


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Suicidal Ideation and Behavior Risk Monitoring 
Orexin-1 is considered to be a CNS-active study intervention. There has been some concern that 
some CNS-active study interventions may be associated with an increased risk of suicidal ideation 
or behavior when given to some participants with major depressive disorder. Therefore, the 
sponsor considers it important to monitor for such events before or during this clinical study.
Participants being treated with Orexin-1 should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. 
Families and caregivers of participants being treated with Orexin-1 should be instructed to monitor 
participants for the emergence of unusual changes in behavior, as well as the emergence of suicidal 
ideation and behavior, and to report such symptoms immediately to the study investigator.
Baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal ideation 
and behavior will be monitored during the study using the Columbia Suicide Severity Rating Scale 
(C-SSRS). The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior 
that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide 
Attempters Study to assess severity and track suicidal events through any treatment16. The C-SSRS 
is a clinical interview providing a summary of both ideation and behavior that can be administered 
during any evaluation or risk assessment to identify the occurrence and intensity of suicidal 
thoughts and suicidal behaviors. It can also be used during treatment to monitor for clinical 
worsening. 
If a suicide-related thought to behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be provided.
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.
Anticipated events will be recorded and reported as described in Section 10.2.
For further details on adverse events and serious adverse events (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints, refer to Section 10.4, Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.


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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until completion of the participant'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 intervention, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
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).
8.3.2.
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
8.3.3.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the intervention caused a 
serious anticipated event, they will submit a safety report in narrative format to the investigators 
(and the head of the institute where required). The sponsor assumes responsibility for appropriate 
reporting of anticipated events to the regulatory authorities according to requirements of the 
countries in which the studies are conducted. 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. 


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8.3.4.
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event 
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any participant who becomes pregnant during the study must promptly discontinue further study 
intervention. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.4.
Treatment of Overdose
For this study, any dose of Orexin-1 greater than 9 capsules of 45mg within a 24-hour time period 
will be considered an overdose. The sponsor does not recommend specific intervention for an 
overdose, given the less-than-dose proportional PK suggesting that the systemic exposure will not 
increase substantially at higher doses.
In the event of an overdose or suspected overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until Orexin-1 can 
no longer be detected systemically (at least 4 days).

Obtain a plasma sample for PK analysis 3 hours after overdose (or as soon as possible 
thereafter) and document dose, date and time of sample collection and date and time of last 
dose.

Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
Plasma samples will be used to evaluate the PK of Orexin-1. Plasma collected for PK may 
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or 
after the study period. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
8.5.1.
Evaluations
Venous blood samples for analysis of JNJ-61393215 plasma concentrations will be collected at 
the time points indicated in the SoA.
Blood samples for analysis of α-1-acid-glycoprotein (plasma) and plasma protein binding will be 
collected as well.


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The following information needs to be recorded on the requisition form: date and time of preceding 
study drug intake, date and time of PK and alpha-1-acid glycoprotein (A1AGP) and plasma protein 
binding blood sampling.
Details on the sample collection (including type and volume), handling, processing and shipping 
procedures will be described in a separate lab manual.
8.5.2.
Analytical Procedures 
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of JNJ-61393215 using a validated, 
specific and sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS)
method by or under the supervision of the sponsor.
If required, some plasma and whole blood samples may be stored for future analysis of other 
analytes or characteristics that may help to unravel the ADME properties of JNJ-61393215, 
including but not limited to co-administered drugs, protein binding and metabolite profiling or 
endogenous markers for potential inhibition or induction of metabolic enzymes or transporters
8.5.3.
Pharmacokinetic Parameters and Evaluations
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of Orexin-1 will be derived using 
population PK (popPK) modelling. Baseline covariates (eg, body weight, age, sex, CrCL, race) 
may be included in the model, if relevant.
8.6.
Genetics
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 allow for the identification 
of genetic (DNA) and/or transcription (RNA) factors that may influence the PK, efficacy, safety, 
or tolerability of JNJ-61393215 and to identify genetic factors associated with MDD. The RNA 
will be collected pre- and posttreatment to allow examination of changes in gene transcription 
related to administration of JNJ-61393215 and/or changes in other biomarkers collected during the 
study (eg, cortisol, cytokines, etc.). DNA genotyping may include, but is not limited to, 
interrogation of single nucleotide polymorphisms (SNPs) at discrete loci implicated in mood 
disorders. DNA samples may be used to help address emerging issues and to enable the 
development of safer, more effective and ultimately individualized therapies in the future.
8.7.
Biomarkers
Exploratory biomarkers related to endocrine, metabolic, and immune system activity (including 
but not limited to cortisol, ACTH, growth factors, inflammation, or metabolic markers) will be
collected for exploratory analyses at the time points indicated in the SoA. 


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Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early, completion of biomarker 
assessments is based on justification and intended utility of the data.
Details on the sample collection (including type and volume), handling, processing and shipping 
procedures will be described in a separate lab manual.
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. 
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.
To help with interpreting biomarker results, menstrual cycle in female participants will be tracked 
during the study per the schedule indicated in the Time & Events schedule.
9.
STATISTICAL CONSIDERATIONS
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 SAP.
9.1.
Sample Size Determination
The estimated sample size of 218 participants (109 participants per group) was determined based 
on the assumption of an effect size of at least 0.4 for the HDRS17 total score (mean change from 
baseline to Week 6 endpoint between the JNJ-61393215 and placebo groups of 3 units with 
SD=7.5). This is considered to be a clinically relevant difference in a population with suboptimal 
response to standard oral antidepressant therapy. The standard deviation of 7.5 in the change in 
HDRS17 total score from baseline is a reasonable assumption based on previously conducted 
clinical trials in a similar patient population (40411813DAX2001 and 42165279MDD2001). 
Power is set at 90%, with a 1-sided alpha of 0.10 and a 6-week drop-out rate of 10%.
It was also assumed that 15% of the randomized participants would be excluded from the primary 
efficacy analysis due to showing a screening response. Thus, the estimated participants to be 
included in the primary analysis is 166.
Sample size may be re-adjusted if the observed screening response rate, the drop-out rate 
(including drop-outs due to the COVID-19 pandemic), or the standard deviation substantially 
deviate from the assumed value. Overall sample size can increase with maximal 25%. The potential 
maximal number of participants to be enrolled in this trial would be 272.


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9.2.
Statistical Analyses
9.2.1.
Efficacy analyses
The intent-to-treat (ITT) analysis set will include all randomized participants who receive at least 
1 dose of study drug and have both the baseline and at least 1 post-baseline measurement on a 
clinician rated assessment relevant for depression and anxiety. The primary analysis set for 
efficacy will be the modified intent-to-treat (mITT) analysis set (enriched population) which 
consists of the ITT set excluding participants who showed a screening response. The criteria for 
screening response that will be used for stratification within the IWRS will be described in the 
SAP and blinded to the investigators. The secondary analysis set for efficacy will be the ITT 
analysis set.
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 3 components:

Population: participants with MDD with anxious distress with suboptimal response to 
standard antidepressants

Endpoint: change from baseline to Week 6 in the HDRS17 total score 

Measure of Intervention: the effect of the initially randomized treatment that would have been 
observed had all participants remained on their treatment throughout the double-blind 
treatment phase. 
The JNJ-61393215 treatment group will be compared with the placebo group using the primary 
efficacy endpoint, change from baseline in HDRS17 total score, with the comparison performed by 
means of a mixed-effects model using repeated measures (MMRM), with time, treatment (placebo, 
JNJ-61393215), country, and time-by-treatment interaction as factors, baseline HDRS17 total score 
as a continuous covariate. An unstructured variance-covariance matrix will be used. 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) (first order autoregressive process) with separate subject random 
effect.  The comparison of JNJ-61393215 versus placebo will be performed using the appropriate 
contrast. In addition, a sensitivity analysis by excluding participants who were ongoing at the time 
of the trial suspension due to the COVID-19 pandemic and/or by excluding noncompliance 
participants will be conducted.
Analyses for secondary endpoints will be carried out in enriched population using the same 
MMRM method that is aforementioned for the primary analysis.
In addition, the analyses for the efficacy endpoints will also be carried out in the full population 
using a mixed-effects model using repeated measures (MMRM), with time, treatment (placebo, 
JNJ-61393215), country, screening response status and time-by-treatment interaction as factors, 
and baseline HDRS17 total score as a continuous covariate. 


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An unstructured variance-covariance matrix will be used. 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) (first order autoregressive process) with separate subject random effect.  
9.2.2.
Safety Analyses
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention through the day of last dose plus 30 days is considered 
to be treatment emergent. All reported treatment-emergent adverse events will be included in the 
analysis. For each adverse event, the percentage of participants who experience at least 
1 occurrence of the given event will be summarized by intervention group. In addition, 
comparisons between intervention groups will be provided if appropriate.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue intervention due to an adverse event, or who experience a 
severe or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. 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 at each scheduled time point. 
Changes from baseline results will be presented in pre- versus posttreatment cross-tabulations 
(with classes for below, within, and above normal ranges). 
Electrocardiogram (ECG)
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline values.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and 
corrected QT (QTc) interval using [some or all of] the following correction methods: QT corrected 
according to Bazett's formula (QTcB) and QT corrected according to Fridericia's formula 
(QTcF)3,9,20.
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of participants with QTc interval >450 msec, >480 msec, or 
>500 msec will be summarized, as will the percentage of participants with QTc interval increases 
from baseline >30 msec or >60 msec.


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All significant abnormalities in ECG waveform that are changes from the baseline readings will 
be reported (e.g., changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, supine blood pressure (systolic and diastolic) 
values and changes from baseline will be summarized at each scheduled time point. The percentage 
of participants with values beyond clinically important limits will be summarized.
Physical Examination
Abnormalities observed during the physical examination will be summarized and listed by 
treatment group at each scheduled time point. 
Columbia Suicide Severity Rating Scale (C-SSRS)
Results from the C-SSRS will be tabulated by treatment group for all participants receiving at least 
one dose of study drug in this study.
9.2.3.
Other Analyses
Pharmacokinetic Analyses 
A popPK analysis using nonlinear mixed effects modeling (NONMEM) may be conducted to 
characterize the disposition characteristics of JNJ-61393215 using the data in the current study or 
combined data with other studies. Details will be given in a popPK analysis plan, and results of 
the popPK analysis will be presented in a separate technical report.
Data will be listed for all participants with available plasma concentrations. 
Based on the individual concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of JNJ-61393215 may be derived using 
popPK modeling, including, but not limited to: AUC, Ctrough, and possibly Cmax. Other PK 
parameters may be determined if deemed useful to evaluate the PK of JNJ-61393215. Descriptive 
statistics, including arithmetic mean, SD, coefficient of variation, median, minimum, and 
maximum may be calculated for all derived PK parameters.
Special attention will be paid to the plasma concentrations and/or PK parameters of those 
participants who have discontinued the study due to an AE, or who experienced an AE of severe 
severity grade, or an SAE.
Exposure-response Analysis
Relationships of JNJ-61393215 population-derived exposure parameters with some efficacy 
endpoints (e.g., HDRS17) or safety parameters may be explored, if deemed appropriate. Results 
will be presented in a separate report.


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Biomarkers Analyses 
The exploratory biomarkers will be tabulated by treatment and summary statistics will be 
calculated. Posttreatment changes in exploratory biomarkers will be summarized by intervention 
group. Associations between baseline biomarker levels and clinical endpoints may be explored. 
Results may be presented in a separate biomarkers report.  
Pharmacogenomic Analyses 
Pharmacogenomic samples may be analyzed if needed. A composite genotype will be derived from 
the raw genotyping data for the analyzed genes, as appropriate. Specific analyses will include, but 
are not limited to, interrogation of SNPs in whole blood DNA at discrete loci implicated in mood. 
The relationship between genetic subgroups and JNJ-61393215 PK endpoints and/or PD markers 
may be examined through descriptive statistics or graphically. Additionally, the relationship 
between genotype and PK of JNJ-61393215 will be explored in this study. Variations in the genes 
orosomucoid 1 (ORM1) and orosomucoid 2 (ORM2), coding for different isoforms of the A1AGP
will be explored for any relationship to A1AGP plasma concentrations. 
Due to the expected small sample size within genetic groups after stratification, analyses will be 
exploratory and are for hypothesis-generation purposes. No statistical tests will be performed.
Results may be presented in a separate report.
9.3.
Interim Analysis
No formal interim analysis is foreseen. 
A blinded data review for purpose of sample size re-estimation may be performed. Sample size 
may be re-adjusted if the observed screening response rate, the drop-out rate (including drop-outs 
due to the COVID-19 pandemic), or the standard deviation substantially deviate from the assumed 
value. Overall sample size can increase with maximal 25%. 
9.4.
Unblinded Data Review
Continuous or periodic blinded safety reviews will be done by the SRP. An unblinded review of 
the data will be conducted if there are safety concerns from this blinded review as a result of severe, 
serious or unexpected AEs that are at least possibly related to the study drug. This review will be 
done by a Data Review Committee (DRC). A DRC will consist of at least one medical expert in 
the relevant therapeutic area and at least one statistician; committee membership responsibilities, 
authorities, and procedures will be documented in its charter.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
ACTH
AE
A1AGP
bid
CNS
COVID-19
Adrenocorticotropic hormone
Adverse event
Alpha-1-acid-glycoprotein
Twice daily (bis in die)
Central nervous system
Coronavirus Disease 19
CRF
CSF
C-SSRS
DNA
case report form(s) (paper or electronic as appropriate for this study)
cerebrospinal fluid
Colombia suicide severity rating scale
Deoxyribonucleic acid
DRC
Data Review Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders (5th edition)
ECG
electrocardiogram
eDC
FIH
electronic data capture
first in human
FSH
Fu
GAD
GAD-7
follicle stimulating hormone
fraction unbound
General Anxiety Disorder
General Anxiety Disorder-7 scale
GCP
GLP
HAM-A
Good Clinical Practice
Good Laboratory Practice
Hamilton Anxiety Rating scale
HBsAg
HDRS17
hepatitis B surface antigen
17-item Hamilton Depression Rating Scale
HIV
HCV
HPA
IB
human immunodeficiency virus
hepatitis C virus
hypothalamic–pituitary–adrenal
Investigator Brochure
ICF
informed consent form
ICH
IDS-C30
International Conference on Harmonisation
Inventory of Depressive Symptomatology, Clinician Rating -30
IEC
Independent Ethics Committee
IRB
ITT
IV
Institutional Review Board
Intention-to-treat
intravenous
IWRS
interactive web response system
LC-MS/MS
MAD
MDD
liquid chromatography/mass spectrometry/mass spectrometry
multiple ascending dose
Major Depressive Disorder
MedDRA
MGH-ATRQ
MINI
mITT
MMRM
MTD
NOAEL
OX1R
OX2R
Medical Dictionary for Regulatory Activities
Massachusetts General Hospital Antidepressant Treatment History Questionnaire
MINI International Neuropsychiatric Inventory
Modified intent-to-treat
mixed-effects model using repeated measures
maximum tolerated dose
no observed adverse event level
orexin-1 receptor
orexin-2 receptor
PD
PHQ-9
pharmacodynamic(s)
Patient Health Questionnaire
PK
popPK
PPB
pharmacokinetic(s)
population pharmacokinetics
plasma protein binding


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PQC
PRN
Product Quality Complaint
As needed (pro re nate)
PRO
PSL-IV
RNA
SAD
SAE
SAFER
SAP
SD
SIGH-A
SIGH-D
SNP
patient-reported outcome(s) (paper or electronic as appropriate for this study)
panic symptoms list IV
Ribonucleic acid
single ascending dose
serious adverse event
acronym for: State versus trait; Assessability; Face validity; Ecological validity; and Rule of three 
Ps (pervasive, persistent, and pathological)]
statistical analysis plan
standard deviation
Structured Interview Guide for the HAM-A
Structured Interview Guide for the HDRS17
single nucleotide polymorphisms
SoA
Schedule of Activities
SUSAR
TEAE
TSH
suspected unexpected serious adverse reaction
treatment emergent adverse event
thyroid stimulating hormone
Definitions of Terms
Electronic source 
system
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in a CRF as determined by the protocol. Data in this system may be 
considered source documentation.


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10.2.
Appendix 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, 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, 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 under All Adverse Events in Section 8.3.1, 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information. 
Any anticipated event that meets serious adverse event criteria will be reported to the sponsor as 
described under Serious Adverse Events in Section 8.3.1, Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information. 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 
intervention, the sponsor will report these events in an expedited manner.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold 
to trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated 
Events Safety Monitoring Plan.


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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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 participants, 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) involve 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.
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.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:


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
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, participant 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 
participant:

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
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 participants)

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable


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
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 participants

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 
participants, data or study conduct, unless required locally), the ICF, applicable recruiting 
materials, and participant compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the participants

Report of deaths of participants 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 participants, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
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At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion.
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 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
INFORMED CONSENT PROCESS 
Each participant 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 participant 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 participants the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Participants 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 participant will receive for the treatment of his or her disease. Participants 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 
participant 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 participant, to the extent permitted by the applicable law(s) or regulations. 
By signing the ICF the participant is authorizing such access. It also denotes that the participant 
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining 
consent for additional safety evaluations, and subsequent disease-related treatments, if needed. 


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The participant 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 participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants 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 participants confidential.
The informed consent obtained from the participant 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 participant 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 pharmacogenomic, biomarker and PK research is not conducted under standards 
appropriate for the return of data to participants. 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 participants 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.
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 Orexin-1, to understand MDD 
and other neuropsychiatric/neurodegenerative disorders, to understand differential intervention 
responders, 
and 
to 
develop 
tests/assays 
related 
to 
Orexin-1, 
MDD 
and 
other 


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neuropsychiatric/neurodegenerative disorders. In this respect, samples may be provided to external 
partners. 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. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal from the Use of Research Samples).
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding Orexin-1 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 Orexin-1 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 for the study. Results of 
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report 
has been issued will be reported in a separate report and will not require a revision of the Clinical 
Study Report. 
Study participant 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 (ICMJE) 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 


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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 sub-study 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 18 months after the study end date, 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 ICMJE Recommendations 
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which 
state that the named authors must have made a significant contribution to the conception or design 
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the 
work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
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. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
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.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant 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.


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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 participant's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a participant visit and the 
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations. Exceptions will 
need to be discussed with and approved by the sponsor.
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.
SOURCE DOCUMENTS
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: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study intervention administration information; and 
date of study completion and reason for early discontinuation of study intervention 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).
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). 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 


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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/discuss issues 
on the study conduct and confirm that the investigator has sufficient oversight of the trial and 
conduct.
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. Participant 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.
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 participant, 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 


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the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate or improper recruitment of participants by the investigator

Discontinuation of further study intervention development


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered 
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the intervention. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse 
Events under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A 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 participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the participant or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For Orexin-1, the expectedness of an adverse event will be 
determined by whether or not it is listed in the IB. 
Adverse Event Associated With the Use of the Intervention
An adverse event is considered associated with the use of the intervention if the attribution is 
possible, probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An adverse event that is not related to the use of the intervention.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant treatment(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the intervention. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the intervention. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant treatment(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant treatment(s), concomitant disease(s). The 
relationship in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SEVERITY CRITERIA 
An assessment of severity grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.


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The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Medication error involving a sponsor product (with or without participant/patient exposure to 
the sponsor study intervention, eg, name confusion)

Exposure to a sponsor study intervention 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.
PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
intervention, must be recorded using medical terminology in the source document and the CRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

Site number

Participant number

Any other information that is required to do an emergency breaking of the blind


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Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the participant's participation in the study, must be followed until any of 
the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a participant's participation in a study must be reported as a serious adverse 
event, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the participant for (part of) the 
duration of the intervention period. 
The cause of death of a participant in a study within 30 days of the last dose of study intervention, 
whether or not the event is expected or associated with the study intervention, is considered a 
serious adverse event.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A 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 participants, 


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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.
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 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.


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10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Participants must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria. 
Pregnancy information will be collected and reported as noted in Section 8.3.4, Pregnancy and 
Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

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 (HRT), however in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman 
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT 
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)


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
Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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Pregnancy During the Study
Pregnancy information will be collected and reported as noted in Section 8.3.4, Pregnancy and 
Section 10.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.






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(INR), and total protein and albumin (compute globulin fraction) should also be documented.  
If INR is abnormal, prothrombin time (PT), partial thromboplastin time (PTT) should be 
obtained and these values should be followed until normal, along with documentation of 
whether parenteral vitamin K was given along with the effect of such treatment on INR.
4.
If initial LTs and ultrasound do not suggest Gilbert’s syndrome,  biliary tract disease or 
obstruction, viral hepatitis serology should be obtained including anti-hepatitis A virus 
immunoglobin M (anti-HAV IgM), anti-HAV total,  hepatitis B surface antigen (HBsAg), 
anti-HBs,  anti-HB core total,  anti-HB core IgM, anti-hepatitis C virus (anti-HCV),  anti-
hepatitis E virus IgM (anti-HEV IgM) (even if has not traveled to an endemic area for hepatitis 
E), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) screen.

If patient is immunosuppressed, test for HCV RNA and HEV RNA.

If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to detect 
active HepB, especially in patients who are immunosuppressed.

If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive 
test, HBV DNA should be obtained to detect reactivation of hepatitis B.
5.
Assuming that the history, physical, and initial imaging and laboratory has not revealed a 
cause of elevated LTs, screen for other causes of liver disease including: Total protein and 
albumin (estimate globulin fraction and obtain quantitative immunoglobulins if elevated), 
antinuclear antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), anti-
liver-kidney microsomal antibodies (anti-LKM antibodies), anti-smooth muscle antibodies 
(ASMA), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). If the pattern 
of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed pattern (see 
definitions in table above), then gamma-glutamyl transferase (GGT), anti-mitochondrial 
antibody (AMA) and anti-neutrophil cytoplasmic antibody (pANCA) should also be tested.  
If there is an indication by history or elevated baseline LTs that there may be an underlying 
chronic liver disease possibly exacerbated by exposure to the study intervention in the clinical 
trial or making the participant more susceptible to DILI, test iron/Total iron binding capacity 
(TIBC) and ferritin (hemochromatosis), and alpha-1-antitrypsin level.  If patient is <50 years 
of age, ceruloplasmin should also be tested to screen for Wilson’s disease.  If patient is sick 
enough to be hospitalized and is under age 50, a slit lamp examination to detect Kayser-
Fleischer rings and a 24-hour urine collection for copper should be measured. Consider serum 
ethanol and/or acetaminophen level and urine drug screen as clinically appropriate.
6.
A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology 
and if immunosuppressive therapy is contemplated.
A liver biopsy may be considered:

if there is unrelenting rise in liver biochemistries or signs of worsening liver function 
despite stopping the suspected offending agent.

if peak ALT level has not fallen by >50% at 30-60 days after onset in cases of 
hepatocellular DILI, or if peak Alk P has not fallen by >50% at 180 days in cases of 
cholestatic DILI despite stopping the suspected offending agent.

in cases of DILI where continued use or re-exposure to the implicated agent is expected.


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
if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence 
of chronic liver diseases and chronic DILI.

if pertinent, copies of hospital discharge summary, radiology, pathology and autopsy 
reports should be obtained.
Abbreviations
AlkP
alkaline phosphatase
ALT
alanine aminotransferase
AMA
anti-mitochondrial antibody
ANA
antinuclear antibody
Anti-LKM1
anti-liver kidney microsomal antibody type 1
ASMA
anti-smooth muscle antibodies
AST
aspartate aminotransferase
BMI
body mass index
CBC 
complete blood count
CHF
congestive heart failure
CMV
cytomegalovirus 
CRP
C-reactive protein
CT
computerized tomography
DM
diabetes mellitus
DNA
deoxyribonucleic acid
EBV
Epstein-Barr virus
ERCP
endoscopic retrograde cholangiopancreatography
ESR
erythrocyte sedimentation rate
EOI
end of intervention
GGT
gamma-glutamyltransferase
HAV 
hepatitis A virus 
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HepB
hepatitis B virus
HEV
hepatitis E virus
IgM
immunoglobin M
INR
international normalized ratio
LT/LFT
liver tests/liver function tests
MRI
magnetic resonance imaging
MRCP
magnetic resonance cholaniopancreatography
NSAID
non-steroidal anti-inflammatory drugs
OTC
over the counter
PT
prothrombin time
PTT
partial thromboplastin time
RNA
ribonucleic acid
Tbili
total bilirubin
TIBC
total iron binding capacity
ULN
upper limit of normal
WBC
white blood count


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10.7.
Appendix 7: Moderate and Strong Inhibitors/Inducers of CYP3A4
Examples of Moderate or Strong Inhibitors/Inducers of CYP3A4
Enzyme
Inhibitors
Inducers
Strong
Moderate
Strong
Moderate
CYP3A4
Boceprevir,
Amprenavir,
Avasimibe,
Bosentan,
clarithromycin,
aprepitant,
carbamazepine,
efavirenz,
conivaptan,
atazanavir,
phenytoin,
etravirine,
grapefruit juice,
ciprofloxacin,
rifampin, St.
modafinil,
indinavir,
crizotinib,
John’s wort
nafcillin.
itraconazole,
darunavir/ritonavir,
ketoconazole,
diltiazem,
lopinavir/ritonavir,
erythromycin,
mibefradil,
fluconazole,
nefazodone,
fosamprenavir,
nelfinavir,
imatinib, verapamil
posaconazole,
fluvoxamine
ritonavir,
saquinavir,
telaprevir,
telithromycin,
voriconazole
Notes:

This is not an exhaustive list.
Source: USFDA - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers


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Appendix 8: Guidance on Study Conduct during the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management, such as safety follow-up, in the event of disruption to the conduct 
of the study. This guidance does not supersede any local or government requirements or the clinical 
judgement of the investigator to protect the health and well-being of participants and site staff. If 
at any time a participant’s safety is considered to be at risk, study intervention will be discontinued, 
and study follow-up will be conducted.
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted after consultation between the participant and investigator, and with the agreement of 
the sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes (e.g., delay or discontinuation in recruitment, site monitoring and audits) will be 
communicated to the sites and to the health authorities according to local guidance.  If a participant 
has tested positive for COVID-19, the investigator should contact the sponsor’s site manager and 
study responsible physician to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
GUIDANCE SPECIFIC TO THIS PROTOCOL: 

Ongoing study participants can complete the study if they are willing and if they can attend 
on site for the scheduled study visits. If participants are unable to attend an onsite study visit, 
they are to be discontinued, and an early withdrawal visit is required via telephone contact. 
The early withdrawal visit can be done by phone for end of study assessments as described in 
the protocol as much as possible, at a minimum: SIGH-D, C-SSRS, AEs and concomitant 
medications. The SIGH-D is to be recorded following the same procedures as for the in-clinic 
visits. Guidance shall be provided for appropriate follow-up treatments for their major 
depressive episode and for follow-up of any ongoing adverse events as part of standard of 
care. For additional safety concerns reported during the early withdrawal visit, an additional 
follow-up by phone contact is advised as outlined in sections 6.6 and 8.3 of the study protocol. 

Participants who are unable to attend an onsite study visit are to be discontinued as it is not 
feasible for this study to remotely perform safety assessments and closely monitor the 
participant’s safety. In addition, study medication cannot be shipped to the participants in all 
the participating countries. 


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
Withdrawal from the study will be captured with the prefix “COVID-19-related” in the eCRF. 

All deviations to protocol will be captured with the prefix “COVID-19-related”.

When site monitoring visits are not allowed, monitors will use available tools to remotely 
review study data (e.g., central lab website, eCRF, dashboard for AiCure platform and IWRS 
online tool). The SDV will be completed on-site once visits are allowed again.
STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR 
NONCOVID-19 CLINICAL TRIALS
Participants enrolled in the trial can receive a COVID-19 vaccine approved for Authorized 
Emergency Use (AEU). This COVID-19 vaccine should be recorded in the eCRF as a 
concomitant therapy.
Adverse events related to the COVID-19 vaccine should be reported in the eCRF and 
relationship with the COVID-19 vaccine should be mentioned. If the event is serious and 
considered related to the COVID-19 vaccine, it has to be recorded as a serious adverse event.


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Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC)
DOCUMENT HISTORY
Document
Date
Amendment 4
29 September 2021
Amendment 3
23 June 2021
Amendment 2
5 August 2020
Amendment 1
24 June 2019
Original Protocol
13 May 2019


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11.
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Psychiatry 1977 Jul; 131: 49-52.
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"Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection". Annals of Internal 
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9338(97)83296-8
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Löwe, Bernd; Decker, Oliver; Müller, Stefanie; Brähler, Elmar; Schellberg, Dieter; Herzog, Wolfgang; 
Herzberg, Philipp Yorck (2008). "Validation and standardization of the Generalized Anxiety Disorder Screener 
(GAD-7) 
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Maier W, Buller R, Philipp M, Heuser I. The Hamilton Anxiety Scale: reliability, validity and sensitivity to 
change in anxiety and depressive disorders. J Affect Disord. 1988;14(1):61-68.
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Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): Classification of suicidal events in the FDA’s pediatric suicidal risk analysis of 
antidepressants. Am J Psychiatry. 2007;164(7):1035–1043
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Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C: The Inventory for Depressive 
Symptomatology (IDS): preliminary findings. Psychiatry Res 1986; 18(1):65-87.
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Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH: The Inventory of Depressive Symptomatology (IDS): 
Psychometric properties. Psychol Med 1996; 26(3):477-486.
19.
Rutherford BR1, Sneed JR, Roose SP. Does study design influence outcome?. The effects of placebo control and 
treatment duration in antidepressant trials. Psychother Psychosom. 2009;78(3):172-81. doi: 10.1159/000209348. 
Epub 2009 Mar 24
20.
Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D (1992). An improved method for adjusting the QT 
interval for heart rate (the Framingham Heart Study). Am J Cardiol. 70(7):797-801.


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Scott MM, Marcus JN, Pettersen A, et al. Hcrtr1 and 2 signaling differentially regulates depression-like 
behaviors. Behav Brain Res. 2011 Sep 23;222(2):289-94.
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Shear MK, Vander Bilt J, Rucci P, et al. Reliability and validity of a structured interview guide for the Hamilton 
Anxiety Rating Scale (SIGH-A). Depress Anxiety. 2001; 13(4): 166–178.
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Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar G: 
The Mini International Neuropsychiatric Interview (M.I.N.I.): The Development and Validation of a Structured 
Diagnostic 
Psychiatric 
Interview. 
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33. http://www.psychiatrist.com/JCP/article/Pages/1998/v59s20/v59s2005.aspx
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Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, Knapp 
E, Sheehan MF, Dunbar GC. Reliability and Validity of the MINI International Neuropsychiatric Interview 
(M.I.N.I.): 
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25.
Spitzer, R.L, Kroenke, K, Williams, J.B, and Patient Health Questionnaire Primary Care Study Group. Validation 
and utility of a self-report version of PRIME-MD: the PHQ primary care study. JAMA. 1999; 282: 1737–1744
26.
Spitzer, Robert L.; Kroenke, Kurt; Williams, Janet B.W.; Löwe, Bernd (22 May 2006). "A brief measure for 
assessing generalized anxiety disorder: The GAD-7". Archives of Internal Medicine. 166 (10): 1092–
7. doi:10.1001/archinte.166.10.1092. PMID 16717171.
27.
Swinson, Richard P. (December 2006). "The GAD-7 scale was accurate for diagnosing generalized anxiety 
disorder". Evidence-Based Medicine. 11 (6): 184. doi:10.1136/ebm.11.6.184. PMID 17213178
28.
Tedeschini E1, Fava M, Papakostas GI. Placebo-controlled, antidepressant clinical trials cannot be shortened to 
less than 4 weeks' duration: a pooled analysis of randomized clinical trials employing a diagnostic odds ratio-
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29.
Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
 MD
Institution:
Janssen Research & Development, a division of Janssen Pharmaceutica N.V.
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

SAP_001.pdf: 
1 
Approved, Date: 30 September 2021 
Janssen Research & Development 
Statistical Analysis Plan 
Double-Blind, Placebo-Controlled, Multi-Centre Study Investigating the Efficacy, Safety, 
and Tolerability of JNJ-61393215 as Adjunctive Treatment in Adults with Major 
Depressive Disorder with Anxious Distress with Suboptimal Response to Standard 
Antidepressants 
Protocol 61393215MDD2001; Phase 2a 
 JNJ-61393215  (Orexin-1) 
Amendment 2 
Approved   
30 September 2021 
Janssen Research & Development, LLC
EDMS-RIM-714672
Status: 
Date: 
Prepared by: 
Document No.:
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. 
NCT04080752


JNJ-61393215  (Orexin-1) 
Statistical Analysis Plan 61393215MDD2001 
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Approved, Date: 30 September 2021 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
ABBREVIATIONS ........................................................................................................................................ 4 
SAP AMENDMENT SUMMARY OF CHANGES TABLE ............................................................................ 5 
1.
INTRODUCTION.................................................................................................................................. 7 
1.1. 
Trial Objectives ................................................................................................................................ 7 
1.2. 
Trial Design ...................................................................................................................................... 9 
1.3. 
Statistical Hypotheses for Trial Objectives ..................................................................................... 10 
1.4. 
Sample Size Justification ............................................................................................................... 10 
1.5. 
Randomization and Blinding .......................................................................................................... 10 
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11 
2.1. 
Visit Windows ................................................................................................................................. 11 
2.2. 
Pooling Algorithm for Analysis Centers .......................................................................................... 13 
2.3. 
Analysis Sets .................................................................................................................................. 13 
2.3.1. 
All Enrolled Analysis Set ............................................................................................................. 13 
2.3.2. 
All Randomized Analysis Set ...................................................................................................... 13 
2.3.3. 
Efficacy Analysis Sets ................................................................................................................. 14 
2.3.4. 
Safety Analysis Set ..................................................................................................................... 14 
2.3.5. 
Pharmacokinetics Analysis Set .................................................................................................. 14 
2.3.6. 
Immunogenicity Analysis Set ...................................................................................................... 14 
2.3.7. 
Pharmacodynamics Analysis Set ............................................................................................... 14 
2.4. 
Definition of Subgroups .................................................................................................................. 14 
2.5. 
Study Day and Relative Day .......................................................................................................... 14 
2.6. 
Baseline ......................................................................................................................................... 15 
2.7. 
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 15 
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW ....................................... 16 
4.
SUBJECT INFORMATION ................................................................................................................ 16 
4.1. 
Demographics and Baseline Characteristics ................................................................................. 16 
4.2. 
Disposition Information................................................................................................................... 17 
4.3. 
Treatment Compliance ................................................................................................................... 17 
4.4. 
Extent of Exposure ......................................................................................................................... 18 
4.5. 
Protocol Deviations ........................................................................................................................ 18 
4.6. 
Prior and Concomitant Medications ............................................................................................... 18 
5.
EFFICACY ......................................................................................................................................... 18 
5.1. 
Analysis Specifications................................................................................................................... 18 
5.1.1. 
Level of Significance ................................................................................................................... 18 
5.1.2. 
Data Handling Rules ................................................................................................................... 19 
5.2. 
Primary Efficacy Endpoint .............................................................................................................. 19 
5.2.1. 
Definition ..................................................................................................................................... 19 
5.2.2. 
Estimand ..................................................................................................................................... 19 
5.2.3. 
Analysis Methods ........................................................................................................................ 19 
5.3. 
Major Secondary Endpoint ............................................................................................................. 21 
5.3.1. 
Definition ..................................................................................................................................... 21 
5.3.2. 
Analysis Methods ........................................................................................................................ 21 
5.4. 
Other Efficacy Variables................................................................................................................. 21 
5.4.1. 
Definition ..................................................................................................................................... 21 
5.4.2. 
Analysis Methods ........................................................................................................................ 22 
6.
SAFETY ............................................................................................................................................. 23 


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6.1. 
Adverse Events .............................................................................................................................. 23 
6.2. 
Clinical Laboratory Tests................................................................................................................ 23 
6.3. 
Vital Signs and Physical Examination Findings ............................................................................. 24 
6.4. 
Electrocardiogram .......................................................................................................................... 24 
6.5. 
Other Safety Parameters ............................................................................................................... 26 
6.5.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................................... 26 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 27 
8. 
BIOMARKERS................................................................................................................................... 27 
9. 
HEALTH ECONOMICS ..................................................................................................................... 27 
 
 
 
 
 


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ABBREVIATIONS 
 
AE 
ALT                     
adverse event 
alanine aminotransferase 
ANCOVA 
AR(1) 
AST 
analysis of covariance 
first order autoregressive process 
aspartate aminotransferase 
BMI 
BP 
body mass index 
blood pressure 
CI 
confidence interval 
CRF 
case report form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DB 
DSM-5 
double blind 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
ECG 
electrocardiogram 
FAS 
FU 
full analysis set 
follow-up 
GAD-7 
HAM-A 
HDRS17 
IDS-C30 
ITT 
IWRS 
generalized anxiety disorder-7 
Hamilton Anxiety Rating scale 
Hamilton Depression Rating Scale 17 items 
Inventory of Depressive Symptomatology, Clinician Rating -30 
Intent-to-Treat 
interactive web response system 
LS 
least-squares 
MDD 
MedDRA 
MINI 
mITT 
major depressive disorder 
Medical Dictionary for Regulatory Activities 
MINI International Neuropsychiatric Inventory 
modified Intent-to-Treat 
MMRM 
mixed model for repeated measures 
PD 
pharmacodynamic(s) 
PHQ-9 
PK 
patient health questionnaire -9 item 
pharmacokinetic(s) 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
Sleep Efficiency 
TEAE 
treatment-emergent adverse event 
US 
United States 
WHO-DD 
World Health Organization Drug Dictionary 
 


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SAP AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
 
Document 
Date 
Amendment 2 
30 September 2021 
Amendment 1 
18 January 2021 
Original SAP 
10 February 2020 
 
Amendment 2  
Section number 
and Name 
Description of Change 
Brief Rationale 
Sections 2.3.3 
(Efficacy Analysis 
Sets) and 5.2.3 
(Analysis Methods) 
Revising the primary analysis dataset by including 
patients who were ongoing at the time of the trial 
suspension due to the COVID-19 pandemic. 
Received feedback from the  FDA 
on the primary analysis set for 
protocol amendment 3: against 
excluding patients who were 
ongoing at the trial suspension due 
to Covid-19 from the primary 
analysis set– it violates the intent-
to-treat principle and may limit 
interpretation of the study results. 
 
Amendment 1  
Section number 
and Name 
Description of Change 
Brief Rationale 
1.1 Trials Objectives 
2.1 Visit Windows 
4.1 Demographics 
and Baseline 
Characteristics 
5.4 Other Efficacy 
Variables 
 
Remove objective, visit window, baseline 
characteristics and efficacy variable related to the 
PDSS-SR 
PDSS-SR will not be performed in 
the study due to logistical reasons 
1.4 Sample Size 
Justification 
 
 
Increase the potential maximum sample size 
increasing from 15% to 25% to count for COVID-
19 related dropouts 
Take into account for potential 
dropouts, and exclusion of 
participants who were ongoing at 
the time of the trial suspension from 
the primary analyses due to 
COVID-19 which is unexpected, 
unforeseen and unprecedented 
circumstance.  
 
2.3.3 Efficacy 
Analysis Sets 
5.2.3 Analysis 
Method 
 
 
 
Revise the primary analysis dataset by excluding 
participants who were ongoing at the time of the 
trial suspension due to the COVID-19 pandemic  
Minimize potential confounding 
effect as the unexpected and 
unprecedented circumstances 
around the COVID-19 pandemic 
may be associated with increased 
anxiety and thus might impact 
primary outcome measures in the 
study population of participants 
with MDD with anxious distress. 


JNJ-61393215  (Orexin-1)  
 
 
 
Statistical Analysis Plan 61393215MDD2001  
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Approved, Date: 30 September 2021  
Section number 
and Name 
Description of Change 
Brief Rationale 
1.1 Trials Objectives 
2.1 Visit Windows 
4.1 Demographics 
and Baseline 
Characteristics 
5.4 Other Efficacy 
Variables 
 
Remove objective, visit window, baseline 
characteristics and efficacy variable related to the 
PDSS-SR 
PDSS-SR will not be performed in 
the study due to logistical reasons 
4.1. Demographics 
and Baseline 
Characteristics 
 
Revised “full analysis dataset” to “all randomized 
analysis dataset” 
To be consistent with other trials 


JNJ-61393215  (Orexin-1)  
 
 
 
Statistical Analysis Plan 61393215MDD2001  
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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 61393215MDD2001. 
This SAP does not include planned analyses on biomarkers or pharmacogenomics data or on 
population pharmacokinetic (PK), pharmacodynamics (PD) and exposure/response analyses, 
which will be specified as appropriate in separate documents. 
1.1. 
Trial Objectives 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of JNJ-61393215 
as adjunctive treatment compared to 
adjunctive placebo, as assessed by the 
change from baseline to week 6 on a 17-
item Hamilton Depression Rating Scale 
(HDRS17) in participants with MDD with 
anxious distress with a score ≥ 2 on item 
26 or 27 of the Inventory of Depressive 
Symptomatology, Clinician Rating -30 
(IDS-C30), who have a suboptimal 
response to current treatment with a 
standard antidepressant. 
 
• 
Change from baseline in HDRS17 total 
score at Week 6 
Key Secondary 
• 
To evaluate the impact of adjunctive 
treatment with JNJ-61393215 compared 
to adjunctive placebo on the severity of 
anxiety as measured by the change in the 
Hamilton Anxiety Rating scale (HAM-A) 
from baseline to week 6. 
• 
Change from baseline in HAM-A total 
score at Week 6 
Secondary 
Efficacy 
• 
To evaluate the impact of adjunctive 
treatment with JNJ-61393215 compared 
to adjunctive placebo on HDRS17 from 
baseline to weeks 2 and 4 
• 
Change from baseline in HDRS17 total 
score at Weeks 2 and 4 


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Objectives 
Endpoints 
• 
To evaluate the impact of adjunctive 
treatment with JNJ-61393215 compared 
to adjunctive placebo on the severity of 
anxiety as measured by the change in 
HAM-A from baseline to weeks 2 and 4 
• 
Change from baseline in HAM-A total 
score at Weeks 2 and 4 
• 
To evaluate the efficacy of JNJ-61393215 
as adjunctive treatment compared to 
adjunctive placebo, as assessed by the 
change from baseline to week 6 on the 
HDRS17 in participants with a baseline 
HAM-A score ≥20 
• 
Change from baseline in HDRS17 total 
score at Week 6 in participants with a 
baseline HAM-A total score ≥20 
• 
To evaluate the efficacy of JNJ-61393215 
as adjunctive treatment compared to 
adjunctive placebo, as assessed by the 
change from baseline to Week 6 on the 
HAM-A in participants with a baseline 
HAM-A score ≥20 
• 
Change from baseline in HAM-A total 
score at Week 6 in participants with a 
baseline HAM-A total score ≥20 
• To evaluate the impact of adjunctive 
treatment with JNJ-61393215 compared to 
adjunctive placebo on participant-reported 
severity of anxiety as measured by the 
change in the General Anxiety Disorder-7 
scale (GAD-7) from baseline to Week 6 
• 
Change from baseline in GAD-7 total 
score at Week 6 
• To evaluate the impact of adjunctive 
treatment with JNJ-61393215 compared to 
adjunctive placebo on participant-reported 
severity of symptoms of major depressive 
disorder (MDD), as measured by the 
change in the Patient Health Questionnaire 
(PHQ-9) from baseline to weeks 2, 4 and 6 
• 
Change from baseline in PHQ-9 total 
score at Weeks 2, 4 and 6 
Safety 
• 
To investigate the overall safety and 
tolerability of adjunctive treatment with 
JNJ-61393215 in participants with MDD 
with anxious distress 
Safety assessments including: 
• 
Adverse events (AEs)  
• 
Proportion of all serious adverse events 
(SAEs)  
• 
Vital 
signs, 
physical 
examinations, 
electrocardiogram (ECG), and laboratory 
parameters 
• 
Columbia Suicide Severity Rating Scale 
(C-SSRS) 
 


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1.2. 
Trial Design 
This is a double-blind (DB), placebo-controlled, randomized, parallel-group, multicenter study in 
participants with MDD with anxious distress. An estimated target of approximately 218 
participants will be randomly assigned in this study with 109 participants planned per treatment 
group. The randomization will be stratified by country and screening response status (whether 
participants have improvement in percent changes in HDRS17 total score ≥ 25% at baseline from 
screening or HDRS17 total score < 18 at baseline). The target study population includes male and 
female participants, between 18 and 64 years of age inclusive, with a Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of MDD with anxious distress, 
confirmed by the Mini International Neuropsychiatric Inventory (MINI) Plus with module for 
MDD with anxious distress 
The study will consist of 3 phases: a screening phase of up to 4 weeks, a double-blind treatment 
phase of 6 weeks, and a posttreatment follow-up (FU) phase of 2 weeks. The total duration of 
participation will be approximately 12 weeks for each participant. 
A schematic overview of the study design is provided in Figure 1. 
Figure 1: Schematic Overview of the Study Design 
 


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1.3. 
Statistical Hypotheses for Trial Objectives 
The primary hypothesis of this study is that treatment with JNJ-61393215 will lead to significant 
improvement in depressive symptoms from baseline compared to placebo when administered as 
an adjunctive treatment to a standard antidepressant in the treatment of MDD patients with anxious 
distress with a score ≥ 2 on item 26 or 27 of the IDS-C30 who have a suboptimal response to 
current standard treatment. Significant improvement will be demonstrated by improvement in 
depressive symptoms from baseline to the 6-week endpoint in the HDRS17 total score. 
1.4. 
Sample Size Justification 
The estimated sample size of 218 participants (109 participants per group) was determined based 
on the assumption of an effect size of at least 0.4 for the HDRS17 total score (mean change from 
baseline to Week 6 endpoint between the JNJ-61393215 and placebo groups of 3 units with 
standard deviation (SD) = 7.5).  This is considered to be a clinically relevant difference in a 
population with suboptimal response to standard oral antidepressant therapy. The SD of 7.5 in the 
change in HDRS17 total score from baseline is a reasonable assumption based on previously 
conducted clinical trials in a similar patient population (40411813DAX2001 and 
42165279MDD2001). Power is set at 90%, with a 1-sided alpha level of 0.10 and a 6-week drop-
-out rate of 10%.  
It was also assumed that 15% of the randomized participants would be excluded from the primary 
efficacy analysis due to having improvement in percent changes in HDRS17 total score ≥ 25% at 
baseline from screening or HDRS17 total score < 18 at baseline. The estimated participants to be 
included in the primary analysis is 166. A blinded data review for purpose of sample size re-
estimation may be performed. Sample size may be re-adjusted if the observed screening response 
rate, the drop-out rate (including dropouts due to the COVID-19 pandemic) or the standard 
deviation (SD) substantially deviate from the assumed value. Sample size can increase by a 
maximal 25%, so that the potential maximal number of participants to be enrolled in this trial would be 
272. 
1.5. 
Randomization and Blinding 
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be stratified 
by country and screening response status (whether participants have improvement in percent 
changes in HDRS17 total score ≥ 25% at baseline from screening or HDRS17 total score < 18 at 
baseline). The criteria for screening response will be blinded for the investigator.  The interactive 
web response system (IWRS) will assign a unique intervention code, which will dictate the 
intervention assignment and matching study intervention kit for the participant. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS and will then give the relevant participant details to uniquely identify the participant. 
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed.  


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2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Visit Windows 
As subjects do not always adhere to the protocol visit schedule, the following rules are applied to 
assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1 (which is the first day the study drug was taken in the 
double-blind phase). If a subject has 2 or more actual visits in one visit window, the visit closest 
to the target day will be used as the protocol visit for that visit window. The other additional visit(s) 
will not be used in the summaries or analyses. 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. Listed below are the visit windows and 
the target days for each visit defined in the protocol.  
Assessments prior to Day 1 of the double-blind phase that are not considered a baseline assessment 
will be labeled as ‘Screening’. 
For subjects who have multiple follow-up visits, the scheduled visit will be used in the summaries, 
however, data for all follow-up visits will be displayed in listings when applicable. 
If there is an unscheduled assessment with collection date that doesn’t fall into any visit window, 
then it will be assigned to a visit window that is closest to its collection date, and if this unscheduled 
assessment has a collection date equidistant from the dates for two adjacent visit windows, then it 
will be assigned to the visit window that is latter.  
Table 1: Visit Window 
 


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Parameter  
Analysis 
Phase 
Scheduled Visit 
Time Interval 
(label on output) 
Time Interval 
(Day)  
Target Time 
Point 
(Day/Time) 
HDRS17, 
HAM-A 
 
Screening 
Screening 
Screening 
< 1 
-28 to -24 
DB 
Baseline 
Baseline 
< 1 
Day 1 
Week 2 
Week 2 
Visit Week 2 (as 
collected on 
eCRF) 
Day 15 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
 FU 
Follow-up 
Follow-up 
FU Visit (as 
collected on 
eCRF) 
Day 57 
PHQ-9 
 
DB 
Baseline 
Baseline 
< 1 
Day 1 
Week 2 
Week 2 
Visit Week 2 (as 
collected on 
eCRF) 
Day 15 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
FU 
Follow-up 
Follow-up 
FU Visit (as 
collected on 
eCRF) 
Day 57 
GAD-7 
 
DB 
 
Baseline 
Baseline 
< 1 
Day 1 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
ECG 
Screening 
Screening 
Screening 
<1 
-28 to -24 
DB 
 
 
Day 1a 
Day 1 
< 1 
Day 1 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
FU 
Follow-up 
Follow-up 
FU Visit (as 
collected on 
eCRF) 
Day 57 
Physical Exam, 
Vital Signs, 
Oral or Tympanic 
Temperature 
Screening 
Screening 
Screening 
<1 
-28 to -24 
DB 
 
Baseline 
Baseline 
< 1 
Day 1 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
FU 
Follow-up  
Follow-up  
FU Visit (as 
collected on 
eCRF) 
Day 57 
C-SSRS 
Screening 
Screening 
Screening 
<1 
-28 to -24 


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Parameter  
Analysis 
Phase 
Scheduled Visit 
Time Interval 
(label on output) 
Time Interval 
(Day)  
Target Time 
Point 
(Day/Time) 
DB 
Baseline 
Baseline 
< 1 
Day 1 
Week 2 
Week 2 
Visit Week 2 (as 
collected on 
eCRF) 
Day 15 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
FU 
Follow-up 
Follow-up 
FU Visit (as 
collected on 
eCRF) 
Day 57 
Labs 
(Hematology, 
Chemistry, 
Urinalysis) 
Screening 
Screening 
Screening 
<1 
-28 to -24 
DB 
Baseline 
Baseline 
< 1 
Day 1 
Week 2 
Week 2 
Visit Week 2 (as 
collected on 
eCRF) 
Day 15 
Week 4 
Week 4 
Visit Week 4 (as 
collected on 
eCRF) 
Day 29 
Week 6 
Week 6 
Visit Week 6 (as 
collected on 
eCRF) 
Day 43 
FU 
Follow-up 
Follow-up 
FU Visit (as 
collected on 
eCRF) 
Day 57 
a: 2 hours postdose 
 
2.2. 
Pooling Algorithm for Analysis Centers 
Subjects will be enrolled at sites in the USA, United Kingdom, Russia, Ukraine and Moldova.  
Actual site enrollment rates will be monitored to avoid gross imbalances across centers. Country 
or sites will not be pooled for analyses. To account for country variability, country will be used as 
a factor in the statistical models to analyze efficacy.  
2.3. 
Analysis Sets 
Subjects will be classified into the following analysis sets. 
2.3.1. 
All Enrolled Analysis Set 
The all enrolled analysis set includes all subjects who were not screen failures and were assigned 
to a treatment group. 
2.3.2. 
All Randomized Analysis Set 
The all randomized analysis set includes all subjects who were randomized in the study. 


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2.3.3. 
Efficacy Analysis Sets  
The full analysis set (FAS) includes all randomized subjects who received at least 1 dose of study 
agent and have both a baseline and at least 1 postbaseline efficacy assessment. 
The enriched analysis set (EAS) includes subjects in FAS with having improvement in percent 
changes in HDRS17 total score < 25% at baseline from screening and HDRS17 total score ≥ 18 at 
baseline. 
2.3.4. 
Safety Analysis Set 
The safety analysis set includes all randomized subjects who received at least 1 dose of study 
agent. 
2.3.5. 
Pharmacokinetics Analysis Set 
Not applicable (NA).  Analyses for pharmacokinetic data will be conducted by the PK group and 
will be provided in a separate document. 
2.3.6. 
Immunogenicity Analysis Set 
NA as there is no immunogenicity data for this trial. 
2.3.7. 
Pharmacodynamics Analysis Set 
NA as there is no pharmacodynamics data for this trial. 
2.4. 
Definition of Subgroups 
Subgroup 
Definition 
Screening response status 
• Improvement in percent changes in HDRS17 total score < 25% 
at baseline from screening and HDRS17 total score ≥ 18 at 
baseline. 
• Improvement in percent changes in HDRS17 total score ≥ 25% 
at baseline from screening or HDRS17 total score < 18 at 
baseline 
Baseline HAM-A status 
• Baseline HAM-A total score ≥ 20 
• Baseline HAM-A total score < 20 
 
Other subgroups may also be explored. 
2.5. 
Study Day and Relative Day 
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'. 


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2.6. 
 Baseline  
Baseline is defined as the last observation prior to the start of the first study agent administration. 
2.7. 
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 
different 
− 
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 the death occurred 
in that month. 
• 
If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of the year or the day and month of the date of death, if the death occurred in 
that year. 
• 
Completely missing resolution dates will not be imputed. 
 
AE onset/resolution dates with missing times will be imputed as follows: 
• 
A missing time of onset of an adverse event will be set to the earlier of: 
− 
00:01 as long as the onset date is after 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. 


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If a missing time is associated with a partial or missing date, the date will be imputed first prior to 
imputing the time. 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
NA as no IA and DMC are planned.  However, a blinded data review for purpose of sample size 
re-estimation may be performed. Sample size may be re-adjusted if the observed screening 
response rate, the drop-out rate or the standard deviation (SD) substantially deviate from the 
assumed value. Sample size can increase with maximal 25%. 
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 country, and site ID will be presented. 
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 all randomized analysis set.   
Table 3 presents a list of the baseline psychiatric history variables that will be summarized by 
treatment group and overall for the all randomized analysis set.   
Table 2: Demographic Variables 
Continuous Variables: 
Summary Type 
Age (years), calculated based on date of informed consent date 
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and maximum]) 
Baseline weight (kg) 
Baseline height (cm) 
Baseline BMI (kg/m2) calculated as Weight (kg)/[Height (m)]2 
Categorical Variables: 
 
Sex (male, female, undifferentiated) 
Frequency distribution with 
the number and percentage 
of subjects in each category 
Racea (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, 
White, Multiple) 
Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
a If multiple race categories are indicated, the Race is recorded as 'Multiple' 
 
 
Table 3: Psychiatric History Variables 
Continuous Variables: 
Summary Type 
Baseline HDRS17 total score 
Descriptive statistics (N, mean, 
standard deviation [SD], 
median and range [minimum 
and maximum]) 
 
Baseline HAM-A total score 
Baseline GAD-7 total score 
PHQ-9 total score 
IDS-C30 total score 
Categorical Variables: 
 


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Baseline HAM-A total score (≥ 20, <20) 
Frequency distribution with 
the number and percentage of 
subjects in each category 
Screening response status (“1” = defined as improvement in 
percent changes in HDRS17 total score ≥ 25% at baseline from 
screening or HDRS17 total score < 18 at baseline; else “2”) 
Anxious distress status (”Yes” if a score ≥ 2 on item 26 or 27 
of the Inventory of Depressive Symptomatology; else ”No”) 
4.2. 
Disposition Information 
Screened subjects and reason for 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 completing the study 
• 
Subjects who discontinued study agent 
• 
Reasons for discontinuation of study agent 
• 
Subjects who terminated study prematurely 
• 
Reasons for termination of study 
 
Listings of subjects will be provided for the following categories: 
• 
Subjects who discontinued study agent 
• 
Subjects who terminated study prematurely 
• 
Subjects who were unblinded during the study period 
• 
Subjects who were randomized yet did not receive study agent. 
4.3. 
Treatment Compliance 
The primary method to capture the treatment compliance will be based on AiCure or the 
combination of eCRF and AiCure if the exposure data from AiCure is insufficient. 
In addition, study agent compliance that from eCRF will be calculated as follows as secondary 
method: 
Compliance (%) = (number of capsules taken / number of capsules supposed to have been 
taken)*100. 
Study agent compliance will be summarized descriptively.  


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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 
The number and percentage of subjects who receive study agent will be summarized by treatment 
group. 
Descriptive statistics for study agent duration (N, mean, SD, median, and range (minimum, 
maximum)) will be presented by treatment group for the safety analysis set. 
4.5. 
Protocol Deviations 
Subjects with major protocol deviations will be identified prior to database lock and the subjects 
with major protocol deviations will be summarized by category. 
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 on after the first dose of study agent. 
Summaries of concomitant medications will be presented by ATC term, treatment group, and study 
phase (DB phase and FU phase). The proportion of subjects who receive each concomitant 
medication will be summarized as well as the proportion of subjects who receive at least 1 
concomitant medication.  
Prior medications will be summarized by treatment group and ATC term. 
5. 
EFFICACY 
Primary analyses will focus on the EAS.  However, all analyses will be done on enriched and full 
analysis set. 
5.1. 
Analysis Specifications 
5.1.1. 
Level of Significance 
Unless otherwise specified, all statistical comparisons will be carried out at a 1-sided significance 
level of 10% and confidence intervals will be presented at 2-sided confidence level of 80% (i.e. 
equivalent to 1-sided confidence level of 90%). 


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5.1.2. 
Data Handling Rules 
Imputation of missing individual item scores will apply only to the HDRS17, as described in the 
next section. For all other scales where multiple items are summed to create a total, if any item of 
the scale is missing on one visit, the total score for that scale at that visit will be left blank. 
5.2. 
Primary Efficacy Endpoint  
5.2.1. 
Definition 
The HDRS17 is a clinician-administered rating scale designed to assess the severity of symptoms 
in subjects diagnosed with depression with a score range of 0 to 52. Each of the 17 items is rated 
by the clinician on either a 3- or a 5-point scale. The HDRS17 consists of 17 items that cover all 
of the core depressive symptoms (depressed mood, feeling of guilt, suicide, insomnia early, 
insomnia middle, insomnia late, work and activities, retardation [psychomotor], agitation, anxiety 
[psychological], anxiety somatic, somatic symptoms general, genital symptoms, hypochondriasis, 
loss of weight and insight). A total score (0 to 52) is calculated by adding the scores of all 17 items.  
For each item as well as the total score, a higher score represents a more severe condition.  If 2 or 
more items are missing, no imputation will be performed, and the total score will be left missing.  
Otherwise, the total score will be calculated as sum of the nonmissing items multiplied by the ratio 
of the maximum number of items (ie, 17) to the number of nonmissing items. 
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: participants with MDD with anxious distress with suboptimal response to standard 
antidepressants. 
Variable: change from baseline to Week 6 in the HDRS17 total score. 
Intervention event: the effect of the initially randomized treatment that would have been observed 
had all participants remained on their treatment throughout the double-blind treatment phase. 
Population-level summary: the difference in mean change from baseline to Week 6 post dose in 
the HDRS17 total score total score between treatment conditions. 
5.2.3. 
Analysis Methods 
The primary efficacy analysis will be based on the EAS. The primary comparison will be between 
Orexin-1 and placebo using the primary efficacy endpoint, i.e., change in HDRS17 total score from 
baseline to Week 6.       
The JNJ-61393215 treatment group will be compared with the placebo group using the primary 
efficacy endpoint, changes from baseline in HDRS17 total score, with the comparison performed 
by means of a mixed-effects model using repeated measures (MMRM), with time, treatment 


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(placebo, JNJ-61393215), country, and time-by-treatment interaction as factors, baseline HDRS17 
total score as a continuous covariate. An unstructured variance-covariance matrix will be used. 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) (first order autoregressive process) with separate subject 
random effect. The comparison of JNJ-61393215 versus placebo will be performed using the 
appropriate contrasts. The contrast on Week 6 changes will be of primary interest and tested at 
one-sided alpha level of 0.10. Time profile of means for values and changes from baseline in 
HDRS17 total score will be represented graphically over time by treatment group.  
The analyses for changes from baseline in HDRS17 total score will also be carried out in the full 
analysis set using a mixed-effects model using repeated measures (MMRM), with time, treatment 
(placebo, JNJ-61393215), country, screening response status 
(using HDRS17) 
and 
time-by-treatment interaction as factors, and baseline HDRS17 total score as a continuous 
covariate. An unstructured variance-covariance matrix will be used. 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.  
In addition, sensitivity analyses with the same MMRM analysis by excluding participants who were 
ongoing at the time of the trial suspension due to the COVID-19 pandemic and/or by excluding 
noncompliance subjects will be conducted. 
Sensitivity Analysis for Missing Data 
The sensitivity analysis will be based on an analysis of covariance (ANCOVA) model using 
change from baseline to Week 6 based on LOCF data. The models will include factors for 
treatment, country and screening response status, and baseline HDRS17 total score as a continuous 
covariate.  
If the overall missingness of the primary endpoint at Week 6 is above 15%, then additional 
sensitivity analysis, the delta adjustment multiple imputation method, that rely on Missing Not at 
Random assumptions may be performed to assess the robustness of the primary analysis and 
MMRM results. This method consists the following 3 steps:  
Step 1 – Multiple imputation  
If there are subjects with non-monotone missing data pattern, datasets with only monotone missing 
data patterns will be created first by imputing the intermediate missing values using the Markov 
Chin Monte Carlo method. If all subjects have a monotone missing data pattern, the MAR-based 
multiple imputation with the regression will be used to impute missing values. 
 
Step 2 – Delta adjustments 
The imputed values for subjects who discontinued will be adjusted by adding δP to the imputed 
values for subjects in placebo group and adding δA to the imputed values for subjects in 
JNJ61393215 group. 
 


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Step 3 – Analysis  
Same MMRM as described for the primary efficacy analysis will be conducted. 
Subgroup Analysis 
Analysis on changes in HDRS17 total score from baseline to Week 6 in baseline HAM-A status 
subgroup (whether subjects had a baseline HAM-A total score ≥20) will also be conducted using 
descriptive statistics and the similar MMRM method that is aforementioned for the primary end 
point.  
5.3. 
Major Secondary Endpoint 
5.3.1. 
Definition 
The HAM-A measures the severity of a patient's anxiety, based on 14 parameters, including 
anxious mood, tension, fears, insomnia, somatic complaints and behavior at the interview. The 
major value of HAM-A is to document the results of pharmaco- or psychotherapy, rather than as 
a diagnostic or screening tool. Each item is simply given a 5-point score - 0 (not present) to 4 
(severe). In this study, the Structured Interview Guide version of the HAM-A (SIGH-A) will be 
used. A total score (0 to 56) is calculated by adding the scores of all 14 items.  For each item as 
well as the total score, a higher score represents a more severe condition. 
5.3.2. 
Analysis Methods 
The analyses for changes from baseline in HAM-A total score at weeks 2, 4 and 6 will be carried 
out using a mixed-effects model using repeated measures (MMRM), with time, treatment (placebo, 
JNJ-61393215), country, screening response status (using HDRS17) and time-by-treatment 
interaction as factors, and baseline HAM-A total score as a continuous covariate. An unstructured 
variance-covariance matrix will be used. 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. The comparison of JNJ-61393215 versus placebo will be performed using 
the appropriate contrasts. The contrast on Week 6 changes will be of primary interest and tested at 
one-sided alpha level of 0.10. Time profile of means for values and changes from baseline in 
HAM-A total score will be represented graphically over time by treatment group. 
In addition, analysis on changes in HAM-A total score from baseline to Week 6 in baseline HAM-
A status subgroup (whether subjects had a baseline HAM-A total score ≥20) will also be conducted 
using the similar MMRM method that is aforementioned. 
5.4. 
Other Efficacy Variables 
5.4.1. 
Definition 
GAD-7 
The GAD-7 is a self-reported questionnaire for screening and severity measuring of generalized 
anxiety disorder (GAD). GAD-7 has seven items, which measure severity of various signs of GAD 
according to reported response categories with assigned points (see below). Assessment is 


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indicated by the total score, which made up by adding together the scores for the scale all seven 
items. The scale uses a normative system of scoring as shown below, with question at the end 
qualitatively describing severity of the patient's anxiety over the past 2 weeks.  
• 
Not at all (0 points) 
• 
Several days (1 point) 
• 
More than half the days (2 points) 
• 
Nearly every day (3 points) 
 
A total score (0 to 21) is calculated by adding the scores of all 7 items.  For each item as well as 
the total score, a higher score represents a more severe condition. 
 
PHQ-9 
The PHQ-9 is a participant-reported measure of depressive symptomatology. The PHQ-9 is a 9-
item scale, where each item is rated on a 4-point scale (0=Not at all, 1=Several Days, 2=More than 
half the days, and 3=Nearly every day), with a total score range of 0 to 27. The recall period is 2 
weeks. For each item as well as the total score, a higher score represents a more severe condition. 
 
5.4.2. 
Analysis Methods 
All analyses will be done on enriched and full analysis set. 
 
GAD-7 
The analyses for changes from baseline in GAD-7 total score at week 6 will be carried out in the 
FAS using an analysis of covariance (ANCOVA) model, with factors for treatment (placebo, 
JNJ-61393215), country, screening response status (using HDRS17) and baseline GAD-7 total 
score as a continuous covariate. The treatment effects will be estimated using least squares means. 
 
PHQ-9 
The analyses for changes from baseline in PHQ-9 total score at weeks 2, 4 and 6 will be carried 
out in the FAS using a mixed-effects model using repeated measures (MMRM), with time, 
treatment (placebo, JNJ-61393215), country, screening response status (using HDRS17) and 
time-by-treatment interaction as factors, and baseline PHQ-9 total score as a continuous covariate. 
An unstructured variance-covariance matrix will be used. 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. The comparison of JNJ-61393215 versus placebo will 
be performed using the appropriate contrasts. The contrast on Week 6 changes will be of primary 
interest and tested at one-sided alpha level of 0.10. Time profile of means for values and changes 
from baseline in PHQ-9 total score will be represented graphically over time by treatment group. 
 


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6. 
SAFETY 
All safety analyses will be based on the safety analysis set based on actual treatment received, 
unless otherwise specified. 
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.  
6.1. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study agent in double blind phase is considered to be treatment emergent. 
If the event occurs on the day of the initial administration of study agent, and either event time or 
time of administration are missing, then the event 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 will be 
included in the analysis.  For each adverse event, the number and percentage of subjects who 
experience at least 1 occurrence of the given event will be summarized by treatment group. 
Summary tables will be provided for treatment-emergent adverse events: 
• 
AEs 
• 
Serious AEs (SAEs) 
• 
AEs leading to discontinuation of study agent 
• 
AEs by severity 
• 
AEs by relationship to study agent 
In addition to the summary tables, listings will be provided for subjects who: 
• 
Had SAEs 
• 
Had AEs leading to discontinuation of study agent 
6.2. 
Clinical Laboratory Tests 
Clinical laboratory tests will be displayed for the subjects included in the safety analysis set. 
Descriptive statistics will be presented for chemistry, hematology, and urinalysis laboratory tests 
at scheduled time points and displayed by treatment group. 
Graphical displays will be presented for aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) laboratory tests at scheduled time points. 
Change from baseline to scheduled time points will be summarized for chemistry, hematology, 
and urinalysis tests and displayed by treatment group. 


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Shift tables will be provided summarizing the shift in laboratory values from baseline to scheduled 
time points with respect to abnormality criteria (low, normal, high). 
6.3. 
Vital Signs and Physical Examination Findings 
Continuous vital sign parameters including temperature, weight, pulse, blood pressure (systolic 
and diastolic), and Body Mass Index (BMI) will be summarized at each assessment time point. 
Body Mass Index will be calculated as weight (kg)/(height (m))2. The weight and height 
measurements collected at screening will be used in the calculation. Change from baseline will be 
summarized for the treatment. Descriptive statistics (mean, standard deviation, median, minimum 
and maximum) will be presented. 
Incidence of treatment-emergent clinically important abnormalities in vital signs while on 
treatment, as defined in Table 5, will be summarized for subjects who had a baseline assessment 
and at least 1 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. 
A listing of subjects with treatment-emergent clinically important abnormalities in vital signs will 
be presented, along with a listing of all vital sign measurements. 
Table 5: Clinically Important/Markedly Abnormal Vital Signs 
Vital Sign 
Criteria 
Pulse 
>[120] bpm and with >[30] bpm increase from baseline 
 
<[50] bpm and with >[20] bpm decrease from baseline 
Systolic blood pressure 
>[180] mm Hg and with >[40] mm Hg increase from baseline 
 
<[90] mm Hg and with >[30] mm Hg decrease from baseline 
Diastolic blood pressure 
>[105] mm Hg and with >[30] mm Hg increase from baseline 
 
<[50] mm Hg and with >[20] mm Hg decrease from baseline 
Temperature 
>[38]oC and with ≥[1]oC increase from baseline 
 
In addition, a by-subject listing of the abnormal physical examination data will be presented. 
6.4. 
Electrocardiogram 
The ECG parameters that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction methods: Bazett’s formula (QTcB), 
and Fridericia’s formula (QTcF). 
Bazett’s formula:  
QTcB (msec) = QT (msec) * (HR(bpm)/60)0.5; 
 
Fridericia’s formula: 
QTcF (msec) = QT (msec) * (HR(bpm)/60)0.33 
 


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The number and percentage of subjects with QTc interval will be summarized at each scheduled 
time point. The number and percentage of subjects with QTc interval increases from baseline to 
the maximum postbaseline value will be summarized. Refer to the following table for summary 
categories. 
Criteria for Abnormal QTc Values and Changes From Baseline 
QTc value 
450  
>450 – 480 
>480 – 500 
>500 
QTc change from baseline 
30  
 
>30 – 60 
> 60 
 
A shift table will be provided summarizing the shift from baseline to maximum QTc interval 
classification at each scheduled time point. 
Descriptive statistics of ECG parameters and change from baseline will be summarized at each 
scheduled time point. 
If ECG measurements are repeated at a visit, they will be averaged. The averaged value will be 
considered the ‘Visit’ ECG result. 
A postbaseline abnormality (abnormality based on criteria defined below) will be considered 
treatment emergent (TE) if it is worse than the baseline abnormality. If the baseline abnormality 
is missing, the abnormality is always considered treatment emergent. If the postbaseline value is 
above the upper limit and the baseline value is below the lower limit, then the postbaseline 
abnormality will be considered TE. The same applies to the postbaseline value being below the 
lower limit with the baseline value being above the upper limit. 
The number and percentage of subjects with treatment-emergent ECG values outside predefined 
limits/abnormal postbaseline values (relative to baseline) will be presented by treatment group 
over time for each phase of the study: 
• 
Heart rate (bpm): [<50] and [>100] 
• 
PR interval (msec): [<120] and [>200] 
• 
QRS interval (msec): [>120] 
• 
QTc (msec): [>500] 
The interpretation of the ECGs as determined by a qualified physician (investigator or qualified 
designee) will be displayed by the number and percentage of subjects meeting the normality 
criteria. The interpretation will be summarized over time by treatment phase. 


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


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7. 
PHARMACOKINETICS/PHARMACODYNAMICS 
The pharmacokinetics analyses will be conducted by the PK group and the details will be provided 
in a separate document.  
Analyses on pharmacodynamics are not applicable as no pharmacodynamics data for the trial. 
8. 
BIOMARKERS 
Details of the biomarker analyses will be provided in a separate SAP. 
9. 
HEALTH ECONOMICS 
Analyses on health economics are not applicable as no health economics data for the trial.